Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Eiji Oki Last modified date:2020.06.16

Lecturer / Department Surgery and Science / Gastrointestinal Surgery (2) / Kyushu University Hospital


Papers
1. Eiji Oki, E. Tokunaga, Y. Kakeji, Yoshihiko Maehara, K. Sugimachi, Relationship of anti-tumor effect and apoptosis induced by 5- fluorouracil (5-FU) and its analogues, Biotherapy, 12, 6, 953-958, 1998.01, 5-fluorouracil (5-FU) and its analogues have been widely prescribed for patients in Japan with gastrointestinal cancers. The active metabolite of 5- FU inhibits thymidylate synthase (TS), resulting in the inhibition of DNA synthesis. However, the process of cell death after the inhibition of DNA synthesis has not been elucidated. In this issue, we investigated antitumor activity of 5-FU and influence on the cell cycle of two different cell lines in vitro, and also examined the induction of apoptosis in seven xenografts in vivo by oral analogue of 5-FU, tegafur and uracil (UFT: a combined preparation of 1 mol tegafur and 4 mol uracil). Though the TS levels in two cell lines were not so different, sensitivities to 5-FU were remarkably different in vitro. The seven xenografts have various sensitivities to UFT, and there was a positive correlation between the extent of apoptotic induction and the anti-tumor effect of UFT. Spontaneous apoptosis observed in untreated tumor xenografts also correlated with the anti-tumor effect of the UFT as well as the apoptosis induced in tumor xenografts treated with the agent. Our results showed that apoptosis in a tumor reflects well anti-tumor drug sensitivity, and it may serve as a predictor of 5-FU effectiveness..
2. Eiji Oki, S. Oda, E. Tokunaga, Yoshihiko Maehara, K. Sugimachi, A new microsatellite instability analysis using fluorescent primers and laser scanning, Gan to kagaku ryoho. Cancer & chemotherapy, 25 Suppl 3, 436-442, 1998.01, To demonstrate the instability of microsatellite sequences, which have been linked to DNA mismatch repair deficiency and indicate a high risk of carcinogenesis, polymerase chain reaction (PCR) and electrophoretic analysis have been used. However, the electrophoretic profiles of PCR-amplified microsatellite sequences are often too complicated, and the conventional method using autoradiography has critical problems in detection characteristics and migration accuracy. First, we made use of fluorescence-labeled PCR and laser scanning to detect bands quantitatively. Second, we characterized Taq polymerase-dependent modification of the amplified microsatellite sequences and optimized the electrophoretic profiles by enzymatic modification with T4 DNA polymerase. Third, we developed a dual fluorescence co-electrophoresis system, in which both samples derived from cancer and normal tissues are electrophoresed in the same lane, in order to minimize migration errors. Furthermore, we classified all of the observed patterns of microsatellite alteration and set up new criteria for assessing microsatellite instability. Using the system developed here and the criteria we proposed, a precise judgment can be made and rates of positivity in various human malignancies may be corrected..
3. Tatsurou Tajiri, Sachiyo Suita, Kumiko Shono, Masayuki Kubota, Yoshimitsu Fujii, Eiji Oki, Shinya Oda, Yoshihiko Maehara, Keizo Sugimachi, A microsatellite instability analysis in neuroblastoma based on a high resolution fluorescent microsatellite analysis, Cancer Letters, 10.1016/S0304-3835(97)00448-5, 124, 1, 59-63, 1998.02, It has recently been reported that mismatch repair enzymes, which are one type of DNA repair enzymes, are the causative genes for a major group of hereditary non-polyposis colon cancers (HNPCC). Abnormalities in the mismatch repair system can be monitored by observing instability at the microsatellite loci (MSI) in cancer cells. MSI has been reported not only in tumors associated with hereditary non-polyposis colorectal cancer but also in sporadic forms of various tumors. No correlation between pediatric malignant tumors and the mismatch repair system has yet been reported. In the present study, we examined the frequency of MSI in 21 neuroblastomas, which are the most common solid tumors in childhood, using a high resolution fluorescent microsatellite analysis. MSI on five microsatellite loci was detected in none of the 21 samples. Other mechanisms independent of mismatch repair deficiency may thus play a role in both tumorigenesis and the development of neuroblastoma..
4. Yoshihiko Maehara, Shota Hasuda, Toru Abe, Eiji Oki, Yoshihiro Kakeji, Shinji Ohno, Keizo Sugimachi, Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer, Clinical Cancer Research, 4, 9, 2129-2134, 1998.09, In a subset of patients with early gastric cancer, there were recurrences of the disease after a curative resection had been done. Direct evidence of tumor seeding in distant organs at the time of surgery for gastric cancer is not available. An immunocytochemical assay for epithelial cytokeratin protein may fill this gap because it is a feature of epithelial cells that would not normally be present in bone marrow. From 1994-1997, the bone marrow of 45 patients with early gastric cancer was examined for tumor cells, using immunocytochemical techniques and an antibody reacting with cytokeratin, a component of the intracytoplasmic network of intermediate filaments. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. Clinicopathological characteristics were determined for subjects with cytokeratin-positive cells in the bone marrow. Of these 45 patients, 9 (20.0%) had cytokeratin-positive cells in the bone marrow at the time of primary surgery. These positive findings were not related to tumor advance- related factors of lymph node metastasis and distinct lymphatic and vascular invasion. Microvessel density in the primary tumor exceeded 2-fold in cytokeratin-positive cells, compared with findings in negative cells (P < 0.05). Tumor cells in bone marrow are indicative of the general disseminative metastasis in patients with early gastric cancer, and the metastatic potential was closely related to angiogenesis in the primary tumor..
5. M. Mizoguchi, T. Inamura, K. Ikezaki, T. Iwaki, S. Oda, Y. Maehara, E. Oki, M. Terasaki, M. Fukui, Patient survival and microsatellite instability in gliomas by high-resolution fluorescent analysis., Oncology reports, 6, 4, 791-795, 1999.01, Deficient repair of nucleotide mismatches in the genome is considered a major factor in tumorigenesis. Such deficiency is evidenced by alterations in dinucleotide repeats of microsatellite sequences, specifically microsatellite instability (MSI) or replication errors. We investigated the frequency of MSI in human gliomas in terms of patient outcome. Frequency of MSI was estimated by examining five loci on chromosomes 2, 5, 10, 11, and 13 in 31 gliomas using high-resolution fluorescent microsatellite analysis. MSI was found at all loci in only 2 malignant gliomas (6.5%). MSI was detected at the D10S197 locus in 3 of 11 glioblastomas (27.2%) and 4 of 8 anaplastic astrocytomas (50%), while no MSI was detected in low-grade gliomas. Among patients with anaplastic astrocytoma, the 4 with MSI at D10S197 died from local recurrence less than 18 months after surgery, while 3 of the patients without MSI survived for more than 20 months. MSI at D10S197 may be a prognostic marker for patients with anaplastic astrocytomas..
6. Yoshihiko Maehara, Akira Kabashima, Eriko Tokunaga, Shota Hasuda, Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Keizo Sugimachi, Recurrences and relation to tumor growth potential and local immune response in node-negative advanced gastric cancer, Oncology, 10.1159/000011986, 56, 4, 322-327, 1999.05, Biological characteristics and the prognosis for subjects with node-negative advanced gastric cancer have been given little attention in related literature. We analyzed data on 112 patients with serosally invasive gastric cancer who were lymph node metastasis-negative; all had been surgically treated in the Department of Surgery II, Kyushu University Hospital, between 1970 and 1992. Recurrences and relation to the growth potential of the tumor and local immune response were examined. Thirty patients died with a recurrence of the gastric cancer, and in these patients, the tumor was larger, the whole stomach was more frequently involved and infiltrative growth was more common, compared to findings in patients who were recurrence-free. Peritoneal recurrence was evident in half the number of patients and the 5-year survival rate was 74.5%. Tumor growth potential was evaluated, based on the level of proliferating cell nuclear antigen (PCNA) of the primary tumor and on dendritic cell infiltration into the tumor, determined as a level of local immune function of the host. Higher growth potential and lower immune levels were more frequent in patients with recurrences. Multivariate analysis revealed that tumor size and PCNA labeling index were significant prognostic factors for node-negative gastric cancers. In a subset of advanced gastric cancers, there was no apparent distinct lymph node metastasis and the prognosis was better. However, cancer cells with a higher growth potential and a lower immune response in the host can biologically amplify and mainly infiltrate the gastric wall, extend to the serosa and disseminate transserosally into the peritoneum..
7. Eiji Oki, Yoshihiko Maehara, Eriko Tokunaga, Yoshihiro Kakeji, Keizo Sugimachi, Reduced expression of p33(ING1) and the relationship with p53 expression in human gastric cancer, Cancer Letters, 10.1016/S0304-3835(99)00288-8, 147, 1-2, 157-162, 1999.12, p33(ING1) is a novel growth inhibitor candidate for a tumor suppressor gene. p33(ING1) cooperates with p53 and negatively regulates cell growth by activating transcription from the p21/WAF1 promoter even though it has no significant sequence similarity to p53. We first compared p33(ING1) expression in human gastric cancers and matched normal tissues using quantitative RT-PCR and real time 'Taqman TM' technology. A significant decrease in p33(ING1) expression was evident in 15 of 20 gastric cancers. In immunohistochemical analysis, p53 protein expression was detected in 4 of 20 (20%) tumors, and 12 of 15 (80%) tumors with decreasing p33(ING1) expression in RT-PCR had the wild type p53. When we examined the sequence of p33(ING1) in 12 gastrointestinal carcinoma cell lines, we found mutation in only one cell line, HCT116. Our findings are interpreted to mean that p33(ING1) may function as a tumor suppressor in gastric carcinogenesis, even though the gene is preserved in the majority of gastrointestinal carcinomas. It should be noted that expression of p33 decreased in many cancer patients, and the biological effects of p33(ING1) and p53 are interrelated and require the activity of both genes. Copyright (C) 1999 Elsevier Science Ireland Ltd..
8. Yoshihiko Maehara, Eiji Oki, Toru Abe, Eriko Tokunaga, Kotaro Shibahara, Yoshihiro Kakeji, Keizo Sugimachi, Overexpression of the heat shock protein HSP70 family and p53 protein and prognosis for patients with gastric cancer, Oncology, 10.1159/000012091, 58, 2, 144-151, 2000.02, The cell synthesis of heat shock proteins is increased by a variety of environmental and pathophysiological stressful conditions. The 70-kD heat shock protein family (HSP70 family) which constitutively expresses hsc70 and heat-inducible hsp70 is thought to be involved in protein-protein interactions, including oncogene products. We investigated the HSP70 family expression and biological behavior of gastric cancer, and its relation to p53 overexpression. Expressions of HSP70 and p53 in 164 primary gastric tumors were determined immunohistochemically. Exploratory data were analyzed on a set of 164 primary gastric cancers, and we constructed in prognostic significance of the HSP70 expression level and the relation to p53 overexpression. Expression of HSP70 (hsc70 and hsp70) were detected in nuclei and/or cytoplasm of cancer cells. Western blotting analysis showed that hsc70 and hsp70 were both expressed in five gastric cancer cell lines. Immunohistochemically stained positive cells of HSP70 varied from 0 (very weak) to 100%, in each case. The median level of positive cell rate was 19.0%. A HSP70 expression of over 19.0% was related to the differentiated tissue type of gastric cancer, but not to other clinicopathological factors. There was no difference in survival rates in subjects with higher and lower groups of HSP70 expression. HSP70 expression was also not related to p53 overexpression in the nuclei and p53 overexpression-related poorer prognosis. Our findings show that the expression of HSP70 is not associated with tumor advance-related characteristics or with the prognosis of gastric cancer. Measurements of HSP70 expression do not appear to be a useful prognostic marker. Copyright (C) 2000 S. Karger AG, Basel..
9. Eriko Tokunaga, Yoshihiko Maehara, Eiji Oki, Kaoru Kitamura, Yoshihiro Kakeji, Shinji Ohno, Keizo Sugimachi, Diminished expression of ING1 mRNA and the correlation with p53 expression in breast cancers, Cancer Letters, 10.1016/S0304-3835(99)00434-6, 152, 1, 15-22, 2000.04, p33(ING1) is a novel candidate tumor suppressor and its overexpression induces growth arrest or apoptosis in different cell lines. These functions of p33(ING1) depend largely on the activity of p53, and p53-dependent activation of the transcription from the p21/WAF1 promoter also requires p33(ING1). We examined the expression of ING1 mRNA in breast cancer cell lines and clinical breast cancer tissues, using quantitative RT-PCR and real time TaqMan(TM) technology. In breast cancer cell lines, ING1 mRNA was expressed at almost the same level. However, in a comparison between the cancer and matched normal tissues, a significant decrease in ING1 mRNA expression was found in 17 of 24 (70.8%) breast cancer tissues. We also examined the correlation between ING1 mRNA expression and p53 expression. There was a significant decrease of ING1 mRNA in nine of 15 tumors negative for p53 immunostaining, most of which were considered to have wild type p53. In these tumors, p53 may not function in case of a decreased expression of p33(ING1), and the lack of cell cycle regulation may correlate with the carcinogenesis and tumor progression. Copyright (C) 2000 Elsevier Science Ireland Ltd..
10. Kazuya Endo, Eiji Oki, Verena Biedermann, Hiromi Kojima, Kiyotsugu Yoshida, Franz Josef Johannes, Donald Kufe, Rakesh Datta, Proteolytic cleavage and activation of protein kinase C μ by caspase-3 in the apoptotic response of cells to 1-β-D-arabinofuranosylcytosine and other genotoxic agents, Journal of Biological Chemistry, 10.1074/jbc.M002266200, 275, 24, 18476-18481, 2000.06, Protein kinase C (PKC) μ is a novel member of the PKC family that differs from the other isozymes in structural and biochemical properties. The precise function of PKCμ is not known. The present studies demonstrate that PKCμ is cleaved during apoptosis induced by 1-β-D-arabinofuranosylcytosine (ara-C) and other genotoxic agents. PKCμ cleavage is blocked in cells that overexpress the anti-apoptotic Bcl-x(L) protein or the baculovirus p35 protein. Our results demonstrate that PKCμ is cleaved by caspase-3 at the CQND378 site. Cleavage of PKCμ is associated with release of the catalytic domain and activation of its kinase function. We also show that, unlike the cleaved fragments of PKCδ and θ, overexpression of the PKCμ catalytic domain is not lethal. Cells stably expressing the catalytic fragment of PKCμ, however, are more sensitive to apoptosis induced by genotoxic stress. In addition, expression of the caspase-resistant PKCμ mutant partially inhibits DNA damage-induced apoptosis. These findings demonstrate that PKCμ is cleaved by caspase-3 and that expression of the catalytic domain sensitizes cells to the cytotoxic effects of ara-C and other anticancer agents..
11. Eriko Tokunaga, Eiji Oki, Shinya Oda, Akemi Kataoka, Kaoru Kitamura, Shinji Ohno, Yoshihiko Maehara, Keizo Sugimachi, Frequency of microsatellite instability in breast cancer determined by high-resolution fluorescent microsatellite analysis, Oncology, 10.1159/000012136, 59, 1, 44-49, 2000.06, In breast cancer, the rates of positivity for microsatellite instability (MSI), vary greatly in the literature. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 75 patients with sporadic breast cancer. In this system, several devices were prepared to improve reproducibility of polymerase chain reaction products, migration accuracy of electrophoresis, and characteristics of the detection system. Precise and objective analyses of microsatellite alterations are made feasible using HRFMA. Seven of the 75 cases were judged to be positive for MSI, the rate of positivity being 9.3%. This rate is relatively low compared to the data in the literature. All the microsatellite changes observed in this system can be classified into two types: type A with relatively small changes in microsatellite sequences observed in limited loci and type B with drastic and widely dispersed changes. The former was thought to be connected to abnormal activity in DNA mismatch repair (MMR). Among the 7 cases, 6 (8.0%) had type A alterations, which means that the tumors may have an abnormal MMR activity. Application of precise and objective systems for microsatellite analysis is expected to be clinically useful to detect patients at high risk for cancers. Copyright (C) 2000 S. Karger AG, Basel..
12. R. Datta, E. Oki, K. Endo, V. Biedermann, J. Ren, D. Kufe, XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage, Journal of Biological Chemistry, 10.1074/jbc.M910231199, 275, 41, 31733-31738, 2000.10, The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human LAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[β-D-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of precaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress..
13. E. Tokunaga, Yoshihiko Maehara, Eiji Oki, T. Koga, Y. Kakeji, K. Sugimachi, Application of quantitative RT-PCR using 'TaqMan' technology to evaluate the expression of CK 18 mRNA in various cell lines, Journal of Experimental and Clinical Cancer Research, 19, 3, 375-381, 2000.11, Reverse transcriptase polymerase chain reaction (RT-PCR) is often used for sensitive detection of micrometastasis in peripheral blood, lymph nodes and bone marrow. While the utility of this method has been documented, it also has limitations in the detection of micrometastasis. The mRNA of target genes can be detected in healthy donors or in samples used for negative control, therefore the non-quantitativeness of conventional RT-PCR has been called into question. We analyzed the expression level of cytokeratin (CK) 18 mRNA in established esophageal and gastrointestinal carcinoma cell lines and non-epithelial cells, using quantitative RT-PCR, based on real time 'TaqMan TM' technology. CK 18 mRNA is more highly expressed in carcinoma cells than in non-epithelial cells. However, the expression level in non-epithelial cells was easily detected using conventional RT-PCR and agarose gel electrophoresis. In an analysis of CK 18 mRNA expression in peripheral venous blood in 13 healthy volunteers, we found that CK 18 mRNA was much less expressed than in cancer cell lines. However, the expression in all samples was at a level which was also detected using conventional RT-PCR. It would thus seem that not only qualitative, but also quantitative analysis, of the target mRNA is important to detect micrometastasis. Quantitative RT-PCR methods will make comparisons of the possible differences in expression levels of the target gene. For clinical applications, much further study is needed..
14. Jian Ren, Rakesh Datta, Hisashi Shioya, Yongqing Li, Eiji Oki, Verena Biedermann, Ajit Bharti, Donald Kufe, p73β is regulated by protein kinase Cδ catalytic fragment generated in the apoptotic response to DNA damage, Journal of Biological Chemistry, 10.1074/jbc.M110667200, 277, 37, 33758-33765, 2002.09, Protein kinase C (PKC) δ is cleaved by caspase-3 to a kinase-active catalytic fragment (PKCδCF) in the apoptotic response of cells to DNA damage. Expression of PKCδCF contributes to the induction of apoptosis by mechanisms that are presently unknown. Here we demonstrate that PKCδCF associates with p73β, a structural and functional homologue of the p53 tumor suppressor. The results show that PKCδCF phosphorylates the p73β transactivation and DNA-binding domains. One PKCδCF-phosphorylation site has been mapped to Ser-289 in the p73β DNA-binding domain. PKCδCF-mediated phosphorylation of p73β is associated with accumulation of p73β and induction of p73β-mediated transactivation. By contrast, PKCδCF-induced activation of p73β is attenuated by mutating Ser-289 to Ala (S289A). The results also demonstrate that PKCδCF stimulates p73β-mediated apoptosis and that this response is attenuated with the p73β(S289A) mutant. These findings demonstrate that cleavage of PKCδ to PKCδCF induces apoptosis by a mechanism in part dependent on PKCδCF-mediated phosphorylation of the p73β Ser-289 site..
15. Yoshihiko Maehara, Yoshihiro Kakeji, Takaaki Masuda, Taro Sakoguchi, Msakazu Imamura, Kippei Ohgaki, Koji Taniguchi, Masato Sakurai, Motonori Futatsugi, Yasue Kimura, Toshihiko Nakamura, Eriko Tokunaga, Eiji Oki, Shin Ushiro, Masayuki Watanabe, Shinya Oda, Shuji Tanaka, Hideo Baba, Treatment of gastric cancer
current state and future prospect, Fukuoka igaku zasshi = Hukuoka acta medica, 94, 10, 285-295, 2003.10.
16. Hideo Baba, Yoshihiro Kakeji, Eiji Oki, Eriko Tokunaga, Shin Ushiro, Masayuki Watanabe, Yoshihiko Maehara, Chemotherapy for gastric cancer, Gan to kagaku ryoho. Cancer & chemotherapy, 30, 12, 1881-1888, 2003.11, 5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combined chemotherapy has been developed. Although several phase III studies have been reported in 1990's, a standard chemotherapeutic regimen has not been established worldwide. Recently, newly developed anticancer agents such as CPT-11, TS-1, Paclitaxel, or Docetaxel can be clinically used for advanced gastric cancer either single agent or in combination that may further improve the quality of life and prolong the survival of patients with gastric cancer. In Japan, postoperative adjuvant chemotherapy has been actively developed to enhance survival benefit of surgery for patients with gastric cancer. There were a few positive single randomized controlled study showing benefit of adjuvant chemotherapy with a high evidence level. However, all reports of meta-analysis of adjuvant chemotherapy for gastric cancer indicated the survival benefit of adjuvant chemotherapy. At present, a nation-wide randomized controlled study in the postoperative adjuvant setting for gastric cancer using TS-1 (ACTS-GC) is under way that may clarify the effect of postoperative adjuvant chemotherapy in gastric cancer..
17. Ichiro Yoshino, Atsushi Osoegawa, Tomofumi Yohena, Toshifumi Kameyama, Eiji Oki, Shinya Oda, Yoshihiko Maehara, Loss of heterozygosity (LOH) in non-small cell lung cancer
Difference between adenocarcinoma and squamous cell carcinoma, Respiratory Medicine, 10.1016/j.rmed.2004.08.008, 99, 3, 308-312, 2005.03, Background: In non-small cell lung cancer, a loss of heterozygosity (LOH) is frequently observed; however, few studies have investigated the differences in the LOH status between adenocarcinoma and squamous cell carcinoma. Patients and methods: In a consecutive series of 49 patients with adenocarcinomas and 22 patients with squamous cell carcinomas, the LOH in tumors was analyzed using polymerase chain reaction employing 5 fluorescence-labeled dinucleotide markers (D2S123, D5S107, D10S197, D11SS904, D13S175) and an autosequencer. Results: LOH was more frequently observed in squamous cell carcinoma (20 of 22, 90%) than in adenocarcinomas (33 of 49, 67%) (P = 0.0348), and the number of LOH per patient was also higher in the patients with squamous cell carcinoma (2.2±1.4) than in those with adenocarcinoma (1.5±1.2, P = 0.037). In adenocarcinomas, the number of LOH per patients correlated significantly with the pack-year index, whereas the pathological stage significantly affected the number of LOH in squamous cell carcinomas. Conclusion: The presence of LOH is relatively uncommon in adenocarcinoma of the lung; however, the incidence of LOH tends to be associated with the smoking status..
18. Yoshihiro Tanaka, Shingo Miyamoto, Satoshi O. Suzuki, Eiji Oki, Hiroshi Yagi, Kenzo Sonoda, Ayano Yamazaki, Hiroto Mizushima, Yoshihiko Maehara, Eisuke Mekada, Hitoo Nakano, Clinical significance of heparin-binding epidermal growth factor-like growth factor and A disintegrin and metalloprotease 17 expression in human ovarian cancer, Clinical Cancer Research, 10.1158/1078-0432.CCR-04-1426, 11, 13, 4783-4792, 2005.07, Purpose: Lysophosphatidic acid, which is enriched in the peritoneal fluid of ovarian cancer patients, plays a key role in the progression of ovarian cancer. Lysophosphatidic acid can generate epidermal growth factor receptor (EGFR) signal transactivation involving processing of EGFR ligands by ADAM (a disintegrin and metalloprotease) family metalloproteases, We aimed to investigate the clinical significance of EGFR ligands and ADAM family in the lysophosphatidic acid - induced pathogenesis of ovarian cancer. Experimental Design: We examined the expression of EGFR ligands and ADAM family members in 108 patients with normal ovaries or ovarian cancer, using real-time PCR, immunohistochemistry, and in situ hybridization, and analyzed the clinical roles of these molecules. Statistical analyses of these data were done using the Mann-Whitney test, Kaplan-Meier method, or Spearman's correlation analysis. Results: Large differences in expression were found for heparin-binding EGF-like growth factor (HB-EGF) and other EGFR ligands and for ADAM 17 and other ADAM family members. HB-EGF expression was significantly increased in advanced ovarian cancer compared with that in normal ovaries (P < 0.01). HB-EGF expression was significantly associated with the clinical outcome (P < 0.01). ADAM 17 expression was significantly enhanced in both early and advanced ovarian cancer compared with that in normal ovaries (both P < 0.01), although it had no clinical significance in the progression-free survival. HB-EGF expression was significantly correlated with ADAM 17 expression (γ = 0.437, P < 0.01). Conclusions: Our findings suggest that HB-EGF and ADAM 17 contribute to the progression of ovarian cancer and that HB-EGF plays a pivotal role in the aggressive behavior of a tumor in ovarian cancer..
19. Eiji Oki, Masayuki Watanabe, Masahiko Ikebe, Masaru Morita, Motonori Futatsugi, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Histological and biological characteristics of esophageal dysplasia, Esophagus, 10.1007/s10388-005-0050-8, 2, 3, 129-132, 2005.09, Dysplasia is an important problem in esophageal carcinogenesis, and there are controversial opinions concerning whether esophageal squamous dysplasia is a cancerous lesion. In the present study, it was histopathologically and biologically confirmed that dysplasia has a close correlation with cancer. Dysplasia was frequently observed with early stages of carcinoma. Although continuity of dysplastic lesions into the carcinoma area is not frequently observed, this continuity is observed in severe dysplasia more often than in mild or moderate dysplasia. The proliferating cell nuclear antigen labeling index (PCNA LI) showed no substantial difference in the cell proliferative activities of dysplasia and intraepithelial carcinoma. In addition, p53 immunohistochemical analysis revealed that p53 positivities in carcinomas and dysplasias were contiguous to each other. These findings indicate that the relationship between the severity of dysplasia and carcinoma has high potential for leading to malignancy. Therefore, dysplasias can be treated as early cancerous lesions of the esophagus to prevent serious results..
20. Eiji Oki, Eriko Tokunaga, Toshihiko Nakamura, Naoyuki Ueda, Motonori Futatsugi, Kohjiro Mashino, Manabu Yamamoto, Masayuki Watanabe, Masahiko Ikebe, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Genetic mutual relationship between PTEN and p53 in gastric cancer, Cancer Letters, 10.1016/j.canlet.2004.12.006, 227, 1, 33-38, 2005.09, Both PTEN (encoding phosphate and tensin homologue) and p53 are known as cancer suppressor genes, and they are assumed that their gene mutations and loss of heterozygosity (LOH) occur frequently in various types of carcinoma. In the present study, we investigated both the p53 mutation and LOH of PTEN in 113 gastric cancer patients. We observed the LOH of PTEN in 11.1% of the patients with normal p53s and 46.2% of the patients with p53 gene mutations. The result that LOH of PTEN was frequently observed in the cases with p53 gene mutations and other data in this study suggested that both PTEN and p53 have complimentary roles in gastric carcinoma development..
21. Shinya Oda, Yoshihiko Maehara, Yoichi Ikeda, Eiji Oki, Akinori Egashira, Yoshikazu Okamura, Ikuo Takahashi, Yoshihiro Kakeji, Yasushi Sumiyoshi, Kaname Miyashita, Yu Yamada, Yan Zhao, Hiroyoshi Hattori, Ken Ichi Taguchi, Tatsuro Ikeuchi, Teruhisa Tsuzuki, Mutsuo Sekiguchi, Peter Karran, Mitsuaki A. Yoshida, Two modes of microsatellite instability in human cancer
Differential connection of defective DNA mismatch repair to dinucleotide repeat instability, Nucleic acids research, 10.1093/nar/gki303, 33, 5, 1628-1636, 2005.10, Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes of ≤6 bp. Type B changes are more drastic and involve modifications of ≥8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected..
22. Manabu Yamamoto, Koujiro Mashino, Kotaro Shibahara, Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Evaluation of positive cases with peritoneal lavage cytology in gastric cancer, Gan to kagaku ryoho. Cancer & chemotherapy, 32, 10, 1389-1392, 2005.10, Peritoneal dissemination with advanced gastric cancer is of significant problem. Peritoneal lavage cytology has been an effective method for the detection of early peritoneal dissemination since 1999. The accurate evaluation of peritoneal lavage cytology is unclear except for the same prognosis of peritoneal dissemination. We examined the clinical findings and the prognosis with positive cases in peritoneal lavage cytology. The prognosis of cases with P1CY1 or P2P3 group was poorer than in the P0CY1 or P0, CY1 group. We thus review the evaluation of peritoneal lavage cytology with gastric cancer in the Japanese and English literature. In addition, we describe the diagnosis of early peritoneal dissemination using peritoneal lavage tumor markers or molecular markers of peritoneal lavage..
23. Eiji Oki, Hideo Baba, Eriko Tokunaga, Toshihiko Nakamura, Naoyuki Ueda, Motonori Futatsugi, Kohjiro Mashino, Manabu Yamamoto, Masahiko Ikebe, Yoshihiro Kakeji, Yoshihiko Maehara, AKT phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer, International Journal of Cancer, 10.1002/ijc.21170, 117, 3, 376-380, 2005.11, Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000. AKT activation was investigated by immunostaining with a phosphorylation- specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p = 0.0008). When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents (5-fluorouracil, adriamycin, mitomycin C and cis-platinum). The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients..
24. Eriko Tokunaga, Yasue Kimura, Kojiro Mashino, Eiji Oki, Akemi Kataoka, Shinji Ohno, Masaru Morita, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Activation of PI3K/Akt signaling and hormone resistance in breast cancer., Breast cancer (Tokyo, Japan), 10.2325/jbcs.13.137, 13, 2, 137-144, 2006, Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy..
25. Eriko Tokunaga, Yasue Kimura, Eiji Oki, Naoyuki Ueda, Motonori Futatsugi, Kojiro Mashino, Manabu Yamamoto, Masahiko Ikebe, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients, International Journal of Cancer, 10.1002/ijc.21358, 118, 2, 284-289, 2006.01, Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy..
26. Yoshihiko Maehara, Eiji Oki, Eriko Tokunaga, Shinichiro Maehara, Eiji Tsujita, Yoichi Yamashita, Akinori Egashira, Akinobu Taketomi, Kakeji Yoshihiro, Development of a molecular target therapy on the basis of global gene analyses of gastrointestinal carcinoma, Fukuoka igaku zasshi = Hukuoka acta medica, 97, 2, 30-36, 2006.02.
27. Eriko Tokunaga, Akemi Kataoka, Yasue Kimura, Eiji Oki, Kojiro Mashino, Kojiro Nishida, Tadashi Koga, Masaru Morita, Yoshihiro Kakeji, Hideo Baba, Shinji Ohno, Yoshihiko Maehara, The association between Akt activation and resistance to hormone therapy in metastatic breast cancer, European Journal of Cancer, 10.1016/j.ejca.2005.11.025, 42, 5, 629-635, 2006.03, In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P < 0.01). pAkt positivity was also associated with a poorer objective response (P < 0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P < 0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P < 0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P < 0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P = 0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy..
28. Ikuo Takahashi, Yasunori Emi, Yoshihiro Kakeji, Eriko Tokunaga, Shin Ushiro, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yoshihiko Maehara, Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer, Oncology reports, 15, 4, 849-854, 2006.04, A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) <1.25 m2:80 mg/day, 1.25≤ BSA <1.50 m2: 100 mg/day, 1.50 m2≤ BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m 2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m 2/day. Initially, patients were administered S-1 and 40 mg/m 2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day..
29. Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Eriko Tokunaga, Toshihiko Nakamura, Naoyuki Ueda, Motonori Futatsugi, Manabu Yamamoto, Masahiko Ikebe, Yoshihiko Maehara, Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer, Journal of Gastroenterology and Hepatology (Australia), 10.1111/j.1440-1746.2005.04028.x, 21, 5, 814-818, 2006.05, Background and Aim: Encoding phosphate and tensin homolog (PTEN) is a cancer suppressor gene and it has been assumed that gene mutation and loss of heterozygosity (LOH) occurs frequently in various types of carcinoma. However, the role of LOH of PTEN and its outcome variables in gastric cancer have not been well established. In the present study, we investigated the roles of PTEN, LOH and their outcomes. Methods: Fresh frozen tumor samples from 119 gastric cancer patients with a primary diagnosis of gastric carcinoma were evaluated for LOH of PTEN using an automated sequencer. Results were compared with pathological parameters. The median follow-up period was 559 days. Results: Loss of heterozygosity of PTEN was observed in 17.1% of patients (13/76) diagnosed with gastric cancer. No particular relationship was found with any clinicopathological factor. However, the prognosis of patients with LOH of PTEN was significantly poor. Multivariate analyses revealed that vascular invasion, invasion depth, LOH of PTEN, histology and lymph node metastasis were correlated with survival of the patient. Conclusions: Even though mutation of PTEN in gastric cancer has rarely been reported, according to our findings, LOH of PTEN frequently occurs in gastric cancers and is correlated with disease-related deaths. The LOH of PTEN is an independent prognostic factor and PTEN is a candidate as a haploinsufficient tumor suppressor in gastric cancers..
30. Eriko Tokunaga, Eiji Oki, Kojiro Nishida, Tadashi Koga, Rintaro Yoshida, Keisuke Ikeda, Aya Kojima, Akinori Egashira, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Aberrant hypermethylation of the promoter region of the CHFR gene is rare in primary breast cancer, Breast Cancer Research and Treatment, 10.1007/s10549-005-9112-9, 97, 2, 199-203, 2006.05, Taxanes are among the most active agents and they are now known to be an indispensable component in chemotherapy for breast cancer. However, some patients are resistant to taxanes and the identification of the molecular characteristics that can predict the sensitivity to taxanes would be useful in selecting the most appropriate patients to receive taxane therapy. Taxanes are antimicrotubular agents that promote microtubular assembly and stabilize microtubules by preventing depolymerization. They interfere with normal mitotic transition and causes cell cycle arrest in the G2-M metaphase. CHFR (checkpoint with forkhead-associated and ring finger) is a recently identified gene, which functions as an important checkpoint protein early in G2-M transition. Its activation delays the cell cycle in prophase and promotes cell survival in response to the mitotic stress induced by either nocodazole or taxane. CHFR is frequently downregulated in human cancers, mostly owing to the hypermethylation of its promoter region. CHFR downregulation has been found in primary cancers or in the established tumor cells of various origins, such as the lung, colon, esophagus, and stomach. The aberrant hypermethylation of CHFR promoter appears to be a good molecular marker to predict sensitivity to taxanes in gastric, lung, and colon cancer. A downregulation of CHFR was observed in breast cancer cells, however, no apparent promoter hypermethylation has yet been reported. In addition, an alteration of the CHFR expression or aberrant promoter hypermethylation in primary breast cancer has not been fully investigated. In this study, we examined the methylation status of the promoter region of CHFR gene in 110 primary breast cancers. We observed the hypermethylation of the CHFR promoter region in only one case (0.9%). We herein show that the aberrant hypermethylation of this region is quite a rare event in primary breast carcinoma..
31. Eiji Oki, Yoshihiro Kakeji, Rintaro Yoshida, Keisuke Ikeda, Kojiro Nishida, Tadashi Koga, Akinori Egashira, Eriko Tokunaga, Masaru Morita, Hideo Baba, Yoshihiko Maehara, [A randomized controlled trial to evaluate the effect of adjuvant oral fluoropyrimidine derivative therapy after curative resection for stage II/III rectal cancer-adjuvant chemotherapy trial of S-1 for rectal cancer (ACTS-RC):], Gan to kagaku ryoho. Cancer & chemotherapy, 33, 138-143, 2006.06, We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009..
32. Eriko Tokunaga, Eiji Oki, Kojiro Nishida, Tadashi Koga, Akinori Egashira, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Trastuzumab and breast cancer
Developments and current status, International Journal of Clinical Oncology, 10.1007/s10147-006-0575-4, 11, 3, 199-208, 2006.06, The emergence of trastuzumab has drastically changed therapy for breast cancer. Trastuzumab (Herceptin; Genentech) is a recombinant humanized monoclonal antibody that targets an epitope in the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. HER2 is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival, and differentiation via multiple signal transduction pathways. Overexpression of HER2 or amplification of the HER2 gene occurs in 20%-30% of human breast cancers. Preclinical models have demonstrated that this antibody has significant antitumor activity as a single agent, and it also has a synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancers that overexpress HER2 have shown trastuzumab to have clinical activity when used as monotherapy, while also improving survival when used as a first-line therapy in combination with chemotherapy. At present, clinical investigations are focusing attention on the efficacy of trastuzumab in both the adjuvant and neoadjuvant setting, as well as in the metastatic setting. In this review, we describe the developments and current status of trastuzumab-based treatment for breast cancer..
33. Ikuo Takahashi, Eiji Oki, Akinori Egashira, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Combination chemotherapy of S-1 plus biweekly docetaxel for advanced and recurrent gastric cancer, Gan to kagaku ryoho. Cancer & chemotherapy, 33 Suppl 1, 87-90, 2006.06, The S-1 +biweekly docetaxel (DOC) combination therapy was evaluated for advanced or recurrent gastric cancer patients. This combination therapy was evaluated in vitro using the nude rat-gastric cancer xenograft system. S-1 alone or DOC alone showed antitumor activity, and the antitumor activity was synergistic when two drugs were combined. In clinical settings, the schedule was S-1 80 mg/m2 (day 1-14, orally) and DOC (day 1 and day 15, intravenously) followed by a 2-week rest. In phase I study, the dose of DOC was evaluated, and a recommended dose for phase II was determined as 35 mg/m2. The entry for phase II study was completed, and the preliminary results of 33 patients showed the response rate of 21.2%. The incidence of more than grade 3 adverse effects was 29%(neutropenia, leukocytopenia, anorexia and mucositis). The S-1 +biweekly DOC combination therapy can be a candidate for outpatient chemotherapy for advanced or recurrent gastric cancer..
34. Eiji Oki, Mitsuhiko Ota, Takuya Honbo, Akinori Egashira, Eriko Tokunaga, Noriaki Sadanaga, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Molecular target therapy for colonic neoplasms, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 10.2169/naika.96.289, 96, 2, 289-294, 2007.01.
35. Eriko Tokunaga, Eiji Oki, Yasue Kimura, Takeharu Yamanaka, Akinori Egashira, Kojiro Nishida, Tadashi Koga, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma, Breast Cancer Research and Treatment, 10.1007/s10549-006-9295-8, 101, 3, 249-257, 2007.03, Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression..
36. Sosei Kuma, Eiji Oki, Toshihiro Onohara, Kimihiro Komori, Yoshihiko Maehara, Angiotensin II-induced growth of vascular smooth muscle cells is associated with modulation of cell surface area and platelet-derived growth factor receptor expression, Clinical and Experimental Pharmacology and Physiology, 10.1111/j.1440-1681.2007.04535.x, 34, 3, 153-160, 2007.03, 1. Excessive growth of vascular smooth muscle cells (VSMC) can lead to critical problems in the treatment of some vascular diseases. Recent studies suggest a connection between this abnormal growth of VSMC and the octapeptide hormone angiotensin (Ang) II. However, the growth-promotive potential of AngII on VSMC is unclear. 2. Using the novel AngII inhibitor E4177 and an original animal model, we confirmed that AngII does function in abnormal growth of VSMC induced after transplantation of vein grafts in an animal model. 3. Furthermore, using a primary culture of human aortic smooth muscle cells (HASMC), we found that AngII augmented the growth of HASMC in a serum-dependent manner and induced enlargement of the cell surface area in HASMC, both effects being nullified by E4177. The latter effect of AngII was associated with an increase in the expression level of platelet-derived growth factor (PDGF) receptors. In specimens obtained from the animal model, PDGF receptors were highly expressed. 4. These data obtained in vitro and in vivo imply that AngII has the potential to promote growth of VSMC and suggest that this growth promotion may be mediated by enlargement of the cell surface area..
37. Akinori Egashira, Masaru Morita, Yoshihiro Kakeji, Noriaki Sadanaga, Eiji Oki, Takuya Honbo, Mitsuhiko Ohta, Yoshihiko Maehara, p53 Gene mutations in esophageal squamous cell carcinoma and their relevance to etiology and pathogenesis
Results in Japan and comparisons with other countries, Cancer Science, 10.1111/j.1349-7006.2007.00524.x, 98, 8, 1152-1156, 2007.08, Esophageal squamous cell carcinoma is a form of cancer that has varying incidence rates among different countries, distinct geographic areas and different ethnic groups. According to previous reports, p53 gene mutations have been identified in 20-80% of these tumors, and these mutations have occurred at an early stage. These findings suggest that such mutations play an important role in esophageal carcinogenesis, and highlight the importance of mutagens, which cause sequence alterations in the p53 gene. In order to clarify the environmental factors and the molecular mechanisms that may be responsible for the occurrence and prevention of a specific mutation in the process of esophageal carcinogenesis, we analyzed p53 gene mutations in 95 samples of esophageal squamous cell carcinoma. We further reviewed published reports investigating the frequency of p53 gene mutations in esophageal cancer from high-risk areas to normal-risk areas and compared these findings to our results in Japan. The frequency of p53 gene mutations in Japanese esophageal cancer is 47.4% and there are three prominent features: (1) a predominance of transversions, in particular the G:C to T:A transversion; (2) a relatively low frequency of transitions; and (3) a relatively high percentage of frameshift mutations. These results indicate the possible importance of the benzo[a]pyrene metabolite and oxidative DNA damage in esophageal carcinogenesis and scarcely correlate with DNA replication errors or alkylation in comparison to other gastrointestinal cancers. In addition, we observed a peculiar sequence of frameshift mutations. Taken together, these data suggest that this tumor suppressor gene plays a critical role in the multistep carcinogenesis process for esophageal squamous cell cancer..
38. Eiji Oki, M. Morita, Y. Kakeji, M. Ikebe, N. Sadanaga, A. Egasira, K. Nishida, T. Koga, M. Ohata, T. Honboh, M. Yamamoto, H. Baba, Y. Maehara, Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer, Diseases of the Esophagus, 10.1111/j.1442-2050.2007.00677.x, 20, 4, 301-304, 2007.08, Salvage esophagectomy is performed for esophageal cancer after definitive chemoradiotherapy. The clinical significance and safety of salvage surgery has not been well established. We reviewed 14 cases of salvage esophagectomy following definitive chemoradiotherapy from 1994 through 2005 and investigated complication rates and outcomes. Seven of 14 cases were completely resected with salvage surgery. Operation time and bleeding were greater in patients who experienced incomplete resection (R1/R2). Anastomosis leakage, pulmonary dysfunction and heart failure were recognized in four, two and one patients, respectively. The postoperative complications were more frequent (71.4%) in patients with incomplete resection (R1/R2) than in patients with complete resection (R0) (28.4%). Two patients with complete resection (R0) showed long-term survival. Salvage esophagectomy may be indicated when the tumor can be resected completely after definitive chemotherapy. However, all cases of T4 cancer cannot be resected completely, resulting in a high risk for complications and poor survival..
39. Masato Sakurai, Yan Zhao, Eiji Oki, Yoshihiro Kakeji, Shinya Oda, Yoshihiko Maehara, High-resolution fluorescent analysis of microsatellite instability in gastric cancer, European Journal of Gastroenterology and Hepatology, 10.1097/MEG.0b013e3281ac20a8, 19, 8, 701-709, 2007.08, BACKGROUND: Microsatellite instability (MSI) is associated with various human malignancies and regarded as reflecting cellular deficiency in DNA mismatch repair (MMR). Analysis of MSI has been prevalent in the field of oncology, and numerous data have accumulated in the literature. It has been reported that the MSI phenotype is relatively frequent in gastric cancer. The reported frequencies of MSI gastric tumors, however, are diverse. AIM AND METHODS: To determine the frequencies of the MSI phenotype and defective MMR in gastric cancer, we examined tumors derived from 167 patients with sporadic gastric cancer, using our unique fluorescent technique, 'high-resolution fluorescent microsatellite analysis'. RESULTS: High-resolution fluorescent microsatellite analysis allowed us the unequivocal designation of MSI. The frequencies of MSI-H and MSI-L were 11 and 9.6%, respectively. In addition to the distinction based on the frequency of microsatellite changes, MSI was classifiable into two distinct categories, type A and type B, according to the mode of length changes in the dinucleotide microsatellites. Type A and type B MSI were observed in 14 and 6.6%, respectively. The overall frequency of MSI was 21%. Intriguingly, MSI did not correlate with any of commonly used clinicopathological variables. In addition, neither MSI-H nor MSI-L correlated with family history of malignancies or patient history of multiple cancers. Instead, type B MSI was significantly more frequent in patients with family history of gastric cancer. Type A MSI appeared to occur more frequently in tumors of patients with a history of double cancer, which, however, was not statistically significant. CONCLUSION: In gastric cancer, contribution of defective MMR to the risk of multiple cancer or familial predisposition appears more limited than has been expected. The relationship between MSI and high risk of cancer may have been oversimplified, at least in gastric cancer..
40. Yasunori Emi, Yasushi Sumiyoshi, Eiji Oki, Yoshihiro Kakeji, Yousuke Fukui, Yoshihiko Maehara, Pharmacokinetics of gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the anti-angiogenic metabolites of oral fluoropyrimidine UFT, in patients with gastric cancer., Fukuoka igaku zasshi = Hukuoka acta medica, 98, 12, 418-424, 2007.12, Gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the metabolites of UFT, which is an oral fluoropyrimidine, have been reported to inhibit angiogenesis with IC50 values of 25.8 ng/ml. The pharmacokinetics of GHB and GBL were examined after the administration of UFT in patients with gastric cancer. The patients received 200 mg of UFT orally twice a day. Peripheral blood samples were collected at 0, 0.5, 1, 2 and 4 hr after the time of dosing on day 5. The baseline and endogenous GBL concentrations in plasma were 20.2 +/- 7.5 ng/ml for patients and 16.8 +/- 4.0 ng/ml for volunteers (P = 0.221). The values of C(max) for tegafur, uracil, 5-FU and GBL were 14.7 +/- 5.2 and 4.0 +/- 2.8 microg/ml, 191.2 +/- 115.3 and 147.5 +/- 57.3 ng/ml, respectively, and the values of Tmax were 1.0 +/- 0.6, 1.1 +/- 0.6, 0.9 +/- 0.6 and 1.2 +/- 0. 6 hr, respectively. The concentration of GBL was much higher than its IC50 value for angiogenesis. GBL is thus suggested to contribute to the anticancer effects of UFT in addition to that of 5-FU, which is continuously metabolized from UFT..
41. Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Kojiro Nishida, Tadashi Koga, Eriko Tokunaga, Akinori Egashira, Keisuke Ikeda, Rintaro Yoshida, Manabu Yamamoto, Masaru Morita, Yoshihiko Maehara, Clinical significance of cytokeratin positive cells in bone marrow of gastric cancer patients, Journal of Cancer Research and Clinical Oncology, 10.1007/s00432-007-0258-1, 133, 12, 995-1000, 2007.12, Bone marrow (BM) is a prognostically relevant indicator organ of micrometastasis; however, the clinical importance of BM micrometastasis in gastric cancer patients is not yet known. In the present study, the BM of 267 consecutive patients with primary gastric cancer was examined for tumor cells using immunocytochemical techniques. Real-time quantitative RT-PCR was used to ensure that the tumor cells were detected properly. Among the 267 cases analyzed, 30 cases (11.2%) had cytokeratine-positive cells in the bone marrow. Positive findings were related to the tumor stage (P < 0.05) and to the prominent depth of invasion (P < 0.05). All patients with liver metastasis at operation had cytokeratine-positive cells in the BM. Recurrence of the disease was confirmed in 50 cases (18.7%); 4 of 30 (13.3%) in the cytokeratine-positive group and 46 of 237 (19.4%) in the cytokeratine-negative group. There were no significant differences in the 5-year survival rates between the cytokeratine-positive and cytokeratin-negative groups. Our study shows that BM micrometastasis increases according to tumor progression; however, only a subset of cancer cells may survive in the BM and finally evolve to a clinically apparent disease. Therefore it does not accurately predict the prognosis or recurrence of the disease..
42. Fusanori Yotsumoto, Hiroshi Yagi, Satoshi O. Suzuki, Eiji Oki, Hiroshi Tsujioka, Touru Hachisuga, Kenzo Sonoda, Tatsuhiko Kawarabayashi, Eisuke Mekada, Shingo Miyamoto, Validation of HB-EGF and amphiregulin as targets for human cancer therapy, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2007.11.015, 365, 3, 555-561, 2008.01, Aberrant expression levels of epidermal growth factor receptor (EGFR) and its cognate ligands have been recognized as one of the causes of cancer progression. To investigate the validity of EGFR ligands as targets for cancer therapy, we examined the expression of EGFR ligands and in vitro anti-tumor effects of small interference RNA (siRNA) for EGFR ligands in various cancer cells. HB-EGF expression was dominantly elevated in ovarian, gastric, and breast cancer, melanoma and glioblastoma cells, whereas amphiregulin was primarily expressed in pancreatic, colon, and prostate cancer, renal cell carcinoma and cholangiocarcinoma cells. Transfection of siRNAs for HB-EGF or amphiregulin into these cells significantly increased the numbers of apoptotic cells with attenuation of EGFR and ERK activation. In lung cancer cells, any EGFR ligand was not recognized as a validated target for cancer therapy. These results suggest that HB-EGF and amphiregulin are promising targets for cancer therapy..
43. Manabu Yamamoto, Hideo Baba, Akinori Egashira, Eiji Oki, Masahiko Ikebe, Yoshihiro Kakeji, Yoshihiko Maehara, Adenocarcinoma of the esophagogastric junction in Japan, Hepato-gastroenterology, 55, 81, 103-107, 2008.01, Background/Aims: The prognosis of adenocarcinoma of the esophagogastric junction is worse than that in adenocarcinoma of other parts of the stomach. In particular, the clinical features and prognosis of adenocarcinoma of the esophagogastric junction and the differences between Siewert's type II and III tumors in Japan were evaluated. Methodology: We analyzed one hundred and forty patients with adenocarcinoma of the esophagogastric junction including one patient with a type I tumor, sixty-seven patients with type II tumors, and seventy-two patients with type III tumors. Results: The prognosis of patients with type III tumors was poorer in comparison to that of type II tumors in adenocarcinoma of the esophagogastric junction (p<0.05). A significant difference was observed in the survival of patients with type III tumors between those with positive and negative lymph nodes (p<0.001). However, there was no such difference in patients with type II tumors. In a multivariate analysis, lymph node metastasis, age and the depth of tumor invasion were all found to be independent prognostic factors. Conclusions: The prognosis of patients with lymph node metastasis of type III adenocarcinoma of the esophagogastric junction was found to be extremely poor. An aggressive treatment after surgery may therefore be necessary to improve the survival of this population..
44. Eriko Tokunaga, Eiji Oki, Akinori Egashira, Noriaki Sadanaga, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Deregulation of the akt pathway in human cancer, Current Cancer Drug Targets, 10.2174/156800908783497140, 8, 1, 27-36, 2008.02, Akt (protein kinase B) is a serine/threonine kinase which is a central regulator of widely divergent cellular processes including proliferation, differentiation, migration, survival and metabolism. Akt is activated by a variety of stimuli, through growth factor receptors, in phosphatidylinositol 3-kinase (PI3K)-dependent manner. Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). A disruption of normal Akt/PKB/PTEN signaling frequently occurs in many human cancers, which plays an important role in cancer development, progression and therapeutic resistance. Numerous studies have revealed the blockage of Akt signaling to result in apoptosis and growth inhibition of tumor cells. Therefore, this signaling pathway, including both upstream and downstream of Akt, has recently attracted considerable attention as a new target for effective cancer therapeutic strategies. In fact, many inhibitors of Akt pathway have been identified and clinical studies of some agents are ongoing. In this review, we describe Akt signaling pathway components and its cellular functions as well as the alterations in human cancers and the therapeutic approaches for targeting the Akt pathway in cancer..
45. Yoshihiko Maehara, Akinori Egashira, Eiji Oki, Yoshihiro Kakeji, Teruhisa Tsuzuki, DNA repair dysfunction in gastrointestinal tract cancers, Cancer Science, 10.1111/j.1349-7006.2007.00671.x, 99, 3, 451-458, 2008.02, The DNA repair system surveys the genome, which is always suffering from exposure to both exogenous as well as endogenous mutagens, to maintain the genetic information. The fact that the basis of this DNA repair system is highly conserved, from prokaryote to mammalian cells, suggests the importance of precise genome maintenance mechanisms for organisms. In the past 15 years, considerable progress has been made in understanding how repair processes interact and how disruptions of these mechanisms lead to the accumulation of mutations and carcinogenesis. In 1993, two groups reported that DNA mismatch repair could be associated with hereditary non-polyposis colorectal cancer, indicating a connection between faulty DNA repair function and cancer. More recently, an inherited disorder of DNA glycosylase, which removes mutagenic oxidized base from DNA, has been reported in individuals with a predisposition to multiple colorectal adenomas and carcinomas. This is the first report that directly indicates the role of the repair of oxidative DNA in human inherited cancer. Studies from gene knockout mice have elucidated the principal role of these repair systems in the process of carcinogenesis. Moreover, clinical samples derived from cancer patients have shown the direct involvement. This review focuses on the function of DNA mismatch repair and oxidative DNA/nucleotide repair among various DNA repair systems in cells, both of which are essentially involved in the carcinogenesis of gastrointestinal tract cancer..
46. Masaru Morita, R. Yoshida, K. Ikeda, A. Egashira, E. Oki, N. Sadanaga, Y. Kakeji, Y. Ichiki, K. Sugio, K. Yasumoto, Y. Maehara, Acute lung injury following an esophagectomy for esophageal cancer, with special reference to the clinical factors and cytokine levels of peripheral blood and pleural drainage fluid, Diseases of the Esophagus, 10.1111/j.1442-2050.2007.00725.x, 21, 1, 30-36, 2008.02, Acute lung injury (ALI) is one of most serious complications to occur after an esophagectomy for esophageal cancer. However, the pathogenesis of ALI is still unclear. The cytokine levels of pleural drainage fluid as well as peripheral blood were measured in 27 patients who had undergone an extended radical esophagectomy. Both the clinical factors and cytokine levels were compared between 11 patients with (group I) and 16 without ALI (group II). ALI occurred more frequently in patients who underwent colon interposition than in those who received a gastric tube reconstruction (86% vs 25%, P = 0.009). The operation time of group I was significantly longer than that of group II. A logistic regression analysis revealed colon interposition to be an independent factor associated with the ALI (P < 0.05). Postoperative anastomotic leakage and systemic inflammatory response syndrome (SIRS) occurred more frequently in group I than in group II (P < 0.01). Both the serum interleukin-6 (IL-6) and IL-8 levels of group I were significantly higher than those of group II. IL-1β and tumor necrosis factor-α were undetectable in the peripheral blood, whereas they were detectable in the pleural effusion. The IL-1β of pleural effusion was higher in group I than group II. In conclusion, greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extra-thoracic site, such as necrosis and local infection around anastomosis may therefore be the second attack. Furthermore, ALI may cause not only SIRS but also other complications such as anastomotic leakage..
47. Eiji Oki, Yoshihiro Kakeji, Akinobu Taketomi, Yoichi Yamashita, Kippei Ohgaki, Noboru Harada, Tomohiro Iguchi, Kotaro Shibahara, Noriaki Sadanaga, Masaru Morita, Yoshihiko Maehara, Transient Elastography for the prediction of oxaliplatin-associated liver injury in colon cancer patients
A preliminary analysis, Journal of Gastrointestinal Cancer, 10.1007/s12029-009-9063-1, 39, 1-4, 82-85, 2008.03, Objective: The prognosis of advanced colon cancer has improved significantly over the last decade since new chemotherapy regimens including oxaliplatin have been developed. However, oxaliplatin-induced liver injury and characterized hepatic hemostatic status can occur after chemotherapy. The assessment of this type of liver injury is often difficult. Methods: Elastography (Fibroscan™) was used to evaluate liver injury in five cases before and after 5-FU, leucovorin, and oxaliplatin combination (FOLFOX) treatment. Results: A clear change was observed in the stiffness of liver after chemotherapy within 48 h, and the hepatic stiffness was normalized in most cases after 2 weeks. Among the five patients, one patient showed aberrant elevation after a FOLFOX treatment, and the patient showed liver injury pathologically. Conclusion: Elastography is a good tool for evaluating hepatic injury after FOLFOX treatment..
48. Tadashi Koga, Masaru Morita, Koujiro Nishida, Eiji Oki, Yoshihiro Kakeji, Yoshihiko Maehara, Successful treatment of tracheomediastinal fistula after tracheal injury obtained during esophagectomy using the pectoralis major muscle
A case report, Esophagus, 10.1007/s10388-007-0141-9, 5, 1, 41-44, 2008.03, When tracheal injury occurs during esophagectomy, it is a very serious and frequently fatal complication. We experienced a case of intractable tracheomediastinal fistula caused by tracheal injury during esophagectomy that was successfully repaired using a pedicle flap of the left pectoralis major muscle. A 55-year-old Japanese man who had congenital right aortic arch was referred to our hospital with a complaint of dysphagia. He had a type 2 carcinoma from the distal part of the cervical esophagus to the upper thoracic esophagus, 4.5 cm in length and attached to the membranous wall of the trachea. Subtotal esophagectomy was performed with left thoracotomy. The tumor adhered tightly to the membranous portion of the trachea, and the trachea was injured during removal of the tumor. The laceration was directly sutured and covered with a latissimus dorsi muscle flap. However, a tracheomediastinal fistula became enlarged and the left subclavian artery became exposed. Repair of the fistula was performed 31 days after the first operation: a permanent tracheotomy was made, laryngectomy was performed, and the fistula was filled with a pedicle flap of the pectoralis major muscle. The postoperative course was uneventful and the patient's general condition improved. The use of a pectoralis major muscle flap was effective for repairing the tracheomediastinal fistula..
49. Eiji Oki, Hidefumi Higashi, Takuya Honboh, Seiji Haraoka, Toshiro Okuyama, Michio Yoshida, Huge gastric carcinoma showing an exophytic growth pattern
A case report and review of the literature, Journal of Gastrointestinal Cancer, 10.1007/s12029-008-9047-6, 39, 1-4, 42-45, 2008.03, Case Report: We herein report a case of huge gastric carcinoma showing an exophytic growth pattern. The gastric carcinoma measured 160×130 mm in size. A radical resection was judged to be impossible preoperatively since the tumor invasion of the pancreas and liver was demonstrated on computed tomography. A pancreaticoduodenectomy combined with a resection of the transverse colon was performed. A pathological examination demonstrated the tumor to directly invade the pancreas and transverse colon; however, no metastasis was observed in the regional lymph nodes. The patient is alive and doing well without any recurrence at 5 years postoperatively. Discussion: To obtain a better prognosis for huge gastric carcinoma showing an exophytic growth pattern, extended radical surgery is recommended since the size of the exophytic mass sometimes does not indicate the extent of the tumor..
50. Masaru Morita, Rintaro Yoshida, Keisuke Ikeda, Akinori Egashira, Eiji Oki, Noriaki Sadanaga, Yoshihiro Kakeji, Takeharu Yamanaka, Yoshihiko Maehara, Advances in esophageal cancer surgery in Japan
An analysis of 1000 consecutive patients treated at a single institute, Surgery, 10.1016/j.surg.2007.12.007, 143, 4, 499-508, 2008.04, Background: In Japan, most esophageal cancers are squamous cell carcinomas, and the results of esophagectomy have improved remarkably in recent years. The object of this study was to evaluate advances in operative therapy for esophageal cancer in Japan. Method: We evaluated mortality, morbidity, and prognosis in 1000 consecutive patients who underwent esophagectomy for esophageal cancer at a single institution in Japan. The patients were divided into 3 groups according to the period when esophagectomy was performed: Group I (n = 197), 1964-1980; group II (n = 432), 1981-1993; and group III (n = 371), 1993-2006. Results: The incidence of squamous cell carcinoma was 94%. The morbidity rates were 62%, 38%, and 33 %, in groups I, II, and III, respectively (P < 0.01, groups I vs II and III), and the in-hospital mortality rates were 14.2%, 5.1%, and 2.4%, respectively (P < 0.01, between each group). The 5-year overall survival rate was 30% (14%, 27%, and 46% in groups I, II, and III, respectively; P < 0.0001). Multivariate analysis revealed age, gender, depth of invasion, node metastasis, distant metastasis, curability, extent of lymphadenectomy, resectability, and the period when the operation was performed as independent prognostic factors. Conclusion: Generally, esophagectomy has been performed safely without critical complications; however, the prognosis has improved remarkably with advances in surgical techniques and treatment modalities..
51. Masaru Morita, Akinori Egashira, Rintaro Yoshida, Keisuke Ikeda, Kippei Ohgaki, Kotaro Shibahara, Eiji Oki, Noriaki Sadanaga, Yoshihiro Kakeji, Yoshihiko Maehara, Esophagectomy in patients 80 years of age and older with carcinoma of the thoracic esophagus, Journal of gastroenterology, 10.1007/s00535-008-2171-z, 43, 5, 345-351, 2008.05, Background: The purpose of this study was to clarify the indications for an esophagectomy in elderly patients (especially patients over 80 years of age) with esophageal cancer. Methods: A total of 668 patients with thoracic esophageal cancer who underwent an esophagectomy by the transthoracic approach were divided into three groups according to age, namely, groups I (>80 years, n = 16), II (70-79 years, n = 158), and III (≤69 years, n = 494). In group I, surgery was only done in patients with PS 0 or 1, as well as normal cardiac and pulmonary functions. Results: The incidence of preoperative pulmonary risk was 16% and 7% in groups II and III, respectively (P < 0.01). The morbidity rates of group II and III were 42% and 32%, respectively (P < 0.05). Pulmonary complications occurred in 18% and 10%, respectively, and cardiovascular complications occurred in 11% and 4%, respectively (P < 0.01). In group I, the morbidity and 30-day mortality rates were 25% and 0%, respectively, and pulmonary and cardiovascular complications occurred only in one patient each (6%). No significant differences were observed in cause-specific survival. Conclusions: In the elderly, preoperative pulmonary risk is frequently present, and careful perioperative management is needed while paying special attention to pulmonary and cardiovascular complications. However, when the indications for surgery can be strictly determined, an esophagectomy is considered a viable treatment alternative with satisfactory prognosis even in patients 80 years of age and older without any increased morbidity or mortality..
52. Tadashi Koga, Eriko Tokunaga, Yasushi Sumiyoshi, Eiji Oki, Shinya Oda, Ikuo Takahashi, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Detection of circulating gastric cancer cells in peripheral blood using real time quantitative RT-PCR, Hepato-gastroenterology, 55, 84, 1131-1135, 2008.05, Background/Aims: Detection of occult cancer cells in peripheral blood or bone marrow has recently received a great deal of attention regarding the prediction of postoperative recurrence of the cancer, and for novel strategies of adjuvant therapy. This study addresses the detection of circulating tumor cells in peripheral blood in patients with gastric cancer using Quantitative RT-PCR. Methodology: Common mRNA targets for RT-PCR for detection of small numbers of cancer cells in gastric cancer are CK18, CK19, CK20, and CEA. Ten milliliter of peripheral venous blood was taken from 14 healthy Japanese volunteers and 101 patients with gastric cancer. Samples were analyzed using real-time TaqMan technology and a Model 7700-sequence system. The group of gastric cancer patients included 69 individuals with curative disease on preoperative diagnosis and 32 individuals with a non-curative operation or recurrence of the disease. Results: The number of CK19 and CK20 mRNA copies was significantly increased in patients with a non-curative operation or recurrence of gastric cancer (CK19; p=0.0087, CK20; p=0.0022) compared with healthy volunteers. Cut-off levels of CK19 or CK20 copy numbers were determined by the maximum value of healthy volunteers. For CK19, there were 61 (88.4%) negative cases and 8 (11.6%) positive cases in 69 individuals with curative gastric cancer. There was a significant difference in tumor stages between CK19 positive and negative patients with curative disease on preoperative diagnosis. For CK20, there were 59 (85.5%) negative cases and 10 (15.5%) positive cases. There was no statistical difference between CK20 positive and negative cases for all clinicopathological factors. On postoperative day 14, there was a significant difference between positive and negative cases regarding tumor size, tumor stage, and lymph node metastasis for CK19, and tumor stage and lymph node metastasis for CK20. Five-year survival rates of patients with CK19 positive or negative cases were 50.0% or 79.0%, respectively (p=0.0347). While, for CK20, 5-year survival rates for positive cases was 51.9%, and for negative cases 78.9% (p=0.0490). Conclusions: Micrometastases of gastric cancer can be detected in circulating peripheral blood using quantitative real-time RT-PCR. CK19 is a better marker than CK18, CK20 and CEA, and could be clinically useful to estimate prognosis or to make a postoperative strategy of adjuvant treatment..
53. Yoko Yamaji, Shigeo Yoshida, Keijiro Ishikawa, Akihito Sengoku, Kota Sato, Ayako Yoshida, Rumi Kuwahara, Kenoki Ohuchida, Eiji Oki, Hiroshi Enaida, Kimihiko Fujisawa, Toshihiro Kono, Tatsuro Ishibashi, TEM7 (PLXDC1) in neovascular endothelial cells of fibrovascular membranes from patients with proliferative diabetic retinopathy, Investigative Ophthalmology and Visual Science, 10.1167/iovs.07-1249, 49, 7, 3151-3157, 2008.07, PURPOSE. Proliferative diabetic retinopathy (PDR) results from the formation of fibrovascular membranes (FVMs) in the posterior fundus that can lead to a severe decrease of vision. Tumor endothelial marker 7 (TEM7) is a protein that is highly expressed in the endothelial cells of tumors, but whether it plays a role in FVMs is unknown. The purpose of this study was to determine whether TEM7 is associated with the formation of FVMs. METHODS. FVMs were obtained during vitrectomy from patients with PDR. RT-PCR was performed to determine the level of expression of the mRNA of TEM7. The splice variants of TEM7 were identified by direct sequencing. Immunohistochemical analyses and in situ hybridization was performed to determine the sites of TEM7 in the FVMs. RESULTS. The level of the mRNA of TEM7 was high in 10 of 10 FVMs but was barely detectable in the five idiopathic epiretinal membranes. Direct sequencing of subcloned TEM7 PCR products revealed several splice variants (intracellular, secreted, and membrane-bound forms of TEM7) in the FVMs. Immunohistochemical analysis showed a colocalization of TEM7 and CD34, an endothelial cell marker, in most of the neovascular endothelial cells in the FVMs. Immunoelectron microscopy revealed that membrane-bound TEM7 was expressed on the luminal surfaces of the vascular endothelial cells of FVMs. CONCLUSIONS. This study indicates that TEM7 may play a significant role in the proliferation and maintenance of neovascular endothelial cells in the FVMs. If correct, TEM7 may be a molecular target for new diagnostic and therapeutic strategies for PDR..
54. Eiji Oki, Yoshihiro Kakeji, Kippei Ohgaki, Kohji Saeki, Masaru Morita, Yasunori Emi, Yoshihiko Maehara, Impact of single nucleotide polymorphisms in glutathione S transferase gene GSTP1 in the treatment with oxaliplatin based chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 35, 7, 1094-1096, 2008.07, Oxaliplatin has been the main treatment of choice in colorectal cancer in advanced settings. However, cellular mechanisms for the uptake, intracellular distribution and efflux of oxaliplatin are unknown. GST(glutathione S transferase)is member of a superfamily of metabolic enzymes that play an important role in the cell defense system. Current data suggest that GST-pi is associated with increased resistance to platinum-based chemotherapy. Specific roles for the single nucleotide polymorphisms in GST-pi gene GSTP1 in the treatment with oxaliplatin based chemotherapy, have been demonstrated in recent years..
55. Koji Ando, Eiji Oki, Yoshihiro Kakeji, Masahiko Sugiyama, Hiroshi Saeki, Kazuya Endo, Masaru Morita, Yasunori Emi, Yoshihiko Maehara, Hepatic artery infusion chemotherapy to three liver metastasis cases in which systemic chemotherapy was impossible or ineffective, Gan to kagaku ryoho. Cancer & chemotherapy, 35, 12, 2192-2194, 2008.11, Recently, standard therapies for either gastric cancer or colorectal cancer have been established through the development of multidrug systemic chemotherapy and the appearance of molecular targeting drugs. For example, either FOLFIRI or FOLFOX therapy is normally chosen for the treatment of unresectable liver metastasis from colorectal cancer. On the other hand, hepatic artery infusion (HAI) chemotherapy is generally used as only a second-line therapy. There are, however, some cases in which systemic chemotherapy is not indicated due to age and/or the risk of side effects. We herein report three cases that were treated by HAI after initially performing systemic chemotherapy in order to treat liver metastasis from either gastric cancer or colorectal cancer..
56. Eiji Oki, Yan Zhao, Rintaro Yoshida, Akinori Egashira, Kippei Ohgaki, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, The difference in p53 mutations between cancers of the upper and lower gastrointestinal tract, Digestion, 10.1159/000167864, 79, SUPPL. 1, 33-39, 2009.01, Background: p53 gene mutations have been reported in over half of all human cancers and they appear to occur in the early stage of cancer, thus indicating the important role that such mutations may play in the carcinogenesis of the digestive tract. This study investigated the differences in p53 abnormalities between cancers of the upper and lower gastrointestinal tract. Materials and Methods: The DNA of 354 specimens of gastrointestinal cancer (esophagus 85, stomach 112, colon 157) was extracted and then p53 gene mutations were investigated by direct sequencing; the loss of heterozygosity was also synchronously analyzed in all cases. Results: (1) p53 gene mutation: p53 gene mutations were found in 41 samples (48.2%) in the esophagus, 18 samples (16.0%) in the stomach and 36 samples (22.9%) in the colon. p53 mutations were more frequently identified in well-differentiated cancers and a close correlation was recognized between p53 mutations and loss of heterozygosity. (2) Mutation spectrum: the ratio of transversion was 43.9% in esophagus, 33.3% in stomach and 25.0% in the colon tumors. Reciprocally, the ratio of transition was 31.7, 66.7, and 72.2%, respectively. Discussion: The frequency of p53 transversion mutations was extremely high in the upper digestive tract, whereas transition mutations were more frequently observed in the lower digestive tract. The investigation of the spectrum of mutations in p53 is therefore expected to lead to a better understanding of the agents responsible for inducing cancer..
57. Takasuke Fukuhara, Akinori Egashira, Masakazu Imamura, Toru Ikegami, Eiji Oki, Yuji Soejima, Noriaki Sadanaga, Akinobu Taketomi, Takashi Yao, Masaru Morita, Yoshihiro Kakeji, Masazumi Tsuneyoshi, Yoshihiko Maehara, Proctocolectomy for colon cancer associated with ulcerative colitis a few months after living donor liver transplantation for primary sclerosing cholangitis
Report of a case, Surgery today, 10.1007/s00595-008-3779-6, 39, 1, 59-63, 2009.01, Colorectal cancer (CRC) frequently develops in patients with ulcerative colitis (UC). We report a case of CRC treated successfully by proctocolectomy 8 months after living donor liver transplantation (LDLT) for primary sclerosing cholangitis (PSC). The lesion was detected early, probably as a result of colonoscopic surveillance after LDLT. Thus, patients with a long history of UC, who undergo LDLT for PSC, should be followed up with regular surveillance colonoscopy. Moreover, surgery, such as radical resection of the colon and rectum should be performed without delay, even shortly after LDLT. To our knowledge, this is the first report of a patient undergoing proctocolectomy after LDLT..
58. Yasushi Toh, Yoshihisa Sakaguchi, Osamu Ikeda, Eisuke Adachi, Kippei Ohgaki, Yoichi Yamashita, Eiji Oki, Kazuhito Minami, Takeshi Okamura, The triangulating stapling technique for cervical esophagogastric anastomosis after esophagectomy, Surgery today, 10.1007/s00595-008-3827-2, 39, 3, 201-206, 2009.03, Purpose: To evaluate the safety and feasibility of the triangulating stapling technique (TST) for cervical esophagogastric anastomosis after esophagectomy (CEGA). Methods: The subjects were 123 patients who underwent transthoracic esophagectomy with three-field lymph node dissection and reconstruction with a 3.5-cm wide gastric tube, for thoracic esophageal cancer. We performed the TST for CEGA in 33 patients operated on after December, 2006 (TST group) and hand-sewn anastomosis in 90 patients operated on between 2002 and 2006 (HSA group). Results: In the TST group, CEGA was performed in an end-to-end fashion using three linear staplers. The first anastomosis was applied to the posterior walls of the remnant esophagus and gastric tube in an inverted fashion. The second and the third anastomoses were done in an everted fashion to make the anterior wall. The end-to-end HSA was performed with interrupted sutures using 4-0 absorbable material. Anastomotic leakage occurred in only 1 (3.0%) of the 33 TST patients, but in 13 (14.4%) of the 90 HSA patients (P = 0.07). The frequency of anastomotic stenosis was 9.1% and 25.6% in the TST and HSA groups, respectively (P < 0.05). Conclusions: Cervical esophagogastric anastomosis using TST may reduce the frequency of anastomotic leakage and stenosis. This technique is a safe and reliable alternative for CEGA after esophagectomy..
59. Eiji Oki, Yan Zhao, Rintaro Yoshida, Takanobu Masuda, Koji Ando, Masahiiko Sugiyama, Eriko Tokunaga, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Checkpoint with forkhead-associated and ring finger promoter hypermethylation correlates with microsatellite instability in gastric cancer, World Journal of Gastroenterology, 10.3748/wjg.15.2520, 15, 20, 2520-2525, 2009.05, Aim: To examine the methylation status of the promoter region of the checkpoint with forkhead-associated and ring finger (CHFR) and microsatellite mutator status in 59 primary gastric cancers. Methods: We investigated the promoter methylation of CHFR in 59 cases of gastric cancer using methylation-specific PCR. Five microsatellite loci were analyzed using high-intensity microsatellite analysis reported previously, and p53 gene mutations were investigated by direct sequencing. Results: Twenty cases (33.9%) showed promoter methylation and no relation was observed with the clinicopathological factors. We found that the promoter methylation of CHFR was frequently accompanied with microsatellite instability (MIN). Seven of 20 (35.0%) cases showed MIN in hypermethylation of the CHFR tumor, while three of 39 (7.7%) cases showed MIN in the non-methylated CHFR tumor (P < 0.01). However, we failed to find any relationship between CHFR methylation and p53 mutation status. Conclusion: The coordinated loss of both the mitotic check point function and mismatch repair system suggests the potential to overcome the cell cycle check point, which may lead to an accumulation of mutations. However, the p53 mutation was not related to hypermethylation of the CHFR promoter and MIN, which indicates that an abnormality in p53 occurs as an independent process from the mismatch repair deficiency in carcinogenesis..
60. Yoshihiro Kakeji, Eiji Oki, Akinori Egashira, Noriaki Sadanaga, Ikuo Takahashi, Masaru Morita, Yasunori Emi, Yoshihiko Maehara, Phase II study of biweekly docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer, Oncology, 10.1159/000226111, 77, 1, 49-52, 2009.07, Objective: This phase II study evaluated the toxicity and efficacy of a novel dosing schedule of docetaxel and S-1 as treatment for advanced gastric cancer. Methods: Patients with measurable advanced or recurrent gastric cancer and no prior exposure to the investigational drugs were treated with intravenous docetaxel 35 mg/m2 on days 1 and 15, and oral S-1 80 mg/m 2/day on days 1-14 every 4 weeks. The primary endpoint was objective response. Results: Thirty-five eligible patients were enrolled and received a total of 151 cycles of treatment (median 3, range 1-19). One complete response and 13 partial responses were observed, with an overall response rate of 40% (95% CI: 24-56%). Median progression-free survival and median overall survival times were 4.5 and 14.2 months, respectively. The most common grade 3-4 toxicities were neutropenia (23%) and leukocytopenia (15%). Conclusion: Biweekly docetaxel combined with S-1 is active in advanced or recurrent gastric cancer, and can be administered with proper management of adverse events in an outpatient clinic..
61. Yasushi Toh, Eiji Oki, Kazuhito Minami, Takeshi Okamura, Evaluation of the feasibility and safety of immediate extubation after esophagectomy with extended radical three-field lymph node dissection for thoracic esophageal cancers, Esophagus, 10.1007/s10388-009-0198-8, 6, 3, 167-172, 2009.09, Background: No standard procedure exists in respiratory management, including mechanical ventilation, which is commonly administered, after thoracic esophagectomy for esophageal cancer. Methods: Various perioperative clinical parameters and complications were retrospectively compared between the patients who underwent mechanical ventilation (MV group, n = 38) and those who were extubated immediately (immediate extubation: IE group, n = 75), following transthoracic esophagectomy with three-field lymph node dissection (3FLND) for thoracic esophageal cancers. Results: There were no significant differences between the two groups in the early postoperative clinical course. The frequencies of postoperative complications were 39% and 47% in the IE and MV groups, respectively, and pulmonary complications tended to occur more frequently in the MV group (23.7%) than in the IE group (12.0%). Mobilization of the patients was significantly earlier in the IE group than in the MV group (P < 0.0001). Conclusions: IE is feasible and safe even after transthoracic esophagectomy with 3FLND. To avoid the possible disadvantages of MV after surgery, IE can be a standard protocol for postoperative management after transthoracic esophagectomy with radical lymph node dissection..
62. Eiji Oki, Yoshihiro Kakeji, Yan Zhao, Rintaro Yoshida, Koji Ando, Takanobu Masuda, Kippei Ohgaki, Masaru Morita, Yoshihiko Maehara, Chemosensitivity and survival in gastric cancer patients with microsatellite instability, Annals of Surgical Oncology, 10.1245/s10434-009-0580-8, 16, 9, 2510-2515, 2009.09, Introduction: Conflicting data exist regarding the relevance of high-frequency microsatellite instability (MSI-H) for predicting the prognosis and benefits of 5-fluorouracil (5-FU)-based chemotherapy. This study investigated the usefulness of MSI as either a prognostic indicator or predictor of distinct clinical attributes regarding the use of adjuvant chemotherapy with 5-FU and its analogues in gastric cancer. Materials and methods: Data and tumor specimens were collected from 240 gastric cancer patients from 1993 to 2002. Five microsatellite loci were analyzed using a high-intensity microsatellite analysis reported previously. A Cox proportional hazard model was used to compare the clinical data and survival as well as any associations between MSI and 5-FU treatment status of patients with MSI or microsatellite stability (MSS) gastric cancers. A 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted in 168 cases to investigate chemosensitivity to 5-FU. Results: This analysis identified 22 MSI-H (9.4%), 25 MSI-L (10.7%), and 193 MSS (79.9%) tumors. Gastric cancer with MSI-H tended to have increased likelihood to show higher age, antral location of the tumor, and lymph vessel involvement (P < 0.05). Univariate analyses failed to show any difference between the MSI-H and MSS/MSI-L groups with respect to overall survival. Furthermore, survival after the administration of 5-FU did not correlate with MSI status, and MSI was not associated with 5-FU sensitivity by MTT assay. Conclusion: The results of this study indicate that MSI status has no clear influence on overall survival or response to 5-FU in gastric cancer..
63. Noritaka Matsumoto, Eiji Oki, Masaru Morita, Yoshihiro Kakeji, Akinori Egashira, Noriaki Sadanaga, Yoshihiko Maehara, Successful treatment of acute esophageal necrosis caused by intrathoracic gastric volvulus
Report of a case, Surgery today, 10.1007/s00595-008-3983-4, 39, 12, 1068-1072, 2009.12, Gastric volvulus is a potentially lethal condition. We report a case of esophageal hiatal hernia with strangulation of the esophagus and stomach caused by gastric volvulus. A 79-year-old woman was admitted to our hospital in a state of shock, and investigations showed necrotic changes in most of her distal esophagus and gastric body. Thus, we performed an emergency total gastrectomy and transhiatal esophagectomy, followed 3 months later by successful reconstruction of the esophagus using the jejunum. Occasionally, a large hiatal hernia accompanies gastric volvulus; however, the extent of esophageal necrosis observed in this patient is very unusual. Although a large hiatal hernia is usually a chronic disorder, surgical treatment is recommended, considering the risk of serious complications..
64. Yan Zhao, Eiji Oki, Koji Ando, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, The impact of a high-frequency microsatellite instability phenotype on the tumor location-related genetic differences in colorectal cancer, Cancer Genetics and Cytogenetics, 10.1016/j.cancergencyto.2009.09.009, 196, 2, 133-139, 2010.01, The purpose of this study was to evaluate the genetic background of colorectal cancer according to the tumor site, and to investigate the impact of the genetic features regarding the lesion location of colorectal cancer. Microsatellite instability (MSI), DNA index, and the mutation and loss of heterozygosity of the TP53 gene were systemically examined in 180 Japanese colorectal cancer cases. The correlation between these genetic features and clinicopathologic factors was analyzed. A logistic regression was undertaken to analyze the association between genetic features and tumor locations. The data demonstrated location-related genetic differences in colorectal cancer. The proximal subset was distinct in patterns of genomic instability and TP53 gene defects. The genetic features of distal colon cancers paralleled those of rectal cancers. Intriguingly, a multivariate analysis implicated MSI as the only factor significantly associated with tumor location. When MSI tumors were excluded, the statistical association between tumor location and alternations in the DNA index and TP53 vanished. The location-related differences of colorectal cancer were derived from the unequal distribution of the MSI tumors. On the other hand, the microsatellite stable colorectal cancers were genetically homogeneous regardless of the tumor location. Therefore, instead of tumor location, microsatellite status should be a major focus for the study of colorectal cancers in the future..
65. R. Yoshida, M. Morita, K. Ando, T. Masuda, H. Saeki, E. Oki, N. Sadanaga, T. Nakashima, Y. Kakeji, Y. Maehara, Salvage esophagectomy after definitive chemoradiotherapy for synchronous double cancers of the esophagus and head-and-neck, Diseases of the Esophagus, 10.1111/j.1442-2050.2009.00973.x, 23, 1, 59-63, 2010.01, Head-and-neck cancer is frequently associated with esophageal cancer. Because the operative procedures for these synchronous double cancers are too invasive, definitive chemoradiotherapy tends to be applied as an initial treatment. A salvage esophagectomy for either recurrent or residual disease after definitive chemoradiotherapy in patients with such double cancer has never been reported. We reviewed 21 patients with esophageal cancer who underwent a salvage esophagectomy after definitive chemoradiotherapy. Among them, the treatment course of five patients who underwent a salvage esophagectomy for patients with synchronous double cancers of the esophagus and head-and-neck region was analyzed. Because head-and-neck cancer was well controlled after chemoradiotherapy in all five patients, a salvage esophagectomy was indicated for either recurrent or residual esophageal cancer after definitive chemoradiotherapy. Anastomotic leakage developed in four patients; however, no other complications including pulmonary complications were recognized. All of them were discharged to home and three of them are still alive without any recurrence for 20-43 months. A salvage esophagectomy should be considered as a treatment option for either recurrent or residual esophageal cancer with well-controlled head-and neck cancer after definitive chemoradiotherapy when complete resection of the esophagus is expected..
66. Masaru Morita, Keisuke Ikeda, Masahiko Sugiyama, Hiroshi Saeki, Akinori Egashira, Keiji Yoshinaga, Eiji Oki, Noriaki Sadanaga, Yoshihiro Kakeji, Junichi Fukushima, Yoshihiko Maehara, Repair using the pectoralis major muscle flap for anastomotic leakage after esophageal reconstruction via the subcutaneous route, Surgery, 10.1016/j.surg.2009.08.013, 147, 2, 212-218, 2010.02, Background: Anastomotic leakage with an intractable cutaneous fistula frequently develops after an esophagectomy and reconstruction via the subcutaneous route. Methods: A pectoralis major muscle (PMM) flap was used for the treatment of 6 patients with esophageal cancer who developed anastomotic leakage with fistula after reconstruction via the subcutaneous route. A gastric tube and colon had been used for reconstruction in 2 and 4 patients, respectively. A trimming and repair of the leakage site was initially performed and the anastomotic site was then covered with a muscle flap. Results: Recurrent anastomotic leakage did not develop in 5 patients. Among these patients, oral intake was initiated from 11-15 days after the repair operation in 4 patients. A patient having recurrent anastomotic leakage after a repair operation recovered well with conservative therapy. Conclusion: The coverage with a PMM flap over the repair site is a simple method for preventing the development of recurrent leakage after a repair operation. Even when recurrent anastomotic leakage has occurred after this operation, healing is normally expected by means of conservative treatment. We, therefore, recommend this method for the repair of intractable anastomotic leakage after reconstruction via the subcutaneous route for esophageal cancer..
67. Koji Ando, Yosihiro Kakeji, Hiroyuki Kitao, Makoto Iimori, Yan Zhao, Rintaro Yoshida, Eiji Oki, Keiji Yoshinaga, Takuya Matumoto, Masaru Morita, Yoshihisa Sakaguchi, Yoshihiko Maehara, High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer, Cancer Science, 10.1111/j.1349-7006.2009.01457.x, 101, 3, 639-645, 2010.03, Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real-time RT-PCR in several gastric cancer cell lines. Ninety-one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN-28 and SNU-1 were transfected with full-length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki-67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer..
68. Yasushi Toh, Eiji Oki, Kazuhito Minami, Takeshi Okamura, Follow-up and recurrence after a curative esophagectomy for patients with esophageal cancer
The first indicators for recurrence and their prognostic values, Esophagus, 10.1007/s10388-009-0221-0, 7, 1, 37-43, 2010.03, Background: No standardized methods exist for the follow-up and treatment of recurrence after a curative esophagectomy for patients with thoracic esophageal cancers. Methods: One hundred seventy-five patients with thoracic esophageal cancer underwent a curative resection and were followed up during a median period of 3.0 years (3 months-18 years). The time to recurrence, the first indicators (FIs) to suspect recurrence, and the factors predictive of prognosis after recurrence were investigated. Results: Recurrence occurred in 72 (41.1%) of 175 patients. Forty (55.6%) and 22 (30.6%) of 72 cases presented with recurrences in the first and second year after the initial operation, respectively. Clinical visit (anamnesis and physical examination), tumor markers, and imaging were FIs in 39 (54.2%), 33 (45.8%), and 49 (68.1%) of 72 patients with recurrence, respectively. Imaging was the exclusive FI in 19 (26.4%) cases. A multivariate analysis showed the favorable prognostic factors after recurrence to be recurrence later than 1 year after the initial operation and a case in which the FI was only imaging. Conclusions: Intensive follow-up is required in the first 2 years after surgery, and early detection of recurrence is important. The accumulation of clinical data based on a fixed schedule with consensus is necessary to obtain more definite evidence for the diagnosis and treatment of recurrent esophageal cancer..
69. Yasushi Toh, Eiji Oki, Kippei Ohgaki, Yasuo Sakamoto, Shuhei Ito, Akinori Egashira, Hiroshi Saeki, Yoshihiro Kakeji, Masaru Morita, Yoshihisa Sakaguchi, Takeshi Okamura, Yoshihiko Maehara, Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus
Molecular mechanisms of carcinogenesis, International Journal of Clinical Oncology, 10.1007/s10147-010-0057-6, 15, 2, 135-144, 2010.04, Esophageal cancer is the eighth most common incident cancer in the world and ranks sixth among all cancers in mortality. Esophageal cancers are classified into two histological types; esophageal squamous cell carcinoma (ESCC), and adenocarcinoma, and the incidences of these types show a striking variety of geographic distribution, possibly reflecting differences in exposure to specific environmental factors. Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC. Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated carcinogenesis, while ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Cigarette smoke contains more than 60 carcinogens and there are strong links between some of these carcinogens and various smoking-induced cancers; these mechanisms are well established. Synergistic effects of cigarette smoking and alcohol consumption are also observed in carcinogenesis of the upper aerodigestive tract. Of note, intensive molecular biological studies have revealed the molecular mechanisms involved in the development of ESCC, including genetic and epigenetic alterations. However, a wide range of molecular changes is associated with ESCC, possibly because the esophagus is exposed to many kinds of carcinogens including alcohol and cigarette smoke, and it remains unclear which alterations are the most critical for esophageal carcinogenesis. This brief review summarizes the general mechanisms of alcohol- and smoking-induced carcinogenesis and then discusses the mechanisms of the development of ESCC, with special attention to alcohol consumption and cigarette smoking..
70. Yoshihisa Sakaguchi, Osamu Ikeda, Kippei Ohgaki, Eiji Oki, Yoshiki Chinen, Yasuo Sakamoto, Kazuhito Minami, Yasushi Toh, Takeshi Okamura, Totally laparoscopic gastrectomy for gastric cancer associated with recklinghausen's disease, Diagnostic and Therapeutic Endoscopy, 10.1155/2010/682401, 2010.08, This paper documents the first case of gastric cancer associated with Recklinghausen's disease, which was successfully treated by a totally laparoscopic operation. A 67-year-old woman with Recklinghausen's disease was referred to this department to undergo surgical treatment for early gastric cancer. The physical examination showed multiple cutaneous neurofibromas throughout the body surface, which made an upper abdominal incision impossible. Laparoscopic surgery requiring only small incisions was well indicated, and a totally laparoscopic distal gastrectomy with lymph node dissection was performed. Billroth I reconstruction was done intra-abdominally using a delta-shaped anastomosis. The patient followed a satisfactory postoperative course with no complications. Since the totally laparoscopic gastrectomy has many advantages over open surgery, it should therefore be preferentially used as a less invasive treatment in the field of gastric cancer..
71. Hiroshi Saeki, Masaru Morita, Noboru Harada, Norifumi Harimoto, Shigeyuki Nagata, Mitsuhiro Miyazaki, Tadashi Koga, Eiji Oki, Yoshihiro Kakeji, Yoshihiko Maehara, A survey of the effects of sivelestat sodium administration on patients with postoperative respiratory dysfunction, Surgery today, 10.1007/s00595-010-4296-y, 40, 11, 1034-1039, 2010.11, Purpose: To clarify the clinical significance of sivelestat sodium (SIV) administration, we surveyed the status of 40 patients treated with SIV for respiratory dysfunction following surgery. Methods: The subjects were patients who received SIV administration due to systemic inflammatory response syndrome (SIRS) and respiratory dysfunction (PaO2/FIO2 ratio ≥300 mmHg) after surgery at the Department of Surgery and Science, Kyushu University, and related facilities between April and December 2008. Results: The most frequent underlying condition was perforation of the digestive tract, followed by cancer of the upper digestive organs. The main causes of SIRS were surgical stress and infection. The mean P/F ratio at the initiation of SIV administration was 185.5 ± 72.0 mmHg. The ratio increased, and the number of SIRS-related factors decreased with time after SIV administration. Sivelestat sodium was administered within 24 h after the onset of respiratory dysfunction in 87.5% of the patients, and the survival rate at 28 days after the initiation of SIV administration was 90.0%. Conclusion: Our findings suggest that multidisciplinary postoperative management, including the administration of SIV, during the early phase after the onset of respiratory dysfunction leads to improvements in respiratory function and survival..
72. Fusanori Yotsumoto, Eiji Oki, Eriko Tokunaga, Yoshihiko Maehara, Masahide Kuroki, Shingo Miyamoto, HB-EGF orchestrates the complex signals involved in triple-negative and trastuzumab-resistant breast cancer, International Journal of Cancer, 10.1002/ijc.25472, 127, 11, 2707-2717, 2010.12, A number of therapeutic strategies targeting epidermal growth factor receptor (EGFR) have not always led to success in the present state of breast cancer therapy. Notably, there is currently no way to treat trastuzumab- resistant and triple-negative breast cancer (TNBC). Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGFR ligands, was predominantly expressed in breast cancer and that treatment with crossreacting material 197 (CRM197), a specific inhibitor of HB-EGF, blocked ERK as well as AKT activation via complexes of EGFR and unknown growth factor receptors in TNBC or through complexes of EGFR and human epidermal growth factor receptor-2 in trastuzumab-resistant breast cancer, caused significant cell apoptosis and inhibited tumor growth. Accordingly, we can provide a novel concept that a certain EGFR ligand is recognized as a rational target against breast cancer. In addition, it is plausible that CRM197 could be an effective anticancer agent for molecularly targeted therapies..
73. Tomonori Nakanoko, Masaru Morita, Kippei Ohgaki, Tomoaki Sadanaga, Kohtaroh Shibahara, Eiji Oki, Yoshihiro Kakeji, Yoshihiko Maehara, ObturatorHernia which contained the fallopian tube in a young woman, Japanese Journal of Gastroenterological Surgery, 10.5833/jjgs.44.200, 44, 2, 200-204, 2011, A 29-year-old woman with lower abdominal pain, high fever, and a leukocyte count of 11,200_mm3 was found in An abdominal computed tomography (CT) to have a low-density mass in the right obturator canal suggesting right obturator hernia. After 2 days of conservative antibiotic treatment before mechanical ileusand ischemic change in some organs were recognized, she was referred forlower right quadrant tenderness and muscle guarding. Laparoscopic examination showed the right fallopian tube to be swollen and tightly incarcerated in the right obturator canal. The fallopian tube was removed from the canal and the pelvic obturator canal orifice was closed. The fallopian tube was nonnecrotic preserved. Obturator hernia in young woman is rare and fallopian tube incarceration has not, to our knowledge, been previously reported. The laparoscopic approach is thus useful for diagnosing and treating obturator hernia..
74. Yutaka Ogata, Shoji Tokunaga, Yasunori Emi, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Hirofumi Hasegawa, Noriaki Sadanaga, Hironori Samura, Fumihiko Fujita, Takaho Tanaka, Masaki Kitazono, Manabu Yamamoto, Tatsuma Morikita, Masafumi Inomata, Yoshihiro Kakeji, Kazuo Shirouzu, Yoshihiko Maehara, A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as second-line treatment for advanced colorectal cancer
A Japanese experience, Surgery today, 10.1007/s00595-010-4418-6, 41, 1, 84-90, 2011.01, Purpose: This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin, levoforinate, and infusional 5-fluorouracil (FOLFOX4) as a second-line therapy for Japanese patients with unresectable advanced or metastatic colorectal cancer. Methods: A total of 53 patients with progressive disease after first-line chemotherapy were enrolled in the study. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred, or the patient chose to discontinue the treatment. Results: Four patients were ineligible and one did not receive the protocol therapy. Therefore, the response rate, overall survival (OS), and progression-free survival (PFS) were evaluated in 48 patients; toxicity was evaluated in 52 patients, excluding the patient who had not received the protocol therapy. A partial response was observed in 10 patients. The overall response rate was 20.8% (95% confidence interval [CI], 10.5%-35.0%). The median PFS was 5.6 months (95% CI, 4.1-7.0 months) and the median OS was 19.6 months (95% CI, 11.4-24.3 months). The most frequently encountered grade 3/4 hematological symptom was neutropenia (43.1%). The toxicity profile was generally predictable and manageable. Conclusion: The results showed good tolerability and efficacy for second-line FOLFOX4 in patients with advanced colorectal cancer, thus indicating the promise of this regimen as an effective second-line therapy for advanced colorectal cancer in the Japanese population..
75. Rintaro Yoshida, Kaname Miyashita, Mayuko Inoue, Akiyoshi Shimamoto, Zhao Yan, Akinori Egashira, Eiji Oki, Yoshishiro Kakeji, Shinya Oda, Yoshihiko Maehara, Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer, European Journal of Human Genetics, 10.1038/ejhg.2010.216, 19, 3, 320-325, 2011.03, Genomic sequences encoding the 3′ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite- unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms..
76. Yo Ichi Yamashita, Eisuke Adachi, Yasushi Toh, Kippei Ohgaki, Osamu Ikeda, Eiji Oki, Kazuhito Minami, Yoshihisa Sakaguchi, Eiji Tsujita, Takeshi Okamura, Risk factors for early recurrence after curative hepatectomy for colorectal liver metastases, Surgery today, 10.1007/s00595-010-4471-1, 41, 4, 526-532, 2011.04, Purpose. With the broadening indications for hepatectomy to treat colorectal liver metastases (CRLM), early recurrence is a major problem. The aim of this study is to identify risk factors of early recurrence, defi ned as recurrence within 1 year after surgery. Methods. A retrospective analysis was performed on 121 consecutive patients who underwent hepatectomy for CRLM. Results. Among 121 patients, 52 (43.0%) developed early recurrence. The independent risk factor for early recurrence was "number of liver metastases ≥3" (odds ratio 2.65). There were signifi cantly more patients with liver recurrence (51.9%) and recurrence beyond curative surgical resection (63.5%) in those with early recurrence. In addition, patients with three or more liver metastases had signifi cantly more liver recurrence (66.7%; P = 0.02) and recurrence beyond curative surgical resection (70.8%; P = 0.04). The overall survival rates of both patients with early recurrence (5-year survival rate 20%) and those with three or more liver metastases (5-year survival rate 24%) were signifi cantly worse. Conclusions. The independent risk factor for early recurrence is the "number of liver metastases ≥3." Patients with three or more liver metastases have a signifi cantly higher risk of liver recurrence and a higher rate of recurrence beyond curative surgical resection, and these are correlated with a poor prognosis..
77. Toru Ikegami, Takashi Maeda, Eiji Oki, Hiroto Kayashima, Kippei Ohgaki, Yoshihisa Sakaguchi, Ken Shirabe, Yoshihiko Maehara, Antegrade En Bloc Distal Pancreatectomy with Plexus Hanging Maneuver, Journal of Gastrointestinal Surgery, 10.1007/s11605-010-1382-9, 15, 4, 690-693, 2011.04, Introduction: Although antegrade en bloc distal pancreatectomy is appropriate for invasive distal pancreatic malignancies, this technique is not easy to perform because the end-point of deep vertical resections cannot be controlled. This report describes the usefulness of the application of hanging maneuver in performing the radical surgery. Methods: A tape for guidance is passed in a space behind the bundles of the left celiac and mesenteric plexus, followed by sagittal resection of the distal pancreas exposing the root of the celiac artery and superior mesenteric artery. After dividing the pancreas down to the level of the roots of the celiac and superior arteries, the distal pancreas is dissected from the retroperitoneum in medial to lateral fashion. Results: This technique was applied in six patients with distal pancreas malignancies, without any positive cancer cells at the resected margin. The mean tumor size was 3.0 ± 0.9 cm. The mean duration of surgery and intraoperative blood loss were 258 ± 71 min and 226 ± 240 ml, respectively. Conclusion: Antegrade en bloc distal pancreatectomy with plexus hanging maneuver is an appropriate technique for treating distal pancreatic malignancies..
78. Eiji Oki, Yoshihisa Sakaguchi, Shoji Hiroshige, Testuya Kusumoto, Yoshihiro Kakeji, Yoshihiko Maehara, Preservation of an aberrant hepatic artery arising from the left gastric artery during laparoscopic gastrectomy for gastric cancer, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2011.01.009, 212, 5, e25-e27, 2011.05.
79. Eiji Oki, Yoshihisa Sakaguchi, Kippei Ohgaki, Kazuhito Minami, Sakamoto Yasuo, Toshifumi Akimoto, Yasushi Toh, Testuya Kusumoto, Takeshi Okamura, Yoshihiko Maehara, Surgical complications and the risk factors of totally laparoscopic distal gastrectomy, Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 10.1097/SLE.0b013e318219a66b, 21, 3, 146-150, 2011.06, Purpose: It has not yet been elucidated whether there are specific complications associated with totally laparoscopic distal gastrectomy (TLDG). We evaluated the complications and the risk factors associated with TLDG. Methods: A retrospective analysis was performed on 138 consecutive patients who underwent TLDG. The clinical and operative data, which included the body mass index, respiratory function, hematological data, pathological data, and the experience of surgeon, were analyzed. Results: Intraoperative and postoperative complications developed in 10 and 28 patients, respectively. A univariate analysis determined that the patient age, concurrent respiratory disease, and operation time were important risk factors. A multivariate analysis found no significant risk factors in this set, although the operation time was the most promising risk factor. Conclusions: The present data suggest that TLDG can be performed with acceptable perioperative complication rates, although a longer operation time may cause a higher frequency of postoperative complications..
80. Eiji Oki, Masaru Morita, Yasushi Toh, Yasue Kimura, Kippei Ohgaki, Noriaki Sadanaga, Akinori Egashira, Yoshihiro Kakeji, Shunichi Tsujitani, Yoshihiko Maehara, Gastric cancer in the reconstructed gastric tube after radical esophagectomy
A single-center experience, Surgery today, 10.1007/s00595-010-4402-1, 41, 7, 966-969, 2011.07, Purpose: Metachronous gastric carcinoma arising in a gastric tube used for esophageal reconstruction has been occasionally encountered in long-term survivors of esophageal cancer. This study investigated 10 cases of gastric tube cancer in order to clarify the characteristics and the outcome of these patients. Methods: Four hundred and seventy-one patients underwent a radical esophagectomy at Kyushu University Hospital between 1989 and 2003. There were 10 cases of gastric tube cancer after an esophagectomy. Results: The interval between the esophagectomy and the development of the gastric tube cancer ranged from 1.1 to 7 years. There was no peak for the incidence of gastric tube cancer. In 6 of 10 cases of gastric tube cancer, endoscopic or surgical resection were performed for the treatment; however, chemotherapy was administered to the other 4 cases for several reasons. The prognosis of patients who underwent resection was better than that of the other patients. Conclusions: Frequent endoscopic examinations are therefore important even several years after performing an esophagectomy, since the risk of gastric tube cancer is higher than the risk of a recurrence of esophageal cancer several years after an esophagectomy. Only an early diagnosis permits a less invasive and appropriate approach for the treatment of gastric tube cancer..
81. Akinori Egashira, Masaru Morita, Rintaro Yoshida, Hiroshi Saeki, Eiji Oki, Noriaki Sadanaga, Yoshihiro Kakeji, Shun Ichi Tsujitani, Yoshihiko Maehara, Loss of p53 in esophageal squamous cell carcinoma and the correlation with survival
Analyses of gene mutations, protein expression, and loss of heterozygosity in Japanese patients, Journal of Surgical Oncology, 10.1002/jso.21920, 104, 2, 169-175, 2011.08, Background A high frequency of p53 protein expression or gene mutation has been reported in the early stages of esophageal squamous cell carcinoma (ESCC), and thus loss of p53 function is thought to be very important in esophageal carcinogenesis. However, there is controversy surrounding the correlation between p53 dysfunction and ESCC tumor progression. The complexity arises from the different modalities, such as mutation analysis, immunohistochemistry, and the detection of loss of heterozygosity (LOH) at the p53 genomic locus. Methods In this study, we comprehensively analyzed p53 gene mutation, p53 protein expression, and LOH at 17p13 in 94 surgically resected Japanese cases of ESCC. Results The frequency of p53 gene mutation was 60.6%. The rate of positive p53 protein expression was 56.4%. The frequency of LOH at 17p13 was 67.5%. There was a statistically significant correlation between the presence of a gene mutation and LOH, whereas, there was no significant correlation between gene mutation and protein expression. Conclusions Despite the importance of loss of p53 function in esophageal carcinogenesis, none of the examined parameters, either singly or combined, correlated with overall survival. Taken together, p53 function is a primary target for esophageal carcinogenesis but there is no apparent correlation with the malignant phenotype in ESCC. J. Surg. Oncol. 2011;104:169-175..
82. Toru Ikegami, Takashi Maeda, Hiroto Kayashima, Eiji Oki, Tomoharu Yoshizumi, Yoshihisa Sakaguchi, Yasushi Toh, Ken Shirabe, Yoshihiko Maehara, Soft coagulation, polyglycolic acid felt, and fibrin glue for prevention of pancreatic fistula after distal pancreatectomy, Surgery today, 10.1007/s00595-010-4433-7, 41, 9, 1224-1227, 2011.09, Purpose: To evaluate the effectiveness of using soft coagulation followed by the application of polyglycolic acid (PGA) felt and fibrin glue to prevent pancreatic fistula (PF) after distal pancreatectomy (DP). Methods: A soft coagulation system was applied on the cut surface of the pancreas after ligating the main pancreatic duct, followed by the application of layers of PGA felt and fibrin glue on the layers, to prevent the development of a PF after DP. Results: This technique was applied in nine patients, with mean drain amylase levels of 372 ± 296, 185 ± 209, 54 ± 40, and 47 ± 34 IU/l on days 1, 3, 5, and 7, respectively, after DP. Only one patient (11.1%) showed a Grade A PF on day 3 after surgery; none of the other patients developed a fistula. Conclusions: This technique is an effective prophylactic measure to prevent the development of a PF after DP..
83. Koji Ando, Eiji Oki, Masahiko Sugiyama, Yan Zhao, Aya Kojima, Hidetaka Yamamoto, Yoichi Yamashita, Hiroshi Saeki, Akinobu Taketomi, Masaru Morita, Yoshihiro Kakeji, Shunichi Tsujitani, Yoshihiko Maehara, Secondary resistance of extra-gastrointestinal stromal tumors to imatinib mesylate
Report of a case, Surgery today, 10.1007/s00595-010-4477-8, 41, 9, 1290-1293, 2011.09, Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate..
84. Hiroshi Saeki, Masaru Morita, Yuichiro Nakashima, Hideto Sonoda, Kenkichi Hashimoto, Akinori Egashira, O. K.I. Eiji, Takefumi Ohga, Yoshihiro Kakeji, Yoshihiko Maehara, Neoadjuvant chemoradiotherapy for clinical stage II-III esophageal squamous cell carcinoma, Anticancer research, 31, 9, 3073-3077, 2011.09, Background: The clinical significance of neoadjuvant chemoradiotherapy (NACRT) for potentially resectable esophageal squamous cell carcinoma (ESCC) is unclear. Patients and Methods: Patients with clinical stage II-III ESCC were classified into an NACRT group (n=76) and surgery alone group (n=92). The prognosis and the incidence of postoperative complications were retrospectively investigated. The pathological response to NACRT and patient prognosis were also analyzed. Results: The 5-year survival rate was 47.7% in the surgery alone group and 56.5% in the NACRT group (p=0.4831). The 5-year survival rates of patients in whom NACRT was markedly effective was clearly better than that of the other patients (ineffective/slightly effective: 36.9%, moderately effective: 53.8%, markedly effective: 100%). The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121). Conclusion: A pathological complete response to NACRT is critical for improving the survival of patients with clinical stageII-III ESCC..
85. Yuichi Endo, Toshifumi Matsumoto, Eiji Oki, Tetsuya Kusumoto, Koji Yoshikawa, Seigo Kitano, A case of true diverticulosis of the appendix with intussusception, Journal of Japanese Society of Gastroenterology, 108, 9, 1566-1570, 2011.09, A 50-year-old woman who was given a diagnosis of acute appendicitis was referred to our hospital. Because an abdominal enhanced CT revealed a dilated and cystic lesion in the appendix, operation was performed under the diagnosis of the suspicion of acute appendicitis or appendiceal mucocele. We performed laparoscopic cecal resection because of the intraoperative diagnosis of intussusception of the appendix. On the resected specimen, an elevated lesion was identified near the base of appendix. Histopathologically it was shown to be a true diverticulum in which the proper muscle layer are intact To the best of our knowledge, this is the first report of true diverticulosis of the appendix with intussusception in the Japanese literature..
86. Nobuhide Kubo, Eiji Oki, Kippei Ohgaki, Kotaro Shibahara, Ichiro Imamura, Noriaki Sadanaga, Masaru Morita, Yoshihiro Kakeji, Kohei Fujita, Shunichi Tsujitani, Yoshihiko Maehara, Surgical resection following combination chemotherapy with oral S-1 and biweekly docetaxel in a patient with advanced gastric cancer and a prior coronary artery bypass graft with the right gastroepiploic artery
Report of a case, Surgery today, 10.1007/s00595-010-4453-3, 41, 11, 1531-1537, 2011.11, Cardiothoracic surgeons commonly use the internal thoracic artery (ITA) and the right gastroepiploic artery (RGEA) when performing a coronary artery bypass graft (CABG). Although the development of CABG surgery has enabled long-term survival in patients with coronary artery disease, malignant diseases are more common in older patients. We present the case of a 75-year-old man who had previously undergone CABG with the RGEA and had later developed advanced gastric cancer. We treated this patient with two courses of combination chemotherapy using S-1 and docetaxel as induction therapy, followed by successful tumor resection. Therefore, neoadjuvant chemotherapy was effective for preserving the CABG with the RGEA in a patient with advanced gastric cancer..
87. Masaru Morita, Ryuichi Kumashiro, Yuichi Hisamatsu, Ryota Nakanishi, Akinori Egashira, Hiroshi Saeki, Eiji Oki, Takefumi Ohga, Yoshihiro Kakeji, Shunichi Tsujitani, Takeharu Yamanaka, Yoshihiko Maehara, Clinical significance of salvage esophagectomy for remnant or recurrent cancer following definitive chemoradiotherapy, Journal of gastroenterology, 10.1007/s00535-011-0448-0, 46, 11, 1284-1291, 2011.11, The purpose of this study was to clarify the effect of preoperative chemoradiotherapy (CRT) for esophageal cancer on the postoperative course, and to determine the clinical significance of salvage esophagectomy after definitive CRT. Based on their preoperative treatment, 477 patients with esophageal cancer were classified into three groups: 253 patients who received surgery alone (Group I), 197 who received planned CRT (30-45 Gy, Group II), and 27 who received a salvage esophagectomy (radiation ≥60 Gy, Group III). Postoperative complications developed in 25, 40, and 59% of the patients in Groups I, II, and III, respectively, with pulmonary complications developing in 10, 15, and 30%, and anastomotic leakage developing in 13, 23, and 37%, respectively. Mortality rates were 2.4, 2.0, and 7.4%, respectively. Multivariate analysis revealed preoperative therapy to be an independent factor associated with postoperative risks: the odds ratios (ORs) of Groups II and III compared to Group I were 1.8 and 4.0 for pulmonary complications, while they were 1.9 and 2.8, respectively, for anastomotic leakage. No critical complications developed in the 14 patients who received salvage surgery performed with strict surgical indications after 2005. The survival of Group III was not significantly different from that of Groups I and II. Most patients who received an R1/R2 resection after definitive CRT died within 2 years after salvage surgery. Preoperative CRT is associated with postoperative complications especially in patients with R2 resection, while long-term survival can be achieved after R0 resections. Salvage surgery should be considered for carefully selected patients in whom R0 resection can be achieved..
88. E. Oki, Y. Sakaguchi, K. Ohgaki, H. Saeki, Y. Chinen, K. Minami, Y. Sakamoto, Y. Toh, T. Kusumoto, Y. Maehara, Feasibility of delta-shaped anastomoses in totally laparoscopic distal gastrectomy, European Surgical Research, 10.1159/000332850, 47, 4, 205-210, 2011.12, Background: Delta-shaped (DS) anastomosis is a new reconstruction method for totally laparoscopic distal gastrectomy (TLDG) using a linear stapler. We evaluated the feasibility of using this method for TLDG. Methods: A retrospective analysis was performed in 114 patients who underwent TLDG with DS anastomosis. Twenty-four patients reconstructed with a Roux-en-Y (RY) anastomosis during the same period were analyzed as control subjects. Results: The patient characteristics of DS and RY anastomoses were slightly different in terms of tumor location and extent of lymph node dissection, since this was not a prospective comparative study. Blood loss, postoperative complication rate and postoperative hospital stay were not different between the two groups. There was only 1 case of anastomotic leakage, and no case of anastomotic stricture after DS anastomosis. The length of the operation using DS anastomosis was significantly shorter than for RY anastomosis. The rates of body weight loss were not significantly different at 1 year after the operation. Conclusions: Although this was a small retrospective analysis, DS anastomosis was feasible, required a shorter operation time, and had no associated complications. This method can therefore be recommended as a standard procedure for TLDG..
89. Hideo Baba, Naoko Hayashi, Yasunori Emi, Yoshihiro Kakeji, Akinori Egashira, Eiji Oki, Ken Shirabe, Tetsuo Toyama, Takefumi Ohga, Manabu Yamamoto, Hirofumi Hasegawa, Fumiko Kohakura, Hidefumi Higashi, Kiyoshi Niwa, Fumihiko Fujita, Yutaka Ogata, Shunji Kohnoe, Masafumi Inomata, Hironori Samura, Shoji Tokunaga, Yoshihiko Maehara, A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as first-line treatment for advanced colorectal cancer
A Japanese experience, Surgery today, 10.1007/s00595-011-4589-9, 41, 12, 1610-1616, 2011.12, Purpose: This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin in combination with levofolinate and infusion 5-fluorouracil (FOLFOX4) as first-line therapy for Japanese patients with unresectable metastatic colorectal cancer. Methods: Sixty consecutive patients with histologically confirmed advanced or metastatic colorectal cancer were enrolled in the study. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred. Results: Two patients were ineligible. Toxicity was evaluated in 60 patients, who had received a part or all of the protocol therapy. A partial response was observed in 20 patients. The overall response rate was 34.5% (95% CI, 22.5%-48.1%) and the tumor control rate (partial response + stable disease) was 82.8%. The median progression-free survival was 6.9 months (95% CI, 5.1-9.8 months), and the median overall survival was 31.5 months (95% CI, 18.1-40.1 months). There were no toxicity-related deaths. Grade 3 or 4 neutropenia occurred in 48.3% of patients and often caused a delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 71.7% of patients. Conclusion: The results showed good tolerability and efficacy for first-line FOLFOX4 in the treatment of patients with advanced colorectal cancer, indicating the promise of this regimen as first-line therapy for advanced colorectal cancer in the Japanese population..
90. Toshiro Okuyama, Takahiro Higashi, A. Edagawa, Shigeyuki Nagata, Kenkichi Hashimoto, Hiroshi Saeki, Eiji Oki, Hideaki Uchiyama, Hirofumi Kawanaka, Masaru Morita, Masahiro Tateishi, Daisuke Korenaga, Hidemichi Yaita, Kenji Takenaka, Ten-year survival of curability B gastric cancer patients treated by tegafur-uracil as postoperative adjuvant chemotherapy in a common public hospital
univariate and multivariate analyses., Fukuoka igaku zasshi = Hukuoka acta medica, 103, 7, 138-144, 2012.01, The prognosis of gastric cancer patients undergoing curability B surgery was retrospectively examined to determine the effectiveness of the administration of oral anti-cancer drugs as postoperative adjuvant chemotherapy. This study was based on the outcomes of 86 potentially curative patients who had undergone curability B resection of gastric cancer with or without the subsequent administration of oral 5-fluorouracil analogue. There were 21 patients who underwent surgery alone with no oral anti-cancer agents (group A) and 65 patients who were treated postoperatively, mainly with UFT (Tegafur and uracil; group B). This study compared the ten-year survival times of these two groups using univariate and multivariate analyses. The amount of UFT in group B was 354.2 +/- 122.0 mg and the administration period was 11.7 +/- 7.2 months. The backgrounds showed significantly more older patients in group A compared than group B (P = 0.0002). A univariate analysis showed the ten-year survival rate in group B to be higher than group A (P = 0.0079). A multivariate analysis showed that the postoperative administration of UFT was an independent factor associated with prolongation of survival times as well as the extent of lymph nodes metastasis and pathological stage (P = 0.0096). This study provided conventional evidence that postoperative administration of oral 5-fluorouracil analogue is associated with better long-term prognoses in patients undergoing curability B resection for gastric carcinoma..
91. Yoshihiko Maehara, Shunichi Tsujitani, Hiroshi Saeki, Eiji Oki, Keiji Yoshinaga, Yasunori Emi, Masaru Morita, Shunji Kohnoe, Yoshihiro Kakeji, Tokujiro Yano, Hideo Baba, Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN®)
Review of development and future perspectives, Surgery today, 10.1007/s00595-011-0075-7, 42, 1, 8-28, 2012.01, The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN®) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-β or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers..
92. Osamu Ikeda, Yoshihisa Sakaguchi, Yasushi Toh, Kippei Oogaki, Eiji Oki, Kazuhito Minami, Takeshi Okamura, Hideo Baba, Evaluation of oncological adequacy of laparoscopic distal gastrectomy with special attention to lymph node dissection
A comparison with conventional open gastrectomy, Hepato-gastroenterology, 10.5754/hge10089, 59, 114, 627-632, 2012.03, Background/Aims: Laparoscopic distal gastrectomy (LDG) with lymphadenectomy has been revealed to be a useful treatment for early gastric cancer but oncological adequacy is controversial. Methodology: To assess the quality of lymphadenectomy, we evaluated the number of dissected lymph nodes and the non-compliance rate (defined as an absence of nodal tissue at a node station that should have been resected) and compared the data obtained from 102 patients treated by LDG with those from 90 patients treated by open distal gastrectomy (ODG). Results: The numbers of nodes of Categories 1 and 2, which correspond respectively to perigastric and retroperitoneal nodes, did not differ significantly between the LDG group and the ODG group. In the LDG group compared to the ODG group, there were significantly more right paracardial nodes (No. 1) but there were significantly fewer infrapyloric nodes (No. 6). However, the difference in infrapyloric nodes (No. 6) became insignificant when we re-analyzed and compared the ODG group and the patients (n=42) whose LDGs were performed by two experienced laparoscopic surgeons. Conclusions: The curability of gastric cancer on LDG was almost equivalent to that of ODG from the viewpoint of lymph node dissection, if the LDG is performed by two experienced laparoscopic surgeons. These data suggested that LDG with lymphadenectomy could possibly be adopted for advanced gastric cancer treatment under proper quality control, such as that provided by an experienced laparoscopic team..
93. Eiji Oki, Yuichi Hisamatsu, Koji Ando, Hiroshi Saeki, Yoshihiro Kakeji, Yoshihiko Maehara, Clinical aspect and molecular mechanism of DNA aneuploidy in gastric cancers, Journal of gastroenterology, 10.1007/s00535-012-0565-4, 47, 4, 351-358, 2012.04, The biological characteristics of cancers depend mostly on genetic alterations in the cancer cells of individuals. Gastric cancers show a high frequency of DNA aneuploidy, a phenotype of chromosomal instability. Compared to diploid tumors, gastric carcinomas with aneuploidy have been shown to have high proliferative activity and high metastatic or invasive potential; these characteristics lead to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. This review, in order to determine whether gastric carcinomas that display aneuploidy are associated with a poorer prognosis than diploid tumors, and to discuss the biological mechanisms that induce aneuploidy, summarizes the results of studies on DNA ploidy in gastric cancer published in the English literature. Analysis of DNA ploidy in gastric cancer may provide clinically useful information from diagnostic, therapeutic, and prognostic standpoints. Further investigations may be needed to clarify the relationship between chromosome instability and DNA ploidy..
94. Satoko Okada, Eriko Tokunaga, Hiroyuki Kitao, Sayuri Akiyoshi, Nami Yamashita, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiro Kakeji, Yoshihiko Maehara, Loss of heterozygosity at BRCA1 locus is significantly associated with aggressiveness and poor prognosis in breast cancer, Annals of Surgical Oncology, 10.1245/s10434-011-2166-5, 19, 5, 1499-1507, 2012.05, Background. BRCA1 and BRCA2 are two major tumor suppressor genes for hereditary breast and ovarian cancer. In sporadic breast cancer, although somatic mutations of these genes are rare, loss of heterozygosity (LOH) at BRCA1 and BRCA2 loci is common. Methods. LOH at BRCA1 and BRCA2 loci were investigated in 202 Japanese invasive breast cancer patients. The relationships between LOH at these gene loci and clinicopathologic characteristics were analyzed. Results. Among 166 informative cases for both BRCA1 and BRCA2 loci, 69 (41.6%) and 52 (31.3%) tumors revealed LOH at BRCA1 and BRCA2 loci, respectively. LOH at BRCA1 LOH or BRCA2 locus was associated with higher nuclear grade (P < 0.0001, P = 0.0187). LOH at BRCA1 locus was associated with estrogen receptor and progesterone receptor negativity (P = 0.001 and P = 0.015) and significantly shorter disease-free survival (P < 0.0001), distant metastasis-free survival (P < 0.0001), and overall survival (P < 0.0001). In contrast, LOH at BRCA2 locus had no associations with estrogen receptor or progesterone receptor status and prognosis. LOH at BRCA1 locus was independently associated with poor prognosis in terms of disease-free survival (hazard ratio 3.08, 95% confidence interval [CI] 1.58-6.18, P = 0.0009), distant metastasis-free survival (hazard ratio 5.18, 95% CI 2.35-12.19, P < 0.0001), and overall survival (hazard ratio 4.97, 95% CI 1.84-15.1, P = 0.0013). Conclusions. LOH at BRCA1 locus could be an independent prognostic biomarker useful in identifying a subgroup of patients with poor prognosis..
95. Yoshihiro Kakeji, Tomonori Nakanoko, Rintaro Yoshida, Kojiro Eto, Ryuichi Kumashiro, Keisuke Ikeda, Akinori Egashira, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, Laparoscopic resection for gastrointestinal stromal tumors in the stomach, Surgery today, 10.1007/s00595-011-0072-x, 42, 6, 554-558, 2012.06, Purpose Gastrointestinal stromal tumors (GISTs) should be surgically resected, even those smaller than 5 cm in size, which is the threshold of clinical malignancy for submucosal tumors (SMTs) in the gastrointestinal tract. This study reviewed the use of laparoscopic surgery for gastric partial resection of GISTs or SMTs that were suspected to be GISTs. Methods Eighteen patients underwent laparoscopic partial resection of the stomach for GISTs or SMTs. The tumor location was confirmed by intraluminal endoscopy. One-half of the circumference around the tumor was dissected, and the tumor was turned toward the abdominal cavity. The nonresected part of the tumor and the edge of the incision line was lifted up using forceps, and the incision line was closed using laparoscopic stapling devices. Results Two cases were diagnosed as GIST by endoscopic biopsy. Six patients underwent endoscopic ultrasound- guided fine-needle aspiration biopsy (EUS-FNAB) examinations, which diagnosed five GISTs. There were 18 tumors smaller than 5 cm, including 10 GISTs, 4 leiomyomas, 3 schwannomas, and one heterotopic pancreas. Conclusions Endoscopic ultrasound-guided FNAB is recommended for definite preoperative diagnosis of histopathologically unknown SMTs to determine the indications for surgery. The laparoscopic approach with the assistance of endoscopy is useful for improving the curability, with minimal invasiveness for the partial resection of GISTs..
96. Toshiro Okuyama, Daisuke Korenaga, Ai Edagawa, Shinji Itoh, Eiji Oki, Hirofumi Kawanaka, Yasuharu Ikeda, Yoshihiro Kakeji, Masahiro Tateishi, Shunichi Tsujitani, Kenji Takenaka, Yoshihiko Maehara, Prognostic effects of oral anti-cancer drugs as adjuvant chemotherapy for 2 years after gastric cancer surgery, Surgery today, 10.1007/s00595-012-0129-5, 42, 8, 734-740, 2012.08, Purpose We conducted this retrospective study to evaluate the effectiveness of giving oral anti-cancer drugs for 2 years as postoperative adjuvant chemotherapy to gastric cancer patients. Methods The subjects were 76 patients with stage II and III gastric cancer, who underwent curative surgery between 1989 and 2008. We divided the 20 years chronologically into the UFT term (1989-2003) and the S-1 term (2004-2008). The patients from each term were then divided into three groups according to the length of drug administration; namely, the surgery alone group, the 1-year group, and the 2-year group. Results The survival time of the 2-year group was better than that of the surgery alone group, not only in the UFT term, but also in the S-1 term (P = 0.0224). Longer relapse-free survival was evident in the S-1 term, especially for the 2-year group (P = 0.0110). A multivariate analysis showed both the stage of the cancer and 2 years of postoperative adjuvant chemotherapy to be independent factors predictive of prolonged survival (P = 0.0040 and P = 0.0022, respectively). Conclusions The 2-year administration of oral anti-cancer drugs as postoperative adjuvant chemotherapy might improve the outcome of stage II, III gastric cancer patients. Randomized control trials are warranted to prove the effectiveness of this 2-year regimen..
97. Masahiko Sugiyama, Masaru Morita, Rintaro Yoshida, Koji Ando, Akinori Egashira, Ohga Takefumi, Hiroshi Saeki, Eiji Oki, Yoshihiro Kakeji, Yoshihisa Sakaguchi, Yoshihiko Maehara, Patterns and time of recurrence after complete resection of esophageal cancer, Surgery today, 10.1007/s00595-012-0133-9, 42, 8, 752-758, 2012.08, Purpose The results and outcomes of surgical resection for esophageal carcinoma have improved remarkably in recent years; however, recurrence still frequently develops, even after complete resection. The purpose of this study is to clarify the characteristics of recurrence in this patient population. Methods Among 208 patients, who underwent R0 resection for esophageal carcinoma, recurrence developed in 61. Clinical data were available for 56 of these patients, who were the subjects of this study. We evaluated the time, patterns, and treatment of recurrence in these patients. Results Recurrence developed within 1 and 2 years after esophagectomy in 71 and 84% of the patients, respectively, and was classified as loco-regional (54%), hematogenous (36%), or mixed type (10%). The prognosis of patients with loco-regional recurrence tended to be better than that of those with distant metastasis, although the difference was not significant (P = 0.088). Patients with recurrence treated by chemotherapy alone or multimodal therapy, such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence (P = 0.016). Conclusion These findings reinforce the importance of careful follow-up for both loco-regional and hematogenous recurrence after esophagectomy, particularly during the first 2 years..
98. Eiji Oki, Yoshihisa Sakaguchi, Kippei Ohgaki, Hiroshi Saeki, Yoshiki Chinen, Kazuhito Minami, Yasuo Sakamoto, Yasushi Toh, Testuya Kusumoto, Takeshi Okamura, Yoshihiko Maehara, The impact of obesity on the use of a totally laparoscopic distal gastrectomy in patients with gastric cancer, Journal of Gastric Cancer, 10.5230/jgc.2012.12.2.108, 12, 2, 108-112, 2012.10, Purpose: Since a patient's obesity can affect the mortality and morbidity of the surgery, less drastic surgeries may have a major benefit for obese individuals. This study evaluated the feasibility of performing a totally laparoscopic distal gastrectomy, with intracorporeal anastomosis, in obese patients suffering from gastric cancer. Materials and Methods: This was a retrospective analysis of the 138 patients, who underwent a totally laparoscopic distal gastrectomy from April 2005 to March 2009, at the National Kyushu Cancer Center. The body mass index of 20 patients was ≥25, and in 118 patients, it was <25 kg/m2. Results: The mean values of body mass index in the 2 groups were 27.3±2.2 and 21.4±2.3. Hypertension was significantly more frequent in the obese patients than in the non-obese patients. The intraoperative blood loss, duration of surgery, post-operative complication rate, post-operative hospital stay, and a number of retrieved lymph nodes were not significantly different between the two groups. Conclusions: Intracorporeal anastomosis seemed to have a benefit for obese individuals. Totally laparoscopic gastrectomy is, therefore, considered to be a safe and an effective modality for obese patients..
99. Yasuo Sakamoto, Yoshihisa Sakaguchi, Eiji Oki, Kazuhito Minami, Yasushi Toh, Takeshi Okamura, Surgical outcomes after resection of both hepatic and pulmonary metastases from colorectal cancer, World journal of surgery, 10.1007/s00268-012-1708-8, 36, 11, 2708-2713, 2012.11, Background: The efficacy and the indications of resection of synchronous or metachronous hepatic and pulmonary metastases from colorectal cancer (CRC) are controversial. This study retrospectively reviewed the cases of CRC patients who underwent both liver and lung resection to define the appropriate indications for surgical resection in patients with hepatic and pulmonary metastases. Methods: A total of 39 patients with both hepatic and pulmonary metastases from CRC underwent both liver and lung resection from January 1987 to December 2009. The relapse-free survival (RFS) and overall survival (OS) from the resection for the first metastasis were evaluated by a Kaplan-Meyer analysis. Prognostic factors were analyzed using the log-rank test and a Cox proportional hazards model. Results: The median RFS and the 5-year RFS rate of all patients were 12 months and 2.6 %, respectively. The median survival time (MST) and 5-year OS rate of all patients were 66 months and 48.3 %, respectively. The MST of the patients with a long (>1 year) disease-free interval (DFI) could not be calculated, but their 5-year OS rate was 73.7 %. In contrast, the MST and 5-year OS rate of the patients with a short (<1 year) DFI were 29 months and 37.5 %, respectively. The short DFI was the only prognostic factor in the multivariate analysis. Conclusions: Aggressive surgical resection of both hepatic and pulmonary metastases from CRC should be undertaken in selective patients, including those with a long DFI..
100. Rintaro Yoshida, Masaru Morita, Ryuichi Kumashiro, Keisuke Ikeda, Akinori Egashira, Hiroshi Saeki, Eiji Oki, Takefumi Ohga, Hideki Shiratsuchi, Junichi Fukushima, Torahiko Nakashima, Yoshihiro Kakeji, Yoshihiko Maehara, Staged operation for synchronous quintuple cancer in the oral cavity, hypopharynx, and esophagus, Esophagus, 10.1007/s10388-012-0322-z, 9, 4, 228-233, 2012.12, Esophageal cancer is frequently associated with head-and-neck cancer. It is difficult to select treatment modalities for synchronous multiple cancers in the upper aerodigestive tract. A 58-year-old woman had synchronous quintuple cancer of the upper aerodigestive tract and was in a poor nutritional state due to oral pain and dysphagia. Clinical stages of cancer in the oral cavity, hypopharynx, cervical esophagus, middle thoracic esophagus, and lower thoracic esophagus were IVA (cT4a N2b M0), I (cT1 N0 M0), IA (cT1 N0 M0), IA (cT1 N0 M0), and IIA (cT3 N0 M0), respectively. After preoperative chemoradiotherapy, curative resection of oral cavity cancer and a tube jeju-nostomy were performed. Then, pharyngolaryngectomy, total esophagectomy, and pharyngostomy were performed. Finally, after additional radiotherapy to the oral cavity, pharyngogastrostomy with gastric tube and microvascular anastomosis were performed. The patient achieved oral intake and is in good condition and has at this writing remained recurrence free for 26 months. This report suggests that even if there are multiple cancers, adopting multimodal treatment strategies for controlling each cancer may lead to a chance to obtain a complete cure..
101. Kenkichi Hashimoto, Yosuke Seki, Kazunori Kasama, Eiji Oki, Noriaki Sadanaga, Hiroshi Saeki, Masaru Morita, Tetsuo Ikeda, Ken Shirabe, Hiroshi Matsuura, Kenichiro Okadome, Yoshihiko Maehara, [Surgery for morbid obesity and diabetes mellitus--from bariatric surgery to metabolic surgery]., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 397-404, 2013.01.
102. Hajime Otsu, Eiji Oki, Hiroyuki Kawano, Koji Ando, Shuhei Ito, Keishi Sugimachi, Hiroshi Saeki, Hideaki Uchiyama, Yuji Soejima, Hirofumi Kawanaka, Masaru Morita, Yoshihisa Sakaguchi, Tetsuya Kusumoto, Tetsuo Ikeda, Yoshihiko Maehara, [Patient with bulky duodenum GIST became complete resection possible after primary systemic therapy
a case report]., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 585-588, 2013.01, A case was a 77 years old male. Exertional breathlessness was a chief complaint, and anemia was pointed out. A duodenum GIST was detected by gastroscopy. The CT scan showed infiltration in an inferior vena cava, the right kidney, and an ascending colon, so we judged that radical cure resection was difficult. We started Imatinib medication. Six months after the medication start, because the border with surroundings also became clear, we became a plan of the operation. The tumor existed in the descending limb of duodenum and the distance with papilla Vater was maintained, so the complete excision by duodenal portion resection was possible for it. Although meaning of primary systemic therapy for GIST was not established, it was shown that medicating Imatinib to the high-level partial advance GIST before an operation may become an effective cure which avoids an extended operation and makes complete resection of a tumor possible..
103. Tetsuo Ikeda, Tomohiko Akahoshi, Hirofumi Kawanaka, Hideaki Uchiyama, Yo ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Keishi Sugimachi, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Ken Shirabe, Koshi Mimori, Masayuki Watanabe, Makoto Hashizume, Yoshihiko Maehara, [Optimum hepatic parenchymal dissection to prevent bile leak
a comparative study using electrosurgical and stapling devices in swine]., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 507-514, 2013.01, Bile leakage is a serious complication of liver resection, and its treatment is very time-consuming. In open liver resection, Glisson's sheaths are usually disconnected by ligation to the extent possible during the parenchyma dissection. However, in laparoscopic surgery, the ligation, suture, and hemostasis are more difficult than in open surgery. For this reason, in laparoscopic liver resection, liver parenchyma dissection is generally accomplished using electrosurgical or stapling devices. The purpose of this study was to verify the authenticity of electrosurgical devices attached an automatic irrigation function (AI) and stapling devices for laparoscopic liver parenchymal dissection. Four devices were used for liver parenchymal dissection in laparoscopic hepatic wedge resection, in pigs: monopolar high-frequency electric cautery attached AI (MCI) (n = 6), bipolar high-frequency electric cautery attached AI (BCI) (n = 6), bipolar tissue sealing system (LigaSure) attached AI (BSI) and an endoscopic stapling device (ECHELON FLEX ENDOPATH) (ES). In each group, burst pressures were tested using an electronic manometer, paying special attention to the location (s) of the first disruption (s). The dissected tissues were examined histologically. Pressures used in electrosurgical devices attach AI were significantly higher compared to pressures used in a ES (P < 0.001). While thermal denaturation of the liver parenchyma occurred at approximately 2-3 mm of depth when bipolar high-frequency electric cautery was used for dissection, it reached up to more than 10 mm with monopolar high-frequency electric cautery. All of the first disruption points of stapling were at stapling line. Electrosurgical devices with an automatic irrigation function are useful devices to dissect the liver parenchyma..
104. Hideaki Uchiyama, Ken Shirabe, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Koushi Mimori, Keishi Sugimachi, Hiroshi Saeki, Masayuki Watanabe, Kenji Takenaka, Yoshihiko Maehara, Verification of our therapeutic criterion for acute cholecystitis
"perform a subemergency laparoscopic cholecystectomy when a patient is judged to be able to tolerate general anesthesia"--the experience in a single community hospital., Unknown Journal, 104, 10, 339-343, 2013.01, Our current therapeutic criterion for acute cholecystitis is: Perform a subemergency laparoscopic cholecystectomy (LC) when a patient is judged to be able to tolerate general anesthesia. The aim of the current study was to verify whether this criterion is justified. The outcomes of 21 cases of LC for acute cholecystitis performed between April 2011 and September 2013 were retrospectively analyzed. Subemergency LC was performed according to the aforementioned criterion (Subemergency group; n = 16). Patient who was judged to be unable to tolerate general anesthesia underwent percutaneous transhepatic gallbladder drainage (PTGBD) first, then LC after the patients' condition became stable (PTGBD group; n = 5). There is no conversion to open surgery throughout the study period. The mean of the total hospital stays in the Subemergency group was significantly shorter than that in the PTGBD group (11.5 +/- 5.3 vs. 30.4 +/- 8.5 days). Although two patients in the Subemergency group, who had already needed oxygen administration preoperatively, suffered postoperative respiratory failure, they completely recovered. On the other hand, there is no postoperative complication in the PTGBD group. Subemergency LC could be safely performed when surgeons as well as anesthesiologists judged a patient to be able to tolerate general anesthesia, which significantly shorten hospital stays compared to elective LC after PTGBD. However, elective LC after PTGBD is an absolutely safer therapeutic option in treating unstable patients..
105. Masayuki Watanabe, Koki Matsuura, Hideo Baba, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Hideaki Uchiyama, Yo ichi Yamashita, Masaru Morita, Eiji Oki, Koshi Mimori, Keishi Sugimachi, Hiroshi Saeki, Yoshihiko Maehara, Thoracoscopic pericardial drainage for gastric tube ulcer penetrated into the pericardium., Unknown Journal, 104, 10, 389-393, 2013.01, Peptic ulcer occurring in the gastric conduit for esophageal reconstruction sometimes penetrates into the mediastinal structures. We herein reported a case of pericardial penetration of gastric tube ulcer successfully treated with thoracoscopic pericardial drainage. A 66-year-old Japanese man, who had undergone esophagectomy for esophageal cancer 20 months before, visited our emergency room complaining severe back pain. Computed tomography revealed gastric tube ulcer penetrated into the pericardial space. Thoracoscopic pericardiotomy and drainage was performed and the patient made an uneventful recovery. Thoracoscopic pericardial drainage is useful to manage acute pyogenic pericarditis due to penetration of peptic ulcer which occurred in the gastric tube..
106. Akinori Egashira, Ken Ichi Taguchi, Yasushi Toh, Manabu Yamamoto, Takeshi Okamura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Koshi Mimori, Masayuki Watanabe, Yoshihiko Maehara, Successful treatment of primary jejunal cancer after esophageal and colon cancer resection., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 435-441, 2013.01, Patients with esophageal cancer are susceptible to other primary cancers, but multiple primary cancers involving the esophagus and jejunum are rare. We herein report a case of primary jejunal cancer as a component of metachronous triple primary cancers including esophageal cancer and ascending colon cancer. A 63-year-old male patient with a history of surgery for esophageal cancer and ascending colon cancer was admitted to our hospital after experiencing 1 month of repeated vomiting and epigastric abdominal pain. Esophagogastroduodenoscopy, duodenography, and computed tomography revealed a jejunal tumor located 2 cm from the ligament of Treitz on the anal side. Partial resection of the jejunum with lymph node dissection was performed. The postoperative course was uneventful, and the patient remains well with no signs of recurrence 10 months after the operation. This is the first report of curative resection of triple primary cancers of the esophagus, jejunum, and colon. Patients with a history of esophageal cancer are susceptible to other primary cancers, and it is important to perform surveillance for the subsequent development of other cancers..
107. Yuji Soejima, Ken Shirabe, Tomoharu Yoshizumi, Hideaki Uchiyama, Toru Ikegami, Yo Ichi Yamashita, Tetsuo Ikeda, Hirofumi Kawanaka, Keishi Sugimachi, Koshi Mimori, Masayuki Watanabe, Masaru Morita, Eiji Oki, Hiroshi Saeki, Yoshihiko Maehara, Rex shunt for portal vein thrombosis after adult living donor liver transplantation., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 464-468, 2013.01, Portal vein thrombosis (PVT) after liver transplantation is a relatively common but serious complication which could lead to portal hypertension or a direct graft loss. A "Rex" shunt created between the superior mesenteric vein (SMV) and the umbilical portion of the left portal vein can be a useful option to treat PVT after pediatric liver transplantation, however, its application to adult patients has not been reported so far because appropriate vein grafts are hardly available. Herein we present a case of PVT after left lobe living donor liver transplantation (LDLT) who underwent the procedure using the own inferior jugular vein and the gonadal vein as a shunt graft. The shunt was patent immediately after the procedure but was thrombosed 2 days after probably due to the insufficient inflow from the SMV and the absence of anticoagulation therapy, for which emergent thrombectomy and ligation of the significant hepatofugal collateral veins followed by full anti-coagulation therapy were performed. The shunt remains open at 8 month after the procedure with a normal anmonia level and liver function. In conclusion, the Rex shunt using recipient's autologous vein grafts is a feasible and valuable option for adult patients to treat PVT after LDLT..
108. Hiroshi Saeki, Eiji Oki, Yasuo Tsuda, Koji Ando, Yukiharu Hiyoshi, Shuhei Ito, Masaru Morita, Tetsuo Ikeda, Keishi Sugimachi, Yo Ichi Yamashita, Toru Ikegami, Hideaki Uchiyama, Tomoharu Yoshizumi, Yuji Soejima, Hirofumi Kawanaka, Koshi Mimori, Masayuki Watanabe, Yoshihiko Maehara, Relevance of totally laparoscopic gastrectomy for patients with advanced gastric cancer., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 405-412, 2013.01, Although the use of laparoscopic gastrectomy for gastric cancer has been widespread, it has remained controversial whether it can be applied for the patients with advanced gastric cancer. The aim of this study was to clarify the safety and usefulness of totally laparoscopic gastrectomy for patients with advanced gastric cancer. Totally laparoscopic gastrectomy was applied for a total of 38 patients with pStage IB-III advanced gastric cancer at our institute. The surgical and long-term results were analyzed in those patients. Twenty-seven patents underwent distal gastrectomy and 11 patients underwent total gastrectomy. The mean number of dissected lymph nodes was 41 (range, 16-87). The mean length of the operation and amount of blood loss was 324 min and 123 ml, respectively. Two cases of postoperative bleeding were noted, while neither anastomosis-related complications nor in-hospital death was observed. The follow-up period after surgery was 8-72 months. Postoperative recurrence was observed in 6 patients (peritoneal dissemination: 3 patients, pleural dissemination: 1 patient, liver metastasis: 1 patient, ovarian metastasis: 1 patient). The overall survival rates at 1, 3 and 5 years were 94.7%, 76.3% and 76.3%, respectively. Totally laparoscopic gastrectomy is safe and can lead to satisfactory long-term outcomes in cases of advanced gastric cancer. Prospective controlled studies are warranted to confirm our findings..
109. Tetsuo Ikeda, Hiroyuki Kawano, Yuichi Hisamatsu, Koji Ando, Hiroshi Saeki, Eiji Oki, Takefumi Ohga, Yoshihiro Kakeji, Shunichi Tsujitani, Shunji Kohnoe, Yoshihiko Maehara, Progression from laparoscopic-assisted to totally laparoscopic distal gastrectomy
Comparison of circular stapler (i-DST) and linear stapler (BBT) for intracorporeal anastomosis, Surgical endoscopy, 10.1007/s00464-012-2433-y, 27, 1, 325-332, 2013.01, Background: Billroth I (B-I) gastroduodenostomy is an anastomotic procedure that is widely performed after gastric resection for distal gastric cancer. A circular stapler often is used for B-I gastroduodenostomy in open and laparoscopic-assisted distal gastrectomy. Recently, totally laparoscopic distal gastrectomy (TLDG) has been considered less invasive than laparoscopic-assisted gastrectomy, and many institutions performing laparoscopic-assisted distal gastrectomy are trying to progress to TLDG without markedly changing the anastomosis method. The purpose of this report is to introduce the technical details of new methods of intracorporeal gastroduodenostomy using either a circular or linear stapler and to evaluate their technical feasibility and safety. Methods: Seventeen patients who underwent TLDG with the intracorporeal double-stapling technique using a circular stapler (n = 7) or the book-binding technique (BBT) using a linear stapler (n = 10) between February 2010 and April 2011 were enrolled in the study. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. Results: There were no intraoperative complications or conversions to open surgery in any of the 17 patients. The usual postoperative complications following gastroduodenostomy, such as anastomotic leakage and stenosis, were not observed. Anastomosis took significantly longer to complete with DST (64 ± 24 min) than with BBT (34 ± 7 min), but more stapler cartridges were needed with BBT than with DST. Conclusions: TLDG using a circular or linear stapler is feasible and safe to perform. DST will enable institutions performing laparoscopic-assisted distal gastrectomy with circular staplers to progress to TLDG without problems, and this progression may be more economical because fewer stapler cartridges are used during surgery. However, if an institution has already been performing δ anastomosis in TLDG but has been experiencing certain issues with δ anastomosis, converting from δ anastomosis to BBT should be beneficial..
110. Keiji Yoshinaga, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Keishi Sugimachi, Yo Ichi Yamashita, Toru Ikegami, Hideaki Uchiyama, Tomoharu Yoshizumi, Yuji Soejima, Hirofumi Kawanaka, Koshi Mimori, Masayuki Watanabe, Yoshihiko Maehara, Prognostic markers for immunochemotherapy using tegafur -uracil (UFT) and protein-bound polysaccharide K (PSK)., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 549-558, 2013.01, We previously reported that PSK-induced lymphocyte blastogenesis reaction (PSK-stimulation index; PSK-SI) may be a prognostic marker for immunochemotherapy using PSK in gastrointestinal cancer patients. In this study we evaluated the usefulness of PSK-SI as a prognostic marker for PSK therapy at higher and lower serum immunosuppressive acidic protein (IAP) levels. 98 gastric and 135 colorectal cancer patients were analyzed. PSK-SI and serum IAP levels were measured preoperatively. After operation, patients received UFT and PSK for two years. There were no differences between patients with higher and those with lower PSK-SI with respect to the clinicopathological factors. In patients with higher serum IAP levels (> or = 500 microg/ml), recurrence-free survival (RFS) and overall survival (OS) were apparently more favorable in the higher PSK-SI group (gastric cancer; > or = 1.75, colorectal cancer; > or = 2.1) than in lower PSK-SI group, although the differences were not significant. Serum IAP levels and PSK-SI may be useful markers for prediction of response to immunochemotherapy using PSK, although further studies are necessary..
111. Hideaki Uchiyama, Ken Shirabe, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Koushi Mimori, Keishi Sugimachi, Hiroshi Saeki, Masayuki Watanabe, Kenji Takenaka, Yoshihiko Maehara, Mirror image hepatectomy in a patient with situs inversus totalis., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 430-434, 2013.01, Hepatectomy in a patient with situs inversus patient is technically challenging because of its complete mirror image anatomy, especially for a tumor located deep in the liver. Incorrectly identifying intrahepatic vessels and biliary system would lead to serious complications. We experienced a hepatectomy for a tumor in a patient with situs inversus totalis with referring to computer-generated mirror images. A 66-year-old female patient with situs inversus totalis was diagnosed with hepatocellular carcinoma, 5 cm in diameter, centrally located just above the hepatic hilum compressing the right and left hepatic duct. The liver infected with hepatitis C was cirrhotic with a moderate amount of ascites. We preoperatively created several diagrams of the mirror image anatomy and made plans for how to resect this tumor, presupposing the patient had an ordinary anatomy. The tumor was successfully enucleated with referring to these diagrams. The operation time was 454 minutes. Five units of fresh frozen plasma was transfused intraoperatively. Although she suffered refractory ascites which needed repeated paracentesis, she managed to leave the hospital two months after the operation. Creating a mirror image anatomy enables surgeons to safely perform a complex hepatectomy in a patient with situs inversus totalis..
112. Shohei Yamaguchi, Norifumi Tsutsumi, Eiji Kusumoto, Kazuya Endo, Koji Ikejiri, Yo ichi Yamashita, Hideaki Uchiyama, Hiroshi Saeki, Eiji Oki, Hirofumi Kawanaka, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, Lumbar hernia treated with lightweight partially absorbable mesh
report of a case., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 575-579, 2013.01, Superior lumbar hernia, also known as Grynfeltt-Lesshaft hernia, is an uncommon abdominal wall defect. We report a case of superior lumbar hernia, which was successfully treated with a lightweight partially absorbable mesh. A 73-year-old man visited our department with complaints of lumbar pain and a feeling of pressure associated with a right lumbar mass. A CT scan of the abdomen demonstrated a defect in the aponeurosis of the transversus abdominis muscle and a protrusion of the small intestine through the defect. The diagnosis of a right superior lumbar hernia was made. The lumbar hernia was surgically treated with a lightweight large-pore polypropylene mesh containing an absorbable component consisting of poliglecaprone (ULTRAPRO Plug). The patient had no evidence of recurrence after 4 years of follow-up without any sense of discomfort. This is the first case report of a lumbar hernia treated with a lightweight partially absorbable mesh. This partially absorbable mesh can be considered to be suitable for the treatment of a lumbar hernia..
113. Satoshi Tsutsumi, Eiji Oki, Satoshi Ida, Koji Ando, Yasue Kimura, Hiroshi Saeki, Masaru Morita, Tetsuya Kusumoto, Tetsuo Ikeda, Yoshihiko Maehara, Laparoscopic gastrectomy for gastric cancer with peritoneal dissemination after induction chemotherapy, Case Reports in Gastroenterology, 10.1159/000357591, 7, 3, 516-521, 2013.01, Gastric cancer with peritoneal dissemination may be diagnosed as unresectable. More recently, as a result of progress in chemotherapy, some patients with peritoneal dissemination have exhibited extended survival. We report on our experience with three patients in whom induction chemotherapy allowed for totally laparoscopic total gastrectomy (TLTG). All three patients were diagnosed as having advanced gastric cancer with peritoneal dissemination using staging laparoscopy. As induction chemotherapy, S-1 combined with cisplatin was administered to two patients and trastuzumab plus capecitabine combined with cisplatin to one patient. TLTG was performed in all patients and there were no postoperative complications. Adjuvant chemotherapy was initiated within 3 weeks after surgery in all three patients. Laparoscopic gastrectomy undertaken after induction chemotherapy was found to be effective and safe; this treatment has the potential to achieve good treatment outcomes in patients with stage IV gastric cancer..
114. Tetsuo Ikeda, Tomohiko Akahoshi, Hirofumi Kawanaka, Hideaki Uchiyama, Yo ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Keishi Sugimachi, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Ken Shirabe, Koshi Mimori, Masayuki Watanabe, Makoto Hashizume, Yoshihiko Maehara, Evaluation of a transection method for distal pancreatectomy
A comparative study on the use of electrosurgical and stapling devices in swine., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 515-522, 2013.01, Despite marked improvements in pancreatic surgery, the high incidence of pancreatic fistula and high morbidity after resection persists. The objective of this study was to evaluate the role of electrosurgical and stapling devices as an alternative to traditional methods of stump closure in an animal model of distal pancreatectomy. Four devices were used for transection of the pancreatic body : a bi-polar thermofusion system attached to an automatic irrigation function (BI, n = 3), a bi-polar tissue sealer (BS, n = 3), an ultrasonic scissor (US, n = 3), and an endoscopic stapling device (ES, n = 3). For each group, burst pressure was tested using an electronic manometer, with a focus on the location (s) of the first disruption (s). Histological examination was performed for the dissected surfaces. The transection line, including staples, was embedded in a polyester resin, and histological examination was performed for these polished sections of the resin. Pressure was significantly higher for BI (P < 0.01) than that for the other devices. In contrast, thermal denaturation of the pancreas parenchyma was observed at a depth of approximately 1 mm from the dissected portion for BS, while it extended beyond 15 mm for BI. The staple line was the first disruption point for all of ES cases. The pellicle of the pancreas is likely to be deficient after a surgical operation. If the pellicle is preserved, the strength of the pellicle may be insufficient for complete closure with high stapling mechanical pressure or the protein coagulation of usually used electrosurgical devices..
115. H. Saeki, M. Morita, N. Harada, A. Egashira, E. Oki, H. Uchiyama, T. Ohga, Y. Kakeji, Y. Sakaguchi, Y. Maehara, Esophageal replacement by colon interposition with microvascular surgery for patients with thoracic esophageal cancer
The utility of superdrainage, Diseases of the Esophagus, 10.1111/j.1442-2050.2012.01327.x, 26, 1, 50-56, 2013.01, Replacing the thoracic esophagus with the colon is one mode of reconstruction after esophagectomy for esophageal cancer. There is, however, a high incidence of postoperative necrosis of the transposed colon. This study evaluated the outcomes of colon interposition with the routine use of superdrainage by microvascular surgery. Twenty-one patients underwent colon interposition from 2004 to 2009. The strategy for colon interposition was to: (i) use the right hemicolon; (ii) reconstruct via the subcutaneous route; (iii) perform a microvascular venous anastomosis for all patients; and (iv) perform a microvascular arterial anastomosis when the arterial blood flow was insufficient. The clinicopathologic features, surgical findings, and outcomes were investigated. The colon was used because of a previous gastrectomy in 18 patients (85.7%) and synchronous gastric cancer in three patients (14.3%). Eight patients (38.1%) underwent preoperative chemoradiotherapy including three (14.3%) treated with definitive chemoradiotherapy. Seven patients (33.3%) underwent microvascular arterial anastomosis to supplement the right colon blood supply. Pneumonia occurred in four patients (19.0%). Anastomotic leakage was observed in five patients (23.8%); however, no colon necrosis was observed. The 3-year and 5-year overall survival rates were both 50.6%. Colon interposition with superdrainage results in successful treatment outcomes. This technique is one option for colon interposition employing the right hemicolon..
116. Takeo Toshima, Tomoharu Yoshizumi, Hideaki Uchiyama, Toru Ikegami, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Koshi Mimori, Keishi Sugimachi, Hiroshi Saeki, Masayuki Watanabe, Ken Shirabe, Yoshihiko Maehara, Effect of CD133-positive stem cells in repeated recurrence of hepatocellular carcinoma after liver transplantation
a case report., Unknown Journal, 104, 10, 383-388, 2013.01, Liver transplantation (LT) is currently one of the best available strategies for treating multiple hepatocellular carcinoma (HCC) and decompensated liver cirrhosis. However, patients often undergo HCC recurrence after LT, with most HCC recurrences detected at 1-2 years. CD133 was the first identified member of the prominin family of pentaspan membrane proteins and is a marker of hepatic stem cells. Here, we report a unique case of seven repeated recurrences of HCC in the lungs after LT, with all HCC recurrences resected curatively by a thoracoscopic approach. Pathological examination revealed moderately differentiated HCC identical to that in the original histology of the liver tumor. Interestingly, no CD133 immunoreactivity was observed in cancerous lesions of the primary HCC and the 1st to 2nd recurrences, as indicated by immunohistochemistry. However, CD133 was strongly stained in the cancerous lesions from the 3rd to 7th recurrences. The patient survived and had no recurrence after 9 years of the initial living donor LT. In conclusion, we investigated an evocative case of seven repeated recurrences of HCC in the lungs to elucidate the significance of circulating CD133-positive hepatic stem cells. This case illustrates the need for further research to clarify the mutual effect of CD133-positive hepatic stem cells for the development of new therapeutic strategies..
117. Yuta Kasagi, Hiroshi Saeki, Koji Ando, Yukiharu Hiyoshi, Shuhei Ito, Keishi Sugimachi, Yo Ichi Yamashita, Eiji Oki, Hideaki Uchiyama, Hirofumi Kawanaka, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, Clinical results of preoperative CDDP/5-FU chemotherapy followed by surgery for patients with clinical stage II/III thoracic esophageal cancer., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 523-529, 2013.01, The purpose of this study was to clarify the outcomes of preoperative CDDP/5-FU chemotherapy (FP therapy) followed by surgery for patients with clinical Stage II/III thoracic esophageal cancer. Seventeen patients with clinical Stage II/III thoracic esophageal cancer who underwent FP therapy followed by esophagectomy were investigated with regard to the perioperative clinical results and postoperative outcomes. Grade 3 or 4 adverse effects associated with FP therapy were recognized in 2 of the 17 (11.8%) cases, and 16 patients completed 2 cycles of FP therapy (94.1%). Complications after surgery occurred in 7 cases (41.2%). There were 7 patients with postoperative recurrences (41.2%), 6 of whom had clinical Stage III disease. Similarly, 4 out of the 5 patients who died of cancer had clinical Stage III disease. All recurrences and cancer-related deaths were recognized in histological effectiveness of Grade 0/1 cases. Preoperative FP therapy was found to be safe for patients with clinical Stage II/III thoracic esophageal cancer. However, the treatment seemed to be less beneficial for Stage III patients than for Stage II patients, thus suggesting that a more powerful preoperative treatment may be necessary for clinical Stage III patients..
118. Munkhbold Tuul, Hiroyuki Kitao, Makoto Iimori, Kazuaki Matsuoka, Shinichi Kiyonari, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiko Maehara, Rad9, Rad17, TopBP1 and Claspin Play Essential Roles in Heat-Induced Activation of ATR Kinase and Heat Tolerance, PloS one, 10.1371/journal.pone.0055361, 8, 2, 2013.02, Hyperthermia is widely used to treat patients with cancer, especially in combination with other treatments such as radiation therapy. Heat treatment per se activates DNA damage responses mediated by the ATR-Chk1 and ATM-Chk2 pathways but it is not fully understood how these DNA damage responses are activated and affect heat tolerance. By performing a genetic analysis of human HeLa cells and chicken B lymphoma DT40 cells, we found that heat-induced Chk1 Ser345 phosphorylation by ATR was largely dependent on Rad9, Rad17, TopBP1 and Claspin. Activation of the ATR-Chk1 pathway by heat, however, was not associated with FancD2 monoubiquitination or RPA32 phosphorylation, which are known as downstream events of ATR kinase activation when replication forks are stalled. Downregulation of ATR, Rad9, Rad17, TopBP1 or Claspin drastically reduced clonogenic cell viability upon hyperthermia, while gene knockout or inhibition of ATM kinase reduced clonogenic viability only modestly. Suppression of the ATR-Chk1 pathway activation enhanced heat-induced phosphorylation of Chk2 Thr68 and simultaneous inhibition of ATR and ATM kinases rendered severe heat cytotoxicity. These data indicate that essential factors for activation of the ATR-Chk1 pathway at stalled replication forks are also required for heat-induced activation of ATR kinase, which predominantly contributes to heat tolerance in a non-overlapping manner with ATM kinase..
119. Aiko Sato, Eiji Oki, Hidenori Kohso, Yuichi Endo, Hiroki Uchida, Shoji Hiroshige, Masaru Ishida, Gankichi Saito, Toshifumi Matsumoto, Hideya Takeuchi, Tetsuya Kusumoto, Yasuji Yoshikawa, Yoichi Muto, Sarcomatoid carcinoma of the remnant stomach
Report of a case, Surgery today, 10.1007/s00595-012-0402-7, 43, 3, 308-312, 2013.03, We herein report a case of sarcomatoid carcinoma that developed in a remnant stomach. A 76-year-old male with a history of distal gastrectomy for a duodenal ulcer 28 years earlier underwent investigation for a tumor in the remnant stomach. An endoscopic survey showed a round elevated tumor measuring 6 cm in diameter, and a biopsy specimen suggested carcinosarcoma. A total gastrectomy of the remnant stomach was performed, and the excised tumor was identified to be a malignant neoplasm consisting of both carcinomatous and sarcomatous components. A diagnosis of sarcomatoid carcinoma was made since the epithelial markers were positive even in the mesenchymal elements of the tumor. To our knowledge, only 4 cases of sarcomatoid carcinoma of the stomach have been reported in the English literature so far..
120. Eiji Oki, Yasunori Emi, Yoshito Akagi, Shoji Tokunaga, Noriaki Sadanaga, Takaho Tanaka, Yutaka Ogata, Hiroshi Saeki, Yoshihiro Kakeji, Hideo Baba, Tadashi Nishimaki, Shoji Natsugoe, Kazuo Shirouzu, Yoshihiko Maehara, Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701) Kyushu study group of clinical cancer, Oncology (Switzerland), 10.1159/000346690, 84, 4, 233-239, 2013.03, Objective: This phase II study examined the efficacy and safety of alternating regimens of mFOLFOX6 and FOLFIRI as a first-line treatment for unresectable or metastatic colorectal cancer. Patients and Methods: Forty-eight patients were enrolled in this study. Patients received an alternating regimen of 4 cycles of mFOLFOX6 followed by 4 cycles of FOLFIRI. Results: The characteristics of the study population were as follows: males/females 34/12, median age 66 years (range 43-75) and Eastern Cooperative Oncology Group performance status 0/1/2 in 37/9/0 patients. The overall response rate was 58.7% [95% confidence interval (CI) 43.9-73.5]. The median progression-free survival was 10.3 months (95% CI 7.5-11.9), and the median overall survival was 28.4 months (95% CI 22.5-35.7). Among the 47 patients evaluated for toxicity, the most common grade 3-4 adverse events were leukopenia (26%), neutropenia (55%), anemia (4%), neurotoxicity (0%), diarrhea (2%), febrile neutropenia (4%), nausea (4%), vomiting (2%), and hypersensitivity (0%). Conclusions: The results of this phase II study indicate that this alternating schedule is effective and well tolerated as a first-line treatment for unresectable or metastatic colorectal cancer. The low rate of grade 3 neurotoxicity is also promising..
121. Yasunori Emi, Yoshihiro Kakeji, Eiji Oki, Hiroshi Saeki, Koji Ando, Masaki Kitazono, Yoshihisa Sakaguchi, Masaru Morita, Hironori Samura, Yutaka Ogata, Yoshito Akagi, Shoji Natsugoe, Kazuo Shirouzu, Shoji Tokunaga, Florin Sirzen, Yoshihiko Maehara, Initial report of KSCC0803
Feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japanese patients, International Journal of Clinical Oncology, 10.1007/s10147-011-0371-7, 18, 2, 254-259, 2013.04, Background: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. Methods: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m2/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. Results: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. Conclusions: This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients..
122. Masaru Morita, Hajime Otsu, Hiroyuki Kawano, Ryuichi Kumashiro, Kenji Taketani, Yasue Kimura, Hiroshi Saeki, Koji Ando, Satoshi Ida, Eiji Oki, Eriko Tokunaga, Tetsuo Ikeda, Tetsuya Kusumoto, Yoshihiko Maehara, Advances in esophageal surgery in elderly patients with thoracic esophageal cancer, Anticancer research, 33, 4, 1641-1648, 2013.04, Aim: To justify esophagectomy for elderly patients. Patients and Methods: A total of 1,002 patients with thoracic esophageal cancer who underwent esophagectomy were divided into three groups: I (≤74 years old, n=898); II (75-79 years, n=81); and III (≥80 years, n=23). Historical changes were compared between the first surgical period (1964-1989) and the second period (1990-2011). Results: The morbidity rates were 40%, 41% and 26% in the respective groups. Pulmonary complications decreased historically in groups II and III (36% to 15% and 43% to 0%, respectively). The mortality was higher in the older groups (4.8%, 8.6% and 13.0%, respectively); however, there was a marked historical decrease in groups II (18.2% to 5.1%) and III (28.6% to 6.3%). The 5-year survival improved from 5% to 35% in group II and from 0% to 17% in group III. Conclusion: The outcomes of esophagectomy for elderly patients have markedly improved, with acceptable mortality even in octogenarians..
123. Hiroshi Saeki, Eiji Oki, Hiroyuki Kawano, Koji Ando, Satoshi Ida, Yasue Kimura, Masaru Morita, Tetsuya Kusumoto, Tetsuo Ikeda, Yoshihiko Maehara, Newly developed liver-retraction method for laparoscopic gastric surgery using a silicone disc
The Φ-shaped technique, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2013.02.005, 216, 5, e43-e46, 2013.05.
124. Fusanori Yotsumoto, Eriko Tokunaga, Eiji Oki, Yoshihiko Maehara, Hiromi Yamada, Kyoko Nakajima, Sung Ouk Nam, Kohei Miyata, Midori Koyanagi, Keiko Doi, Senji Shirasawa, Masahide Kuroki, Shingo Miyamoto, Molecular hierarchy of heparin-binding EGF-like growth factor-regulated angiogenesis in triple-negative breast cancer, Molecular Cancer Research, 10.1158/1541-7786.MCR-12-0428, 11, 5, 506-517, 2013.05, Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HBEGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under two-dimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1α and NF-κB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis..
125. Yuta Kasagi, Eiji Oki, Koji Ando, Yasue Kimura, Toru Ikegami, Hiroshi Saeki, Masaru Morita, Tetsuya Kusumoto, Yoshihiko Maehara, A case of panitumumab-responsive metastatic rectal cancer initially refractory to cetuximab, Case Reports in Oncology, 10.1159/000353781, 6, 2, 382-386, 2013.05, A 64-year-old man was initially diagnosed with rectal cancer and liver metastasis. He underwent rectal amputation and partial hepatectomy. mFOLFOX6 was begun as first-line chemotherapy, but multiple pulmonary and right femoral lymph node metastases were found 1 year postoperatively. FOLFIRI plus bevacizumab was then started, but the tumors recurred after 2 years and 11 months. The regimen was changed to cetuximab with CPT-11. The lesions partially responded after 3 months, and the patient was free from progression for 1.5 years. Four years and 7 months after the adjuvant chemotherapy was started, the metastatic lesions gradually increased again, and the regimen was changed to panitumumab. After 2 months, the lesions had markedly decreased again and showed a partial response for 6 months. Although the pulmonary lesions became progressive again, the patient has been alive for 5 years and 8 months since the first operation..
126. Masaru Morita, Hiroyuki Kawano, Hajime Otsu, Yasue Kimura, Hiroshi Saeki, Koji Ando, Satoshi Ida, Eiji Oki, Tetsuo Ikeda, Tetsuya Kusumoto, Jun Ichi Fukushima, Torahiko Nakashima, Yoshihiko Maehara, Surgical resection for esophageal cancer synchronously or metachronously associated with head and neck cancer, Annals of Surgical Oncology, 10.1245/s10434-013-2875-z, 20, 7, 2434-2439, 2013.07, Background: Esophageal cancer is frequently associated with head and neck cancer, and esophagectomy is usually difficult in such a case. The purpose of this study was to clarify the clinical significance of esophagectomy for patients with esophageal cancer associated either synchronously or metachronously with head and neck cancer. Methods: The clinical outcomes of surgical resections for esophageal cancer were compared between 26 patients with head and neck cancer (double cancer group) and 176 without head and neck cancer (control group). Results: Staged operations were performed in 5 patients in the double cancer group, while microvascular anastomosis as well as a muscle flap was added for 3 and 4 patients, respectively. The mortality and morbidity of the double cancer group were 0 and 35 %, respectively, which were not significantly different from those of the control group (3 and 31 %, respectively). There were no significant differences in overall survival in the double cancer and control groups, which had 5-year survival rates of 59 and 49 %, respectively. Conclusions: Esophagectomy can be an effective treatment when techniques are adopted that are appropriate for each case, such as staged operations, muscular flaps, and microvascular anastomosis, even in patients with double cancers of the esophagus and the head and neck..
127. Gen Hidaka, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, [Simultaneous totally laparoscopic total gastrectomy and low anterior resection for synchronous gastric and rectal cancer; a case report], Fukuoka igaku zasshi = Hukuoka acta medica, 104, 8, 257-261, 2013.08, Simultaneous operations for synchronous cancers are thought to increase in the near future due to recent advancement of laparoscopic surgery. A 75-year-old male patient was admitted to our hospital and diagnosed as synchronous gastric and rectal cancer (gastric cancer: cT2N0M0 StageIB, rectal cancer: cSEN0M0 StagII). The simultaneous totally laparoscopic total gastrectomy and low anterior resection was scheduled. The low anterior resection was first performed with five ports on the lower abdomen, and followed by the total gastrectomy with addition of 3 ports on the upper abdomen. The postoperative course was uneventful. This case suggest that the simultaneous totally laparoscopic total gastrectomy and low anterior resection was useful operation for patients with synchronous gastric and rectal cancers. We herein report the case and discuss based on some literatures..
128. Hiroshi Saeki, Masaru Morita, Yasuo Tsuda, Gen Hidaka, Yuta Kasagi, Hiroyuki Kawano, Hajime Otsu, Koji Ando, Yasue Kimura, Eiji Oki, Tetsuya Kusumoto, Yoshihiko Maehara, Multimodal treatment strategy for clinical T3 thoracic esophageal cancer, Annals of Surgical Oncology, 10.1245/s10434-013-3192-2, 20, 13, 4267-4273, 2013.08, Purpose. Our goal was to create a multimodal treatment strategy for patients with locally advanced esophageal cancer (EC). Methods. A retrospective review identified a total of 193 patients with clinical T3 thoracic EC were categorized into 3 groups: 81 who had surgery only (group I); 102 who had planned neoadjuvant chemoradiotherapy (NACRT; group II); and 10 who had salvage esophagectomy after definitive chemoradiotherapy (dCRT; group III). Results. Postoperative complications developed in 27, 45, and 80 % of patients in group I, group II, and group III, respectively. NACRT and dCRT were independent risk factors associated with postoperative complications; the odds ratios for group II and group III, compared with group I, were 2.1 and 8.8, respectively. The respective mortality rates were 4, 2, and 20 % (group I vs. group III, p\0.05; group II vs. group III, p\0.01). The 5-year survival rate was 25.2 % in group I and 41.6 % in group II. The 5-year survival rate in group II patients with markedly effective NACRT (89.2 %) was significantly better than in patients with ineffective/slightly effective (11.8 %; p\0.0001) and moderately effective treatment (51 %; p\0.05). Four patients who had noncurative surgery died within 4 months after salvage esophagectomy, whereas four of six patients were still alive after curative surgery. Conclusions. A pathological complete response to NACRT is critical for improving survival in patients with clinical T3 thoracic EC. Salvage surgery should be considered only in carefully selected patients with locally advanced EC..
129. Ayae Ikawa-Yoshida, Koji Ando, Eiji Oki, Hiroshi Saeki, Ryuichi Kumashiro, Kenji Taketani, Satoshi Ida, Eriko Tokunaga, Hiroyuki Kitao, Masaru Morita, Yoshihiko Maehara, Contribution of BubR1 to oxidative stress-induced aneuploidy in p53-deficient cells, Cancer Medicine, 10.1002/cam4.101, 2, 4, 447-456, 2013.08, DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO3) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO3 did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO3-induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy. We found that OS could contribute to the emergence of polyploid cells when p53 was deficient in normal human fibroblast cells. Importantly, this polyploidization could be suppressed by downregulating the expression of one spindle assembly checkpoint factor, BubR1. We also found that p53 dysfunction and BubR1 accumulation strongly correlate with the extent of aneuploidy in gastric cancer specimen and our data suggest that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy..
130. Hirokazu Kitahara, Eiji Oki, Hiroki Saeki, Koji Ando, Ken Shirabe, Shunji Kounoe, Shinichi Aishima, Yoshihiro Kakeji, Yoshihiko Maehara, A case of liver metastasis from gastric cancer responding completely to S-1/docetaxel chemotherapy, Japanese Journal of Cancer and Chemotherapy, 40, 8, 1093-1097, 2013.08, A 68-year-old man was introduced to our hospital with right lower abdominal pain. Endoscopic examination and abdominal CT revealed gastric cancer with liver metastasis. We started chemotherapy using S-1 (120 mg/body/day), orally administered for 2 weeks followed by a 2-week rest period, and docetaxel (35 mg/m2), administered intravenously on day 1 and 15 as 1 course. After 4 courses of chemotherapy, the liver tumor reduced markedly and no new cancerous region was found by examination; therefore total gastrectomy and partial hepatectomy were performed. Histological examination showed an undifferentiated adenocarcinoma remaining as Grade 1b in the resected stomach. A resected specimen of the liver showed necrotic tissue without any cancer cells. This case suggests that S-1/docetaxel chemotherapy may reduce the stage of unresectable liver metastasis from gastric cancer and make a curative operation possible..
131. Eiji Oki, Total laparoscopic distal gastrectomy for elderly patients with gastric cancer, Fukuoka igaku zasshi = Hukuoka acta medica, 104, 9, 290-298, 2013.09, INTRODUCTION: This study evaluated the feasibility of totally laparoscopic distal gastrectomy (TLDG) in elderly patients with gastric cancer.
METHODS: We retrospectively analyzed the data from 138 patients who underwent TLDG from April 2005 to March 2009. Of these 138 patients, 20 were older than 75 years of age, and 118 were 75 years of age or younger.
RESULTS: The preoperative respiratory function and American Society of Anesthesiologists (ASA) -physical status were significantly worse in the elderly patients than in the younger patients (P = 0.013). Hypertension and respiratory disease were more common in the elderly patients than in the younger patients (P = 0.032 / P = 0.005). The findings for the following parameters were similar in the two groups: intraoperative blood loss, operation time, severe postoperative complication rate, time required to start a solid diet, and duration of postoperative hospital stay. The rate of major complications was not different between the two groups, although minor complications were more commonly observed in the elderly patients.
CONCLUSION: TLDG was found to be a safe procedure for elderly patients. This method can be used as one of the standard treatments for gastric cancer in elderly patients..
132. Koichi Kimura, Toru Ikegami, Yo ichi Yamashita, Hiroshi Saeki, Eiji Oki, Tomoharu Yoshizumi, Hideaki Uchiyama, Hirofumi Kawanaka, Yuji Soejima, Masaru Morita, Ken Shirabe, Tetsuo Ikeda, Yoshihiko Maehara, Rendezvous technique treatment for late-onset biliary leakage after major hepatectomy of a living donor
report of a case., Fukuoka Acta Medica, 104, 9, 309-314, 2013.09, Biliary leakage is a major complication after hepatectomy. We report the case of a living-donor liver transplantation (LDLT) donor with a late-onset bile leak from the trifurcation of the hepatic duct who was successfully treated using rendezvous technique. A 52-year-old man underwent extended left hepatectomy for donation and was discharged on postoperative day (PD) 13. However, he was rehospitalized on PD 26 with severe abdominal pain. Physical examination suggested panperitonitis, and abdominocentesis showed bilious ascites. Emergent laparotomy for biliary leakage and peritonitis was performed. There was bilious ascites in the peritoneal cavity. A biliary fistula was recognized at the trifurcation of B8a, B8b, and B5. Intraoperative transhepatic biliary drainage of each bile duct was performed. Endoscopic transpapillary drainage was performed on PD 24. Finally, external drains were removed and complete internal drainage established on PD 70. The bile leak was considered to be the result of injury from electrocautery device. Appropriate making choices of the electrocautery devices enable us to avoid over thermal injury of the liver surface. Rendezvous bidirectional drainage effectively treated late-onset bile leakage from the trifurcation of a hepatic bile duct..
133. Yasue Kimura, Hiroyuki Matsuda, Hiroshi Saeki, Eiji Oki, Masaru Morita, Keishi Sugimachi, Yo ichi Yamashita, Toru Ikegami, Hideaki Uchiyama, Tomoharu Yoshizumi, Yuji Soejima, Hirofumi Kawanaka, Tetsuo Ikeda, Shinichi Tsutsui, Megumu Fujihara, Koshi Mimori, Masayuki Watanabe, Teruyoshi Ishida, Yoshihiko Maehara, Case of early adenosquamous carcinoma of the stomach., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 9, 315-320, 2013.09, Adenosquamous carcinoma of the stomach is very rare; at present, there are only seven published reports. We report here an eighth case involving a 77-year-old Japanese man who was diagnosed with gastric cancer by upper endoscopy and computed tomography (CT). He underwent laparoscopic-assisted distal gastrectomy for early gastric cancer and the resected specimen was diagnosed as adenosquamous carcinoma limited to the submucosal layer. Only one lymph node metastasis was noted. Seven months later, liver metastasis (3 tumors, 15 mm maximum in diameter) was detected by abdominal CT. He was started on chemotherapy with S-1 and cisplatin (CDDP) and is alive 14 months after surgery. Almost all cases of adenosquamous carcinoma of the stomach are diagnosed in advanced stages and carry a very poor prognosis. Most patients with early adenosquamous carcinoma of the stomach survive for 2 or more years without recurrence, however our patient experienced recurrence 7 months after surgery. Therefore, future treatment for recurrent adenosquamous carcinoma of the stomach should be considered..
134. Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Hideaki Uchiyama, Yo ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Koshi Mimori, Keishi Sugimachi, Masayuki Watanabe, Ken Shirabe, Yoshihiko Maehara, Application of splenectomy to decompress portal pressure in left lobe living donor liver transplantation., Fukuoka Acta Medica, 104, 9, 282-289, 2013.09, This study was conducted to evaluate the impact of splenectomy in living donor liver transplantation (LDLT) using left lobe grafts. The two hundred and fifty LDLT cases were divided into two groups: Group-S (n = 98, simultaneous splenectomy) and Group-NS (n = 152). Group-S had significantly increased recipient age (54.5 +/- 10.9 years vs. 46.3 +/- 17.0 years, p < 0.01), advanced liver diseases including Child class C (64.8% vs. 51.5%, p < 0.01), higher model for end-stage liver score (17.8 +/- 8.1 vs. 15.4 +/- 5.8, p < 0.01) and more patients with hospitalized status (67.4% vs. 48.0%, p < 0.01), and smaller graft volume/standard liver volume ratio (36.5 +/- 6.1% vs. 40.2 +/- 8.2%, p < 0.01). In Group-S, splenectomy decreased portal venous (PV) pressure decreased from 23.5 +/- 5.2 mmHg to 19.2 +/- 4.8 mmHg (p < 0.01). Group-S had significantly increased PV pressure at laparotomy (24.9 +/- 5.3 mmHg vs. 22.5 +/- 6.3 mmHg, p < 0.01) and decreased PV pressure at closure (16.4 +/- 3.5 mmHg vs. 18.0 +/- 4.7 mmHg, p < 0.01), compared with Group-NS. On the 14th day after LDLT, Group-S had lower total bilirubin (5.7 +/- 6.5 mg/dl vs. 8.7 +/- 8.9 mg/dl, p < 0.01) and smaller ascites output (0.4 +/- 0.7 L/day vs. 0.7 +/- 0.4 L/day, p = 0.01) than Group-NS. The cumulative 5-year graft survival rate was 86.8% in Group-S and 76.2% in Group-NS (p = 0.03). In conclusion, splenectomy had beneficial impacts on graft outcomes in left-lobe LDLT..
135. Junji Kurashige, Genta Sawada, Yusuke Takahashi, Hidetoshi Eguchi, Tomoya Sudo, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Hideaki Uchiyama, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Keishi Sugimachi, Masayuki Watanabe, Masaki Mori, Hideo Baba, Koshi Mimori, Suppression of MAL gene expression in gastric cancer correlates with metastasis and mortality., Unknown Journal, 104, 10, 344-349, 2013.10, The Myelin and lymphocyte-associated protein gene (MAL), which is located on the long arm of chromosome 2, assigned to the region cen-q13 in humans, has been reported as tumor suppressor in several cancers. The aim of this study was to clarify the clinical significance of MAL gene in gastric cancer. The expression levels of MAL mRNA was examined using 50 resected gastric cancer specimens used by laser microdissected to determine the clinicopathological significance. MAL expression was then examined by real-time quantitative PCR assay, and we analyzed the correlation between MAL expression and clinicopathological factors. In clinicopathologic analysis, the low MAL expression group showed significantly higher incidence of lymph node metastasis than the high expression group (79% and 46%, respectively, p < 0.05). Furthermore, the low MAL expression group had a significantly poorer prognosis than the high expression group (p < 0.05). The MAL gene repression related with lymph node metastasis and poor prognosis in gastric cancer, suggesting that the MAL may be a new candidate node metastasis-suppressor gene for gastric cancer..
136. Norifumi Harimoto, Hiroyuki Matsuyama, Kiyoshi Kajiyama, Takashi Nagaie, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Ken Shirabe, Tetsuo Ikeda, Hirofumi Kawanaka, Hideaki Uchiyama, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Hiroshi Saeki, Yoshihiko Maehara, Significance of stroke volume variation during hepatic resection under infrahepatic inferior vena cava and portal triad clamping., Unknown Journal, 104, 10, 362-369, 2013.10, Stroke volume variation (SVV), which is measured by analyzing arterial blood pressure waveform characteristics, is a simple and sensitive indicator of fluid responsiveness. The current retrospective study was to investigate SVV and central venous pressure (CVP) during hepatic resection under clamping of both the infrahepatic inferior vena cava (IVC) and the portal triad. All hepatic resections performed from December 2009 to February 2010 at the Department of Surgery at Iizuka Hospital in Japan were included in this study. Invasive hemodynamic monitoring including CVP and SVV were performed in 14 patients. CVP was significantly lower in patients with blood loss < or = 486 g than in those with blood loss > 486 g. SVV was significantly higher in patients with blood loss < or = 486 g than those with blood loss > 486 g during both IVC clamping and IVC + portal triad clamping. Estimated blood loss was significantly less in the group with SVV values > 18% compared to the group with values < or = 18%. There was a significant correlation between SVV and CVP (R2 = 0.714; P < .01). SVV is a useful indicator of intraoperative blood loss without the monitoring of CVP during hepatic resection under clamping of both the infrahepatic IVC and the portal triad..
137. Hideki Ijichi, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Tetsuo Ikeda, Hirofumi Kawanaka, Hideaki Uchiyama, Yo Ichi Yamashita, Masaru Morita, Eiji Oki, Koshi Mimori, Keishi Sugimachi, Hiroshi Saeki, Masayuki Watanabe, Ken Shirabe, Yoshihiko Maehara, Recurrent hepatitis B following recurrence of hepatocellular carcinoma after living donor liver transplantation., Unknown Journal, 104, 10, 376-382, 2013.10, Hepatitis B virus (HBV) recurrence after liver transplantation for HBV-associated liver diseases results in decreased patient and graft survival. Herein we have reported two cases of HBV recurrence following relapse of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT). Both cases had LDLT for end-stage liver disease secondary to HBV infection with nodules of HCC exceeding the Milan criteria. HBV prophylaxis using hepatitis B immunoglobulin with nucleos (t) ide analogues were given and HBV DNA levels were consistently undetectable after LDLT. HCC recurred at 5 months and 13 months posttransplant respectively, and chemotherapy and radiation therapy were performed. HBV recurrence occurred during the treatment of HCC. HBV DNA levels increased despite the treatment with anti-HBV agents after HBV recurrence. In hepatitis B surface antigen positive recipients, HBV prophylaxis should be intensified during the treatment of recurrent HCC..
138. Yasuharu Ikeda, Kiyoshi Kajiyama, Yo Ichi Yamashita, Toru Ikegami, Hideaki Uchiyama, Yuji Soejima, Hirofumi Kawanaka, Tetsuo Ikeda, Masaru Morita, Eiji Oki, Hiroshi Saeki, Taketoshi Suehiro, Kohshi Mimori, Keishi Sugimachi, Ken Shirabe, Yoshihiko Maehara, Differential expression of insulin-like growth factor 1 in human primary liver cancer., Unknown Journal, 104, 10, 334-338, 2013.10, Insulin-like Growth Factor 1 (IGF-1) antigen was immunohistochemically examined in 28 patients of the primary hepatocellular carcinoma with hepatectomy. IGF-1 was expressed in 93% (26/28) of the primary lesion and 100% (28/28) of the normal liver. Compared with expression in normal liver, decreased expressions in primary lesions were noted in 36% (10/28) for IGF-1. Histological examination revealed that there were significant correlations between patients with decreased expressions of IGF-1 in primary lesions and poor differentiated hepatocellular carcinoma, and portal vein infiltration. These results indicate that expression of IGF-1 has the relationship with the differentiation in human primary hepatocellular carcinoma..
139. Mizuki Ninomiya, Tetsuo Ikeda, Ken Shirabe, Hiroto Kayashima, Norifumi Harimoto, Tomohiro Iguchi, Keishi Sugimachi, Yo Ichi Yamashita, Toru Ikegami, Hiroshi Saeki, Eiji Oki, Hideaki Uchiyama, Tomoharu Yoshizumi, Yuji Soejima, Hirofumi Kawanaka, Masaru Morita, Yoshihiko Maehara, Three-dimensional computed tomography image based endovascular treatment for hepatic vein., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 469-472, 2013.11, Along with the expansion of living donor liver transplantation, whereby hepatic venous anastomosis is mandatory, the frequency of hepatic venous stenosis that need interventional treatment is increasing. Due to its anatomical features, there are several pitfalls in the process of endovascular intervention for hepatic vein. Insufficient information of and around the hepatic vein may lead to miss-diagnosis of target lesion. Simulation by using three-dimensional computed tomography images was useful in planning the direction of X-ray projection and, as a consequence, contributed to safe endovascular treatment for hepatic venous stenosis..
140. Yasue Kimura, Masaru Morita, Hiroshi Saeki, Tetuo Ikeda, Koji Ando, Eiji Oki, Keishi Sugimachi, Yo Ichi Yamashita, Hideaki Uchiyama, Hirofumi Kawanaka, Mitsuhiko Ohta, Yoshihisa Sakaguchi, Tetsuya Kusumoto, Sei Yoshida, Torahiko Nakashima, Masayuki Watanabe, Toshiya Furuta, Yoshihiko Maehara, Minimally invasive total pharyng-laryngo-esophagectomy and reconstruction with gastric tube
report of three cases., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 442-448, 2013.11, Total pharyngo-laryngo-esophagectomy (TPLE) is indicated for either cervical esophageal cancer or synchronous double cancer of the thoracic esophagus and head and neck and this operation is extremely invasive. We adopted minimally invasive surgery for three patients who underwent this operation: VATS (video-assisted thoracoscopic surgery) esophagectomy was undergone in left semi-prone position and laparoscopic approach was also applied to reconstruction with gastric tube. After pharyngo-laryngectomy and gastric tube pull-up through post-mediastinal route, cervical anastomosis was performed. Free jejunal interposition was added in a case, while microvascular venous anastomosis between short gastric vein and cervical vein in another two cases. All patients recovered well without any postoperative complications. This is the first report, which describes minimally invasive TPLE using both VATS and laparoscopic technique in addition with plastic surgery..
141. Tetsuya Kusumoto, Yasue Kimura, Masahiko Sugiyama, Mitsuhiko Ohta, Norifumi Tsutsumi, Yoshihisa Sakaguchi, Koji Ikejiri, Eiji Oki, Hiroshi Saeki, Masaru Morita, Tetsuo Ikeda, Toshiya Furuta, Yoshihiko Maehara, Leptomeningeal carcinomatosis originating from advanced gastric cancer--a report of three cases and review of the literatures., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 11, 456-463, 2013.11, Leptomeningeal carcinomatosis (LMC) is a rare complication of gastric cancer. Case 1. A 57-year-old female was diagnosed with gastric cancer and underwent distal gastrectomy with D2 lymph node dissection. Two years later, the patient suffered from para-aortic lymph node metastases and provided chemotherapy. During the chemotherapy, the patient emergently visited our hospital with chief complaints of a severe headache and dizziness. The above symptoms promptly abated by meningeal drainage, with a high value of the cerebrospinal fluid (CSF) pressure. Despite the administration of subsequent chemotherapy, the patient's clinical state rapidly worsened, including gradual progression of both blindness and hearing loss. Case 2. A 42-year-old male was diagnosed with Stage IV gastric cancer due to both distant lymph node metastases and an ascites. Chemotherapy with S-1 plus docetaxel was initiated. Upon finishing the fifth course of treatment, the patient complained of a severe headache. The magnetic resonance imaging (MRI) findings were suggestive of LMC. Under suspicion of carcinomatous meningitis, the patient underwent both cerebrospinal drainage with a high pressure value of 180 mmH2O and a cytological examination with a diagnosis of Class V. Immediately following the cerebrospinal drainage, the patient's symptoms promptly diminished. Case 3. A 66-year-old female was diagnosed with gastric cancer and underwent total gastrectomy with D2 dissection. About a year later, the patient suffered from the peritoneal dissemination, and provided serial chemotherapy regimens for 13 months. Thereafter the patient suffered from mildly stiff shoulders followed by serial severe headaches, and meningeal drainage was performed. The CSF showed pleocytosis and the presence of neoplastic cells, leading a diagnosis of LMC. After the placement of an Ommaya reservoir, the intrathecal chemotherapy was performed. Within two weeks of treatment, the patient's condition improved significantly, and the cell counts in the CSF obtained from the Ommaya reservoir remained low for six months after the first diagnosis of LMC. Although gastric LMC-affected patients often exhibit a fatal clinical course, the administration of intrathecal chemotherapy may improve survival. Systemic chemotherapy may be also administered in a limited number of patients with a superior performance status. At present, each case requires the individual making treatment decisions. Further accumulation of clinical cases and improving the overall understanding of the pathogenesis of this disease is needed in order to advance in the treatment of gastric LMC..
142. Hiroki Ueo, Yuki Takano, Tae Matsumura, Junji Kurashige, Yoshiaki Shinden, Hidetoshi Eguchi, Tomoya Sudo, Keishi Sugimachi, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, Koshi Mimori, [Identification of genes that predict lymph node metastasis in colorectal cancer cases]., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 559-563, 2013.12, Currently, Endoscopic mucosal resection (EMR) and laparoscopic surgery with colorectal cancer (CRC) and has been expanding rapidly. In handling of colon cancer, adaptation of EMR is determined by the depth of tumor invasion. It is important to identify genes to predict lymph node metastasis in early CRC tumors precisely in a reproducible fashion to determine the adaptation of EMR treatment. We performed the comprehensive analysis of gene expression and genomic copy number simultaneously in CRC primary tumors to identify the bona-fide indicator of lymph node metastasis. We collected cancer cells specifically by Laser Microdissection (LMD) on 157 cases of primary colorectal cancer, and performed oligo microarrays for gene expression (GE) and aCGH for copy number aberration. As for candidate genes to be associated with lymph node metastasis, we examined reprodicibility by quantitative RT-PCR using cDNA created from the RNA extracted from 172 cases of CRC. As for the association of lymph node metastasis, we found that 240 genes and 54 genes by aCGH and by oligo GE microarray, respectively. According to database of those two arrays, 501 genes were significantly correlated (correlation coefficient > 0.7) with each other, and we found that 11 out of 501 genes were identified as lymph node metastasis related genes with copy number alteration. Of these 11 genes, we focused on PCM1, MTUS1, ASAH1 on 8p22. Then, we confirmed that the decreased expression and genomic deletion of MTUS1 were observed in lymph node positive cases (p = 0.0195) in another subset of 172 cases of CRC. To measure the expression of MTUS1 of the tumor by PCR, we can predict the presence of lymph node metastasis. We expected that the loss of MTUS1 should be an important marker in determining the adaptation of endoscopic resection..
143. Akira Kabashima, Dai Kitagawa, Toshihiko Nakamura, Naoko Kondou, Fumihiro Shoji, Hirofumi Hasegawa, Seiichi Teramoto, Satoru Funahashi, Youichi Ikeda, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, [Case of early antral gastric cancer diagnosed during follow up of pyloric stenosis by the gastro-duodenal ulcer]., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 589-594, 2013.12, A 65-year-old man was admitted to our hospital with nausea, vomiting and appetite loss. First upper endoscopic examination and X-ray examination showed a peptic ulcer and a pyloric stenosis. Fiberscope could not go through the pyloric ring. Computed tomography examination and biopsy showed no evidence of malignancy. Though we considered surgical resection of the stenosis at first, he could eat a staple food with therapy of proton pump inhibitor. So we followed up with upper endoscopic examinations. Second, third and forth upper endoscopic examinations showed no evidence of malignancy. Fifth upper endoscopic examination showed an ulcer scar on the pyloric ring and a 0-IIc carcinoma in the antral greater curvature. Distal gastrectomy with D2 lymph node dissection and B-II reconstruction. Pathologically, a mucosal carcinoma with no lymph node metastasis and U1-III peptic ulcer were diagnosed..
144. Noboru Harada, Ken Shirabe, Tomoharu Yoshizumi, Toru Ikegami, Hideaki Uchiyama, Yuji Soejima, Yo Ichi Yamashita, Hiroshi Saeki, Eiji Oki, Hirofumi Kawanaka, Masaru Morita, Tetsuo Ikeda, Hiroshi Matsuura, Kenichiro Okadome, Yoshihiko Maehara, Surgical treatment and adjuvant chemotherapy for patients with biliary tract cancer
single institution experience of 100 patients., Fukuoka igaku zasshi = Hukuoka acta medica, 104, 12, 539-548, 2013.12, Surgery remains the treatment of choice for patients with resectable biliary tract cancer, enhancing the chance of cure and increasing long-term survival. Early recurrence, however, is frequent in patients who have undergone curative resection. To date, no randomized controlled trials have assessed adjuvant chemotherapy in patients with biliary tract cancer. The aim of this study was to evaluate the outcomes of surgical management followed by adjuvant chemotherapy in patients with biliary tract cancer. This study enrolled 100 patients with Union for International Cancer Control (UICC) stages I-IV biliary tract cancer who underwent surgical resection, including 16 who received sequential adjuvant chemotherapy with gemcitabine or S-1. Overall survival (OS), disease-free survival (DFS), and prognostic factors were analyzed. The median duration of follow-up was 12.6 months. Forty-one patients had lymph node metastasis and 81 underwent RO resection. The 1-, 3-, and 5-year OS rates were 80.9%, 48.6%, and 38.3%, respectively, and the 1-, 3-, and 5-year DFS rates were 59.8%, 39.9%, and 24.9%, respectively. Five-year OS rates were similar in patients who did (40.4%) and did not (32.4%) receive adjuvant chemotherapy. The morbidity and mortality rates were 59% and 3%, respectively. Multivariate analysis showed that only lymph node metastasis (p = 0.042) was independently associated with long-term survival. The presence of lymph node metastasis significantly affected long-term survival, whereas adjuvant chemotherapy did not affect outcomes in our patients with resectable biliary tract cancer..
145. Ryota Nakanishi, Jun Harada, Munkhbold Tuul, Yan Zhao, Koji Ando, Hiroshi Saeki, Eiji Oki, Takefumi Ohga, Hiroyuki Kitao, Yoshihiro Kakeji, Yoshihiko Maehara, Prognostic relevance of KRAS and BRAF mutations in Japanese patients with colorectal cancer, International Journal of Clinical Oncology, 10.1007/s10147-012-0501-x, 18, 6, 1042-1048, 2013.12, Background: Mutations of the KRAS or BRAF genes are now recognized as prognostic markers for colorectal cancer (CRC). They are also important predictive markers for resistance to the monoclonal antibodies that target the epidermal growth factor receptor. Methods: In this retrospective study, KRAS and BRAF mutations were analyzed using a direct sequence method in 254 Japanese CRC patients, and the associations between KRAS or BRAF mutations and clinicopathological characteristics or outcome were evaluated. Results: KRAS and BRAF mutations were detected in 33.5 and 6.7 % of all patients, respectively. Consistent with previous reports, BRAF mutations were significantly correlated with the anatomical site of the tumor (P < 0.001), tumor grade (P = 0.001) and high frequency of microsatellite instability (P < 0.001). BRAF mutations were correlated with poor overall survival in the full patient cohort (P = 0.009). KRAS mutations were significantly correlated with poor recurrence-free survival (P = 0.03), particularly in patients with stage II CRC (P = 0.007). Cox regression analysis showed that KRAS mutations were a negative predictor of recurrence-free survival in patients with stage II CRC. Conclusion: KRAS mutation status could be a novel biomarker for predicting disease recurrence in Japanese patients with stage II CRC..
146. Yuichiro Nakashima, Keiji Yoshinaga, Hiroyuki Kitao, Koji Ando, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiro Kakeji, Minako Hirahashi, Yoshinao Oda, Yoshihiko Maehara, Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion, Cancer Science, 10.1111/cas.12286, 104, 12, 1718-1725, 2013.12, The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial-mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT-related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays and 3-D culture. Transfection of ectopic podoplanin into a podoplanin-negative ESCC cell line (TE-15) induced cell migration and invasive activity (P < 0.001 and P < 0.05, respectively) without downregulation of E-cadherin. In contrast, transfection of si-podoplanin RNA into a podoplanin-positive ESCC cell line (TE-13) reduced cell migration and invasive activity (P < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E-cadherin (P < 0.01), deeper wall invasion (P < 0.01), venous invasion (P < 0.05) and poorer prognosis (P < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (P < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT..
147. Eriko Tokunaga, Yuichi Hisamatsu, Kenji Taketani, Nami Yamashita, Sayuri Akiyoshi, Satoko Okada, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Shinichi Aishima, Yoshinao Oda, Masaru Morita, Yoshihiko Maehara, Differential impact of the expression of the androgen receptor by age in estrogen receptor-positive breast cancer, Cancer Medicine, 10.1002/cam4.138, 2, 6, 763-773, 2013.12, We evaluated the expression of the androgen receptor (AR) to determine its significance in breast cancer. AR expression levels were analyzed in 250 invasive breast cancers by immunohistochemistry and any association with the clinicopathological features was evaluated. AR expression was higher in estrogen receptor (ER)-positive cases than in ER-negative cases (P < 0.0001). AR expression was associated with ER level, and it increased with age in ER-positive cases. The cut-off value was determined to be 75% (Cancer Res. 2009;69:6131-6140), and AR expression was considered to be high in 155 (62%) cases. High AR expression significantly correlated with lower nuclear grade (P < 0.0001), ER and progesterone receptor (PR) positivity (P < 0.0001 and P = 0.0022), HER2 negativity (P = 0.0113), lower Ki67 index (P < 0.0001) and a longer disease-free survival (DFS) and distant metastasis-free survival (DMFS) (P = 0.0003 and 0.0107). This association between a high AR expression and a good DFS and DMFS was significant for ER-positive tumors (P < 0.0001 and P = 0.0018); however, no association existed between AR expression and prognosis for ER-negative tumors. In patients ≤51 years old, a high AR expression level significantly correlated with a better prognosis, but this was not significant in patients who were 50 or younger. Multivariate Cox hazard analyses revealed AR expression to be independently associated with a good prognosis in overall patients (HR 0.46, P = 0.0052) and in the ER-positive cohort (HR 0.34, P = 0.0009). AR expression is associated with a less aggressive phenotype and a good prognosis in patients with ER-positive breast cancer. This is considered to be a specific phenomenon for postmenopausal breast cancer patients..
148. Kenji Taketani, Eriko Tokunaga, Nami Yamashita, Kimihiro Tanaka, Sayuri Akiyoshi, Satoko Okada, Koji Ando, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tetsuya Kusumoto, Yoshihiko Maehara, The early discontinuation of adjuvant hormone therapy is associated with a poor prognosis in Japanese breast cancer patients, Surgery today, 10.1007/s00595-013-0762-7, 44, 10, 1841-1846, 2014.01, Purpose: It is important for patients to complete the planned hormone therapy to reduce both the recurrence and mortality rates of hormone receptor-positive breast cancer. We investigated the rates and factors related to the early discontinuation of adjuvant hormone therapy at our institution.
Methods: We identified 145 females prescribed adjuvant hormone therapy who were followed up for longer than 5 years. The rate of completing the planned hormone therapy and factors related to early discontinuation were examined. The relapse-free survival rate was examined between the completion group and the discontinuation group.
Results: The completion rate was 90.6 %. The primary reason for discontinuing hormone therapy within 5 years was side effects, such as arthritic pain. The primary factor related to early discontinuation was a significantly younger age. The relapse-free survival rate was significantly lower in the discontinuation group (p = 0.025).
Conclusions: More than 90 % of the patients completed the planned adjuvant hormone therapy, and early discontinuation was related to a shorter RFS. To improve the rate of the successful completion of adjuvant hormone therapy, it is important to provide supportive care to reduce the occurrence of side effects and to care for young females with a desire to become pregnant..
149. Hiroshi Sawayama, Takatsugu Ishimoto, Masayuki Watanabe, Naoya Yoshida, Hidetaka Sugihara, Junji Kurashige, Kotaro Hirashima, Masaaki Iwatsuki, Yoshifumi Baba, Eiji Oki, Masaru Morita, Yoshinobu Shiose, Hideo Baba, Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer, Cancer Research, 10.1158/0008-5472.CAN-13-1836, 74, 2, 575-585, 2014.01, The transcription factor PPAR-γ plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-γ agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-γ agonist that selectively activates PPAR-γ target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-γ status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-γ was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-γ expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-γ agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, the combination of efatutazone with the antiepithelial growth factor receptor antibody cetuximab synergized to negatively regulate the phosphoinositide 3-kinase-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC..
150. Yoshifumi Baba, Masayuki Watanabe, Asuka Murata, Hironobu Shigaki, Keisuke Miyake, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Naoya Yoshida, Eiji Oki, Kentaro Sakamaki, Mitsuyoshi Nakao, Hideo Baba, LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma, Clinical Cancer Research, 10.1158/1078-0432.CCR-13-1645, 20, 5, 1114-1124, 2014.01, Purpose: Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed. Experimental Design: To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1-hypomethylated and LINE-1-hypermethylated ESCC tumors by comparative genomic hybridization array. Results: LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6- negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression. Conclusion: LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such asCDK6..
151. Hiroyuki Kawano, Hiroshi Saeki, Hiroyuki Kitao, Yasuo Tsuda, Hajime Otsu, Koji Ando, Shuhei Ito, Akinori Egashira, Eiji Oki, Masaru Morita, Yoshinao Oda, Yoshihiko Maehara, Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma, Annals of Surgical Oncology, 10.1245/s10434-014-3818-z, 21, 4, 696-702, 2014.01, Background: Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear.
Methods: Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis.
Results: The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability.
Conclusions: Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC..
152. Eiji Oki, Yasuo Tsuda, Hiroshi Saeki, Koji Ando, Yu Imamura, Yuichiro Nakashima, Kippei Ohgaki, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, Book-binding technique for billroth i anastomosis during totally laparoscopic distal gastrectomy, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2014.09.001, 219, 6, e69-e73, 2014.01.
153. Tomonori Nakanoko, Hiroshi Saeki, Masaru Morita, Yuichiro Nakashima, Koji Ando, Eiji Oki, Takefumi Ohga, Yoshihiro Kakeji, Yasushi Toh, Yoshihiko Maehara, Rad51 expression is a useful predictive factor for the efficacy of neoadjuvant chemoradiotherapy in squamous cell carcinoma of the esophagus, Annals of Surgical Oncology, 10.1245/s10434-013-3220-2, 21, 2, 597-604, 2014.02, Background: Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear. Methods: Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT. Results: Lymph node metastasis was more frequently observed in Rad51-positive cases than negative cases (58.5 vs. 30.6 %, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51-positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3 %, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5 %, P = 0.0171). Conclusions: Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT..
154. Masaru Morita, Hajime Otsu, Hiroyuki Kawano, Yuta Kasagi, Yasue Kimura, Hiroshi Saeki, Koji Ando, Satoshi Ida, Eiji Oki, Eriko Tokunaga, Tetsuo Ikeda, Tetsuya Kusumoto, Yoshihiko Maehara, Gender differences in prognosis after esophagectomy for esophageal cancer, Surgery today, 10.1007/s00595-013-0573-x, 44, 3, 505-512, 2014.03, Purpose: The purpose of this study was to clarify the gender differences in the prognosis, as well as mortality and morbidity, of patients who have undergone esophagectomy for esophageal cancer. Methods: The clinical results of esophagectomy were compared between 975 male and 156 female patients with esophageal cancer. Results: The male to female ratios of cervical and thoracic esophageal cancer were 1.87 and 7.38, respectively (P < 0.01). The incidence of preoperative comorbidities was 32.4 and 17.4 %, respectively, and the rates of both tobacco and alcohol abuse were significantly lower in the females than in the males. The mortality rate was lower in the females (3.8 %) than in the males (5.7 %), although the differences were not significant. The overall survival was significantly better in the female than in the male patients (P = 0.039). The 5- and 10-year overall survival rates were 32.6 and 20.5 % in the males and 39.5 and 32.5 % in the females, respectively. A multivariate analysis revealed gender to be an independent prognostic factor. However, no significant differences were recognized in disease-specific survival. Conclusions: These results suggest that the prognosis of females with esophageal cancer is better than that of males after esophagectomy, most likely due to multiple clinical factors, such as a more favorable lifestyle and general status..
155. Kenichi Honma, Ryota Nakanishi, Tomonori Nakanoko, Koji Ando, Hiroshi Saeki, Eiji Oki, Makoto Iimori, Hiroyuki Kitao, Yoshihiro Kakeji, Yoshihiko Maehara, Contribution of Aurora-A and -B expression to DNA aneuploidy in gastric cancers, Surgery today, 10.1007/s00595-013-0581-x, 44, 3, 454-461, 2014.03, Purpose: DNA aneuploidy, which is characterized by cells containing an abnormal number of chromosomes, is closely associated with carcinogenesis and malignant progression. Aneuploidy occurs during cell division when the chromosomes do not separate properly. Aurora kinases (Aurora-A, -B, and -C) contribute to accurate cell division, and are candidate molecular targets for mitosis-specific anticancer drugs. Methods: We determined the expression of Aurora-A and -B in 110 gastric cancer specimens by performing an immunohistochemical analysis. We also determined the DNA content, TP53 gene mutations, and microsatellite instability in the same samples. Results: We found the nuclear expression of Aurora-A and -B to increase in tumor tissue in comparison to that in normal epithelial tissue. A high Aurora-B expression significantly correlated with aneuploidy and TP53 mutations, but not with microsatellite instability. In contrast, the Aurora-A expression did not correlate with either aneuploidy or microsatellite instability. In addition, the expression of Aurora-A or -B was not significantly associated with the clinical outcomes or prognosis. Conclusions: Our results suggest that an overexpression of Aurora-B, but not of Aurora-A, might contribute to DNA aneuploidy in gastric cancers by promoting chromosomal instability..
156. Satoshi Ida, Masaru Morita, Yukiharu Hiyoshi, Keisuke Ikeda, Koji Ando, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Tetsuya Kusumoto, Sei Yoshida, Torahiko Nakashima, Masayuki Watanabe, Hideo Baba, Yoshihiko Maehara, Surgical resection of hypopharynx and cervical esophageal cancer with a history of esophagectomy for thoracic esophageal cancer, Annals of Surgical Oncology, 10.1245/s10434-013-3454-z, 21, 4, 1175-1181, 2014.04, Background. Cancer of the hypopharynx and cervical esophagus (PhCe cancer) frequently develops synchronously or metachronously with esophageal cancer. The surgical approach is usually difficult, especially in metachronous PhCe cancer after esophagectomy. The purpose of this study was to clarify the treatment outcomes of patients with metachronous PhCe cancer with a history of esophagectomy. Methods. The subjects evaluated in this study were 14 patients with metachronous PhCe cancer who underwent pharyngo-laryngo-esophagectomy after subtotal esophagectomy and gastric tube pull-up for primary esophageal cancer. Results. Definitive chemoradiotherapy (CRT; radiation dose >50 Gy) was performed for primary laryngeal (n = 1), pharyngeal (n = 2), esophageal (n = 1), and recurrent esophageal cancer (n = 2). For seven patients with metachronous PhCe cancer, induction CRT (radiation dose <40 Gy) was performed. In all 14 patients, pharyngo-laryngo-esophagectomy was followed by free jejunal graft interposition with reconstruction of the jejunal vessels. Although postoperative complications developed in four patients, no perioperative death or necrosis of the reconstructed free jejunum occurred. The 2- and 5-year overall survival rates were 84 and 50 %, respectively. Conclusions. Pharyngo-laryngo- esophagectomy with free jejunal transfer is considered to be safe for metachronous PhCe cancer, even in patients with a history of CRT and esophagectomy..
157. N. Kubo, M. Morita, Y. Nakashima, H. Kitao, A. Egashira, H. Saeki, E. Oki, Y. Kakeji, Y. Oda, Y. Maehara, Oxidative DNA damage in human esophageal cancer
Clinicopathological analysis of 8-hydroxydeoxyguanosine and its repair enzyme, Diseases of the Esophagus, 10.1111/dote.12107, 27, 3, 285-293, 2014.04, Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression..
158. Koji Ando, Eiji Oki, Yan Zhao, Ayae Ikawa-Yoshida, Hiroyuki Kitao, Hiroshi Saeki, Yasue Kimura, Satoshi Ida, Masaru Morita, Tetsuya Kusumoto, Yoshihiko Maehara, Mortalin is a prognostic factor of gastric cancer with normal p53 function, Gastric Cancer, 10.1007/s10120-013-0279-1, 17, 2, 255-262, 2014.04, Background: Mortalin is a heat-non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53. Methods: Expression of mortalin and p53 was examined by immunohistochemical staining of 182 clinical samples of gastric cancer. Results: Mortalin-positive and aberrant p53-positive tumors were found in 75.2 and 49.5 % of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (P < 0.01, P < 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.035). Moreover, in tumors with normal p53 function, mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.017). Conclusions: Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53..
159. Asuka Murata, Yoshifumi Baba, Masayuki Watanabe, Hironobu Shigaki, Keisuke Miyake, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Naoya Yoshida, Eiji Oki, Masaru Morita, Mitsuyoshi Nakao, Hideo Baba, IGF2 DMR0 methylation, loss of imprinting, and patient prognosis in esophageal squamous cell carcinoma, Annals of Surgical Oncology, 10.1245/s10434-013-3414-7, 21, 4, 1166-1174, 2014.04, Background. Insulin like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, to our knowledge, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC). Methods. The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfite pyrosequencing assay with 216 ESCC tissue specimens. Results. Twelve (40 %) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42 %) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean 23 %) than IGF2 non-LOI cases (37 %). Conclusions. The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality. The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker..
160. Masaru Morita, Hiroshi Saeki, Shuhei Ito, Keisuke Ikeda, Nami Yamashita, Koji Ando, Yukiharu Hiyoshi, Satoshi Ida, Eriko Tokunaga, Hideaki Uchiyama, Eiji Oki, Tetsuo Ikeda, Sei Yoshida, Torahiko Nakashima, Yoshihiko Maehara, Technical improvement of total pharyngo-laryngo-esophagectomy for esophageal cancer and head and neck cancer, Annals of Surgical Oncology, 10.1245/s10434-013-3453-0, 21, 5, 1671-1677, 2014.05, Purpose: Total pharyngo-laryngo-esophagectomy (PLE) is highly invasive, and the subsequent reconstruction is difficult. The purpose of this study was to clarify the techniques that can decrease the surgical stress and allow for safe reconstruction after this operation. Methods: The surgical method and clinical outcomes of total PLE were reviewed in 12 patients with either cervicothoracic esophageal cancer or double cancer of the esophagus and pharynx. Microscopic venous anastomosis was principally performed, and arterial anastomosis was added, if needed. Results: A narrow gastric tube was used in ten patients, including two patients who underwent free jejunal interposition, while the colon was used as the main reconstructed organ in two other patients. Staged operations were performed in three high-risk patients. All six patients treated after 2010 were able to undergo thoracoscopic and/or laparoscopic surgery. No critical postoperative complications developed, although minor anastomotic leakage developed in two patients who were successfully treated conservatively. Conclusion: When performing PLE, it is important to decrease the surgical stress and ensure a reliable reconstruction by adopting techniques that are appropriate for each case, such as thoracoscopic and laparoscopic surgery, staged operations, microvascular anastomosis, and muscular flaps..
161. K. Imai, Y. Emi, K. I. Iyama, T. Beppu, Y. Ogata, Y. Kakeji, H. Samura, E. Oki, Y. Akagi, Y. Maehara, H. Baba, Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome, European Journal of Surgical Oncology, 10.1016/j.ejso.2013.12.009, 40, 5, 559-566, 2014.05, Aims The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS. Methods Seventy-nine patients who received OX-based chemotherapy with (OX + Bmab group: n = 48) or without Bmab (OX group: n = 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy. Results A significant increase in the splenic volume was observed in the OX group, but not in the OX + Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX + Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX + Bmab group (50.0% vs. 16.0%, p = 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p = 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS. Conclusions: This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS..
162. Shuhei Ito, Shohei Yamaguchi, Hiroshi Saeki, Eiji Oki, Eiki Tayama, Koji Ikejiri, Masaru Morita, Yoshihiko Maehara, Significance of preoperative evaluation of the right gastroepiploic artery graft to the coronary artery in patients undergoing abdominal surgery, World journal of surgery, 10.1007/s00268-013-2375-0, 38, 5, 1051-1057, 2014.05, Background: A major concern with the use of the right gastroepiploic artery (RGEA) as the graft for coronary artery bypass grafting (CABG) is the potential for injury, which can result in critical myocardial ischemia during future abdominal surgery. Methods: We examined the availability of preoperative image evaluation, preoperative recognition of the RGEA graft, and operative findings such as graft identification, graft injury, and cardiac events in 11 patients who underwent abdominal surgery after CABG using the RGEA as the graft. Results: Prior to the abdominal surgery, contrast-enhanced computed tomography (CT) was performed in all 11 patients, while coronary angiography or three-dimensional CT angiography was performed in five patients. We detected the RGEA graft retrospectively in nine of ten patients in whom the images from contrast-enhanced CT were still available. Among the seven patients whose RGEA grafts were in the operative field, the RGEA graft was identified in five patients, while the RGEA graft was not identified in the remaining two patients because of adhesions. There were no intraoperative cardiac events in any of the 11 patients. Conclusions: It is important to determine whether an RGEA graft is present when repeat laparotomy is required after CABG. In cases where an RGEA graft is present, it is essential to evaluate the patency and location of the graft since this will be crucial for planning the reoperation strategy. Preoperative recognition and evaluation of the RGEA graft can help avoid graft injury, even if the graft cannot be detected intraoperatively..
163. Satoshi Ida, Eiji Oki, Koji Ando, Yasue Kimura, Yo ichi Yamashita, Hiroshi Saeki, Toru Ikegami, Tomoharu Yoshizumi, Masayuki Watanabe, Masaru Morita, Ken Shirabe, Tetsuya Kusumoto, Tetsuo Ikeda, Hideo Baba, Yoshihiko Maehara, Pure laparoscopic right-sided hepatectomy in the semi-prone position for synchronous colorectal cancer with liver metastases, Asian journal of endoscopic surgery, 10.1111/ases.12098, 7, 2, 133-137, 2014.05, INTRODUCTION: Simultaneous resection for colorectal cancer and synchronous colorectal liver metastases (SCRLM) has been found to be safe and effective. However, pure laparoscopic simultaneous resection (PULSAR) for primary colorectal cancer and SCRLM is usually difficult, especially in the right lobe of the liver. The purpose of this study was to assess the feasibility of PULSAR for patients with primary colorectal cancer and SCRLM.
METHODS: From January 2008 to December 2012, a total of 10 patients (9 men and 1woman; mean age, 64 years) underwent PULSAR for a primary tumor and SCRLM.
RESULTS: Seven patients (70%) with lesions in the right lobe (segments 6, 7, and 8) successfully underwent resection with a pure laparoscopic procedure while in the left semi-prone position. No patient was converted to conventional open surgery. The mean operative duration, volume of bleeding, and postoperative hospital stay were 606 ± 46 min, 585 ± 145 mL, and 18 ± 3.5 days, respectively. Although a liver abscess developed in one patient, no colonic complications or perioperative death occurred.
CONCLUSION: PULSAR for primary colorectal cancer and SCRLM is a feasible multidisciplinary treatment. Moreover, PULSAR can be safely and effectively performed with the patient in the semi-prone position, even when SCRLM exists in the right lobe of the liver..
164. Hideaki Uchiyama, Ken Shirabe, Tomoharu Yoshizumi, Toru Ikegami, Yuji Soejima, Yoichi Yamashita, Hirofumi Kawanaka, Tetsuo Ikeda, Masaru Morita, Eiji Oki, Yoshihiko Maehara, Use of living donor liver grafts with double or triple arteries, Transplantation, 10.1097/01.TP.0000442687.33536.c4, 97, 11, 1172-1177, 2014.06, BACKGROUND: Hepatic grafts used in living donor liver transplantation (LDLT) sometimes have two or more arteries, in which surgeons are required to perform complex arterial reconstruction. The aim of the current study was to demonstrate whether selecting living donor liver grafts with double or triple arteries yielded the same outcomes as grafts with a single artery. METHODS: We retrospectively investigated the outcomes of LDLT focusing on the numbers of arteries on grafts. Four hundred forty-six cases of LDLT performed between October 1996 and October 2012 were retrospectively analyzed. The cases were divided into the following three groups according to the number of arteries on a graft: the single (n=331), the double (n=108), and the triple (n=7) groups. RESULTS: Artery-related complications occurred in five cases in the single group, two cases in the double group, and no case in the triple group. Although the overall graft survival was comparable among the three groups, there was a tendency of worsened graft survival and increased incidence of anastomotic biliary stricture after liver transplantation in right hepatic grafts with double arteries. CONCLUSIONS: The use of grafts with double or triple arteries yielded favorable outcomes with minimum artery-related complications compared with grafts with a single artery. However, the use of right hepatic grafts with double arteries is discouraging in the current study..
165. Eiji Oki, Yasunori Emi, Tetsuya Kusumoto, Yoshihisa Sakaguchi, Manabu Yamamoto, Noriaki Sadanaga, Mototsugu Shimokawa, Takeharu Yamanaka, Hiroshi Saeki, Masaru Morita, Ikuo Takahashi, Naoki Hirabayashi, Kenji Sakai, Hiroyuki Orita, Shinichi Aishima, Yoshihiro Kakeji, Kazuya Yamaguchi, Kazuhiro Yoshida, Hideo Baba, Yoshihiko Maehara, Phase II study of docetaxel and S-1 (DS) as neoadjuvant chemotherapy for clinical stage III resectable gastric cancer, Annals of Surgical Oncology, 10.1245/s10434-014-3594-9, 21, 7, 2340-2346, 2014.07, Background: We conducted a phase II trial to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel (DTX) plus S-1 for resectable advanced gastric cancer. Patients and Methods: A total of 47 patients from 14 centers were centrally registered. Patients received DTX (35 mg/m2) on days 1 and 15, and daily oral administration of S-1 (80 mg/m2/day) for days 1-14 every 4 weeks for two courses, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological response rate (pRR). This study was registered in the UMIN clinical trial registry (UMIN000000875). Results: The primary endpoint pRR was 47 % (90 % confidence interval (CI), 34-60 %; p < 0.0001). The response rate to preoperative chemotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) was 34 %. Forty-six patients (98 %) underwent surgery, and curative resection was performed in 44 patients. Thirty-seven patients completed the protocol treatment. The most common toxicities of neoadjuvant chemotherapy were grade 3/4 neutropenia (42 %), febrile neutropenia (4 %), grade 2 anorexia (21 %), and fatigue (15 %). Treatment-related death and operative mortality was not observed in this study. Conclusions: The combination of docetaxel and S-1 was well tolerated. This is promising as a preoperative chemotherapy regimen for patients with potentially resectable advanced gastric cancer..
166. Koji Ando, Eiji Oki, Tetsuo Ikeda, Hiroshi Saeki, Satoshi Ida, Yasue Kimura, Yuuji Soejima, Masaru Morita, Ken Shirabe, Tetuya Kusumoto, Yoshihiko Maehara, Simultaneous resection of colorectal cancer and liver metastases in the right lobe using pure laparoscopic surgery, Surgery today, 10.1007/s00595-013-0801-4, 44, 8, 1588-1592, 2014.08, It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery..
167. Yasue Kimura, Eiji Oki, Ayae Yoshida, Shinichi Aishima, Yoko Zaitsu, Hajime Ohtsu, Koji Ando, Satoshi Ida, Hiroshi Saeki, Masaru Morita, Tetsuya Kusumoto, Yoshinao Oda, Yoshihiko Maehara, Significance of accurate human epidermal growth factor receptor-2 (HER2) evaluation as a new biomarker in gastric cancer, Anticancer research, 34, 8, 4207-4212, 2014.08, Background: HER2 testing in gastric cancer differs from testing in breast cancer because of inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency and accuracy of detection of HER2 expression by application of standard criteria in Japanese patients with gastric cancer. Material and Methods: A total of 198 tumor specimens were assessed for HER2 expression by immunohistochemistry (IHC) using the antibodies HercepTest™ and 4B5. Both hand-operated and automated IHC were performed. Results: HER2 expression differed according to the IHC method and antibodies used. HER2 IHC3+ tumors were identified in 21 (10%) and 7 (3.5%) cases by hand-operated and automated IHC, respectively. Conclusion: Among patients with gastric cancer, FISH may be performed in cases of IHC1+ by automated IHC. Further research is required to clarify the relevance of HER2 staining and scoring for the clinical response to HER2-targeted therapy..
168. Yuta Kasagi, Hiroshi Saeki, Tomohiko Akahoshi, Junji Kawasaki, Koji Ando, Eiji Oki, Takefumi Ohga, Morimasa Tomikawa, Yoshihiro Kakeji, Ken Shirabe, Yoshihiko Maehara, Non-cirrhotic portal-systemic encephalopathy caused by enlargement of a splenorenal shunt after pancreaticoduodenectomy for locally advanced duodenal cancer
Report of a case, Surgery today, 10.1007/s00595-013-0679-1, 44, 8, 1573-1576, 2014.08, We report a case of portal-systemic encephalopathy occurring secondary to a splenorenal shunt, 2 years after a pancreaticoduodenectomy for locally advanced duodenal carcinoma. A 55-year-old woman was brought to our hospital with a decreased level of consciousness. Laboratory testing revealed an elevated serum ammonia level (221 μg/dl) and normal liver function. Retrospective review of a series of contrast-enhanced computed tomography scans of the abdomen identified a splenorenal shunt, which had gradually enlarged over the past 2 years (Fig. 1). The decreased level of consciousness was thought to be due to portal-systemic encephalopathy secondary to the splenorenal shunt. We performed balloon-occluded retrograde transvenous obliteration to occlude the splenorenal shunt, following which her serum ammonia level returned to normal (28 μg/dl) and an alert level of consciousness was maintained..
169. Sho Nishimura, Hiroshi Saeki, Toru Ikegami, Koji Ando, Yo Ichi Yamashita, Eiji Oki, Tomoharu Yoshizumi, Masaru Morita, Ken Shirabe, Yoshihiko Maehara, Living donor liver transplantation followed by total gastrectomy - A two-stage planed operative strategy for early gastric cancer concomitant with decompensated liver cirrhosis, Anticancer research, 34, 8, 4307-4310, 2014.08, Aim: With the recent popularization of living donor liver transplantation (LDLT), providing treatment for comorbidities in LDLT recipients has become important. We report the first case of a patient who was successfully treated with LDLT followed by total gastrectomy for early gastric cancer concomitant with decompensated liver cirrhosis. Case Report: A 64-year-old female was admitted for the treatment of severe liver cirrhosis. The patient's preoperative liver function was evaluated as Child-Pugh classification grade C. Upper gastrointestinal endoscopy revealed early gastric cancer. We first performed LDLT to improve her liver function and coagulopathy. Nineteen days after the LDLT, we performed total gastrectomy. Results: The patient's postoperative course was uneventful and she left our hospital on the 18th day after gastrectomy. The final pathological diagnosis of gastric cancer was Stage IA. Conclusion: Aggressive and adequate surgical strategy including LDLT is effective as curative treatment in patients with controllable malignancy concomitant with severe liver dysfunction..
170. Keisuke Ikeda, Eiji Oki, Hiroshi Saeki, Koji Ando, Masaru Morita, Yoshinao Oda, Masakazu Imamura, Yoshiniro Kakeji, Yoshihiko Maehara, Intratumoral lymphangiogenesis and prognostic significance of VEGFC expression in gastric cancer, Anticancer research, 34, 8, 3911-3916, 2014.08, Aim: Vascular endothelial growth factor C (VEGFC) is thought to promote lymphangiogenesis in various human cancer tissues. Materials and Methods: The present study analyzed data from 72 patients with gastric cancer. The lymphatic vessel density (LVD) was determined by immunohistochemical staining using a monoclonal antibody (mAb) against D2-40, and the expression of VEGFC was investigated using a mAb against VEGFC. Results: The intratumoral LVD was higher in cases with nodal metastasis. The VEGFC-positive cases had a higher intratumoral LVD and were more invasive to the lymphatic vessels or lymph nodes than negative cases. Patients with VEGFC-positive cancer had significantly lower survival than those with negative cancer (p<0.05). Conclusion: The expression of VEGFC was related to intratumoral lymph angiogenesis and serves as a pertinent predictive factor for lymphatic invasion or metastasis, while also providing prognostic value..
171. Hiroshi Saeki, Yasunori Emi, Ryuichi Kumashiro, Hajime Otsu, Hiroyuki Kawano, Koji Ando, Satoshi Ida, Yasue Kimura, Eriko Tokunaga, Eiji Oki, Masaru Morita, Mototsugu Shimokawa, Yoshihiko Maehara, Impact of second-line and later cetuximab-containing therapy and KRAS genotypes in patients with metastatic colorectal cancer
A multicenter study in Japan, Surgery today, 10.1007/s00595-013-0716-0, 44, 8, 1457-1464, 2014.08, Purposes: This retrospective study evaluated the treatment outcomes and clinical relevance of the KRAS mutation status in Japanese metastatic colorectal cancer patients treated with second-line and later cetuximab-containing therapy. Methods: The subjects comprised 65 patients with metastatic colorectal cancer who received cetuximab-containing therapy. At the start of cetuximab-containing therapy, the KRAS mutation status had been proven to be wild type in 12 patients. Tumors were retrospectively screened for KRAS mutations using direct sequencing. Results: A detailed analysis revealed the presence of 24 wild-type (57.1 %) and 18 mutant tumors (42.9 %). Grade 3-4 neutropenia and anemia were observed in 21 (32.3 %) and nine (13.8 %) patients, respectively. An acne-like rash was observed in 50 patients (76.9 %), and among them three patients (4.6 %) experienced a Grade 3 rash. A KRAS mutation was associated with resistance to cetuximab-containing treatment (11.1 vs. 41.7 % responders among 18 mutant and 36 wild-type patients, respectively; P = 0.03). A KRAS mutation was also associated with poorer survival (MST: 6.9 vs. 14.1 months in 18 mutant and 36 wild-type patients, respectively; P = 0.018). Conclusions: The present results indicated the clinical relevance of KRAS mutations in predicting the efficacy of cetuximab-containing therapy for metastatic colorectal patients in the Japanese population..
172. Yukiharu Hiyoshi, Eiji Oki, Yoko Zaitsu, Koji Ando, Shuhei Ito, Hiroshi Saeki, Masaru Morita, Hidetaka Yamamoto, Hideo Baba, Yoshihiko Maehara, IgG4-related disease of the ileocecal region mimicking malignancy
A case report, International Journal of Surgery Case Reports, 10.1016/j.ijscr.2014.08.003, 5, 10, 669-672, 2014.08, Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease characterized by chronic fibrosing inflammation with abundant IgG4-positive plasma cells, and responds well to steroids. Previous reports of IgG4-RD have focused on pancreatic and extrapancreatic including the gastrointestinal tract, however, the colonic IgG4-RD is rare.
Presentation OF CASE: We herein report the case of a 74-year-old female with edematous wall thickening of the terminal ileum to the lower ascending colon confirmed by several preoperative imaging studies, who underwent right hemi-colectomy for suspected malignant lymphoma. The resected specimen showed an irregular wall thickness with subserosal sclerosis, and the lesion was 10 cm in length from the terminal ileum to the ascending colon. The patient was diagnosed with IgG4-RD by pathological examinations, which demonstrated an increased number of IgG4-positive plasma cells (150/HPF), and an elevated IgG4/IgG ratio (50%).
Discussion: Gastrointestinal IgG4-RD appears to be difficult to diagnose prior to surgical resection because of its rarity, and the similarity of its features to malignancy. The measurement of the serum IgG4 levels, immunohistochemical examination of biopsy specimens and use of several imaging modalities might help us to diagnose the disease without surgical resection, and this disease can generally be treated with steroid therapy. However, surgical resection for IgG4-RD may still be also necessary for patients with concerns regarding malignancy or with intractable gastrointestinal obstruction caused by this disease.
Conclusion: Gastrointestinal IgG4-RD often mimics malignancy, and we should therefore consider this disease in the differential diagnosis of colonic lesions in order to optimize the treatment..
173. Masaru Morita, Hiroshi Saeki, Shuhei Ito, Yasue Kimura, Nami Yamashita, Koji Ando, Yukiharu Hiyoshi, Eriko Tokunaga, Eiji Oki, Tetsuo Ikeda, Sei Yoshida, Torahiko Nakashima, Yoshihiko Maehara, Surgical strategies for esophageal cancer associated with head and neck cancer, Surgery today, 10.1007/s00595-013-0713-3, 44, 9, 1603-1610, 2014.09, Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol's staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis..
174. Takafumi Yukaya, Hiroshi Saeki, Kenji Taketani, Koji Ando, Satoshi Ida, Yasue Kimura, Eiji Oki, Mitsuhiro Yasuda, Masaru Morita, Ken Shirabe, Yoshihiko Maehara, Clinical Outcomes and Prognostic Factors After Surgery for Non-Occlusive Mesenteric Ischemia
a Multicenter Study, Journal of Gastrointestinal Surgery, 10.1007/s11605-014-2579-0, 18, 9, 1642-1647, 2014.09, Background: To date, no large-scale study has been undertaken to understand the clinical features of non-occlusive mesenteric ischemia (NOMI) after surgery. We thus performed a multicenter investigation to clarify the clinical outcomes and prognostic factors of NOMI. Patients and Methods: Clinical databases from 22 Japanese facilities were reviewed for evaluation of patients who received surgery for NOMI between 2004 and 2012. NOMI patients (n = 51) were divided into two groups: group I (n = 28) consisted of patients who survived, and group II (n = 23) consisted of patients who did not survived. Prognostic factors were compared between the two groups. Results: NOMI surgery represented 0.04 % of the total number of operations performed in this time period. The overall mortality rate for NOMI surgery was 45 %. Hemodialysis was a significant negative prognostic factor (p = 0.027). Preoperative elevation of transaminases, potassium, and white blood cell count, as well as metabolic acidosis and colon ischemia was poor prognostic factors. The mean Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) score of group I versus group II was 54.5 ± 3.6 and 85.2 ± 4.1, respectively (p < 0.001). Conclusions: Currently, NOMI surgery has a 45 % mortality rate. POSSUM scores can be used to predict the clinical outcome of patients who receive NOMI surgery..
175. Yan Zhao, Koji Ando, Eiji Oki, Ayae Ikawa-Yoshida, Satoshi Ida, Yasue Kimura, Hiroshi Saeki, Hiroyuki Kitao, Masaru Morita, Yoshihiko Maehara, Aberrations of BUBR1 and TP53 gene mutually associated with chromosomal instability in human colorectal cancer, Anticancer research, 34, 10, 5421-5427, 2014.10, Background/Aim: Defects in mitotic checkpoint and p53-dependent pathways associate with chromosomal instability. In the present study, we investigated the interplay between BUBR1 and p53 and their association with genetic instability in colorectal cancer. Patients and Methods: 139 colorectal cases were examined for BUBR1, p53 and genetic instability indicators. BUBR1 expression was evaluated by immunohistochemistry and TP53 gene was directly sequenced. DNA ploidy was studied by laser scanning cytometry; MSI and TP53 loss of heterozygosity was also examined. Results: 64% of cases had high BUBR1 expression and were associated with the TP53 mutation. High BUBR1 expression and TP53 mutation associated with DNA aneuploidy and showed an inverse association with MSI. Cases with high BUBR1 expression and TP53 mutation had profound aneuploidy phenotypes and less frequent MSI compared to cases with one or neither aberration. Conclusion: Our findings indicated an interplay between BUBR1 and p53 in colorectal cancer. Altered expression of both molecules was associated with chromosomal instability..
176. Takanobu Masuda, Yuichiro Nakashima, Koji Ando, Keiji Yoshinaga, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshinao Oda, Yoshihiko Maehara, Nuclear expression of chemokine receptor CXCR4 indicates poorer prognosis in gastric cancer, Anticancer research, 34, 11, 6397-6403, 2014.11, Background: The CXCL12/CXCR4 axis plays a pivotal role in cancer progression and metastases in various epithelial cancer cells. The aim of the present study was to evaluate the localization and correlation between CXCL12/CXCR4 expression and clinicopathological features in gastric cancers. Materials and Methods: This study included 111 Japanese patients with primary gastric cancers, which invade submucosa or more, all of whom underwent gastrectomy between 1992 and 1996. Immunohistochemical analysis was performed. Results: A significant correlation was found in the immunoreactivity of nuclear CXCR4 and poor differentiation (p=0.0026), infiltrated pattern (p<0.0001), larger size (p<0.0001), advanced stage (p=0.0342) and reduced 5-year survival rate (30% vs. 61%, p=0.0012). Multivariate analysis revealed that high nuclear CXCR4 immunoreactivity (RR: 3.077, p=0.0329) retained its strength as an independent prognostic factor for overall survival. Conclusion: High immunoreactivity of nuclear CXCR4 in gastric cancer suggests that CXCL12 binds to its unique receptor CXCR4 at the membrane, translocates to the nucleus and then becomes more invasive, and thus can be considered a prognostic factor..
177. Eriko Tokunaga, Yuichi Hisamatsu, Kimihiro Tanaka, Nami Yamashita, Hiroshi Saeki, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara, Molecular mechanisms regulating the hormone sensitivity of breast cancer, Cancer Science, 10.1111/cas.12521, 105, 11, 1377-1383, 2014.11, Breast cancer is a heterogeneous disease. Approximately 70% of breast cancers are estrogen receptor (ER) positive. Endocrine therapy has dramatically improved the prognosis of ER-positive breast cancer; however, many tumors exhibit de novo or acquired resistance to endocrine therapy. A thorough understanding of the molecular mechanisms regulating hormone sensitivity or resistance is important to improve the efficacy of and overcome the resistance to endocrine therapy. The growth factor receptor signaling pathways, particularly the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway can mediate resistance to all forms of endocrine therapy. In contrast, FOXA1 transcription factor is a key determinant of ER function and endocrine response. Intriguingly, a link between hormone resistance induced by the PI3K/Akt/mTOR pathway and the function of FOXA1 has been suggested. In this review, we focus on the PI3K/Akt/mTOR pathway and functions of FOXA1 in terms of the molecular mechanisms regulating the hormone sensitivity of breast cancer. Endocrine therapy has dramatically improved the prognosis of ER-positive breast cancer, however, many tumors exhibit de novo or acquired resistance to endocrine therapy. A thorough understanding of the molecular mechanisms regulating hormone sensitivity or resistance is important to improve the efficacy of and overcome the resistance to endocrine therapy. In this review, we focus on the PI3K/Akt/mTOR pathway and functions of FOXA1 in terms of the molecular mechanisms regulating the hormone sensitivity of breast cancer..
178. , Toru Beppu, Yasunori Emi, Shoji Tokunaga, Eiji Oki, Ken Shirabe, Shinichi Ueno, Masafumi Kuramoto, Akira Kabashima, Ikuo Takahashi, Hironori Samura, Susumu Eguchi, Yoshito Akagi, Shoji Natsugoe, Yutaka Ogata, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Liver resectability of advanced liver-limited colorectal liver metastases following mFOLFOX6 with bevacizumab (KSCC0802 study), Anticancer research, 34, 11, 6655-6662, 2014.11, Background/Aim: The Kyushu Study group of Clinical Cancer (KSCC) conducted phase II trials (KSCC0802 - UMIN000001308) concerning liver resectability after first-line treatment of advanced liver-limited colorectal metastases (CRLM) by a prospective, multi-center study. Patients and Methods: Patients received 6 cycles of mFOLFOX6 with bevacizumab followed by evaluating liver resectability. The primary end-point was liver resection rate. Results: The 40 patients enrolled from September 2008 to August 2010. The median number of administration cycles was 6 (range=1-7). The liver resectability cases were 16/40 (40.0 %) and the number of R0 cases was 10 patients (25.0%). An overall response rate was 30.0% (95% CI=15.2%-44.8%). Median progression-free and overall survival of all patients was 9.7 months and 33.0 months), respectively. Conclusion: mFOLFOX6 with bevacizumab regimen is safe and effective for advanced liver-limited CRLM and might lead to high liver resectability..
179. Tomonori Nakanoko, Hiroshi Saeki, Masaru Morita, Yuichiro Nakashima, Koji Ando, Eiji Oki, Takefumi Ohga, Yoshihiro Kakeji, Yasushi Toh, Yoshihiko Maehara, Erratum to
Rad51 Expression Is a Useful Predictive Factor for the Efficacy of Neoadjuvant Chemoradiotherapy in Squamous Cell Carcinoma of the Esophagus [Ann Surg Oncol, 10.1245/S10434-013-3220-2], Annals of Surgical Oncology, 10.1245/s10434-013-3332-8, 21, 4, 2014.11.
180. Yukiharu Hiyoshi, Eiji Oki, Koji Ando, Shuhei Ito, Hiroshi Saeki, Masaru Morita, Hideo Baba, Yoshihiko Maehara, Outcome of esophagojejunostomy during totally laparoscopic total gastrectomy
A single-center retrospective study, Anticancer research, 34, 12, 7227-7232, 2014.12, Aim: The present study aimed to clarify the safety and feasibility of esophagojejunostomy during totally laparoscopic total gastrectomy (TLTG). Patients and Methods: In 45 consecutive patients who underwent TLTG for gastric cancer, esophagojejunostomy was performed with a functional end-to-end anastomosis (FEEA) using a linear stapler in 24 patients or with a double stapling technique (DST) using a trans-orally inserted anvil (OrVil) in 21 patients. Results: The DST was more likely to be chosen in patients with tumors located in the upper stomach. In the FEEA group, both the mean length of the operation and the mean postoperative hospital stay were significantly shorter compared to those in the DST group. Two patients in the FEEA group and four patients in the DST group developed postoperative complications but there were no postoperative deaths in either group. Conclusion: Both FEEA and DST in esophagojejunostomy during TLTG are safe and feasible..
181. Kazuaki Matsuoka, Makoto Iimori, Shinichiro Niimi, Hiroshi Tsukihara, Sugiko Watanabe, Shinichi Kiyonari, Mamoru Kiniwa, Koji Ando, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hiroyuki Kitao, Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks, Molecular cancer therapeutics, 10.1158/1535-7163.MCT-14-0236, 14, 4, 1004-1013, 2015.01, Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2′-deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTDinduced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102..
182. Yasuo Tsuda, Masaru Morita, Hiroshi Saeki, Koji Ando, Satoshi Ida, Yasue Kimura, Eiji Oki, Takefumi Ohga, Tetsuya Kusumoto, Koichiro Abe, Shingo Baba, Takuro Isoda, Yoshihiko Maehara, Esophagectomy-related thoracic duct injury detected by lymphoscintigraphy with 99mTc-diethylenetriamine pentaacetic acid-human serum albumin
report of a case, Surgery today, 10.1007/s00595-014-0968-3, 45, 4, 517-521, 2015.01, Chylothorax is an uncommon but potentially life-threatening complication of esophagectomy. A 72-year-old man underwent thoracoscopy-assisted subtotal esophagectomy and reconstruction with a gastric tube, through a retrosternal route, after preoperative chemoradiotherapy. Chylothorax was detected after starting enteral feeding on postoperative day (POD) 7. Despite conservative therapy such as fasting, total parenteral nutrition, and octreotide administration, massive fluid drainage continued. On POD 19, lymphoscintigraphy with 99mTc-diethylenetriamine pentaacetic acid-human serum albumin (HSA-D) was performed and the site of leakage was detected at the level of the fourth thoracic vertebra. On POD 23, the thoracic duct was ligated, following which the volume of chylothorax decreased. Lymphoscintigraphy 12 days after the reoperation showed no leakage from the thoracic duct. We recommend lymphoscintigraphy with 99mTc-HSA-D for locating the chyle leakage site and helping decide about the operative indication..
183. Hideo Baba, Yoshifumi Baba, Shinji Uemoto, Kazuhiro Yoshida, Akio Saiura, Masayuki Watanabe, Yoshihiko Maehara, Eiji Oki, Yasuharu Ikeda, Hiroyuki Matsuda, Masakazu Yamamoto, Mitsuo Shimada, Akinobu Taketomi, Michiaki Unno, Kenichi Sugihara, Yutaka Ogata, Susumu Eguchi, Seigo Kitano, Kazuo Shirouzu, Yasumitsu Saiki, Hiroshi Takamori, Masaki Mori, Toshihiko Hirata, Go Wakabayashi, Norihiro Kokudo, Erratum to Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer
Results of a multicenter study [Oncotarget., 6 (2015) 34004-34013], Oncotarget, 10.18632/oncotarget.6335, 6, 36, 2015.01.
184. Tetsuo Ikeda, Ryuichi Kumashiro, Kenji Taketani, Koji Ando, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Tomohiko Akahoshi, Makoto Hashizume, Yoshihiko Maehara, Endoscopic evaluation of clinical colorectal anastomotic leakage, Journal of Surgical Research, 10.1016/j.jss.2014.07.009, 193, 1, 126-134, 2015.01, Background: Anastomotic leakage (AL) is a major complication after anterior resection. However, its therapeutic strategies and technical risk factors have not been well established. Therefore, we endoscopically evaluated anastomotic regions after laparoscopic colorectal anastomosis using a double-stapling technique (DST) for determination of treatment and investigation of technical factors. Methods: In total, 191 consecutive patients underwent laparoscopic anterior resection with a DST from September 2008-January 2013. Anastomotic regions were endoscopically evaluated in patients suspected to have AL after surgery. Results: Anastomotic dehiscence was observed in 19 patients, and AL was diagnosed in 18 (9.3%). Of the 19 patients, 12 were treated by creation of an intestinal stoma and 7 were treated conservatively based on their clinical status and endoscopic findings. Twentythree dehiscences were observed among 19 anastomotic regions; all 23 were observed on the circular stapler anastomosis lines. Of these 23 dehiscences, 13 (56.5%) were located at the point at which the anastomosis lines of the circular and linear staplers overlapped, and 10 (43.5%) were located on the circumferential aspect between the overlapping points. Conclusions: Endoscopic evaluation of anastomotic regions is safe and useful for the determination of therapeutic strategies. The DST anastomotic technique itself may be closely related to the development of AL..
185. Koji Ando, Eiji Oki, Hiroshi Saeki, Zhao Yan, Yasuo Tsuda, Gen Hidaka, Yuta Kasagi, Hajime Otsu, Hiroyuki Kawano, Hiroyuki Kitao, Masaru Morita, Yoshihiko Maehara, Discrimination of p53 immunohistochemistry-positive tumors by its staining pattern in gastric cancer, Cancer Medicine, 10.1002/cam4.346, 4, 1, 75-83, 2015.01, Immunohistochemistry staining of p53 is a cheap and simple method to detect aberrant function of p53. However, there are some discrepancies between the result of immunohistochemistry staining and mutation analysis. This study attempted to find a new definition of p53 staining by its staining pattern. Immunohistochemistry staining of p53 and TP53 gene mutation analysis were performed in 148 gastric cancer patients. Also SNP-CGH array analysis was conducted to four cases. Positive staining of p53 was observed in 88 (59.5%) tumors. Tumors with positive p53 staining showed malignant features compared to negative tumors. Mutation of TP53 gene was observed in 29 (19.6%) tumors with higher age and differentiated type. In positive p53 tumors, two types could be distinguished; aberrant type and scattered type. With comparison to TP53 gene mutation analysis, all the scattered type had wild-type TP53 gene (P = 0.0003). SNP-CGH array showed that scattered-type tumors had no change in the structure of chromosome 17. P53-scattered-type staining tumors may reflect a functionally active nonmutated TP53 gene. In interpretation of p53 immunohistochemistry staining, distinguishing p53-positive tumors by their staining pattern may be important in gastric cancer..
186. Yuta Kasagi, Masaru Morita, Hajime Otsu, Hiroyuki Kawano, Koji Ando, Yukiharu Hiyoshi, Shuhei Ito, Yuji Miyamoto, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Clinicopathological Characteristics of Esophageal Squamous Cell Carcinoma in Patients Younger Than 50 years, Annals of Surgical Oncology, 10.1245/s10434-014-3856-6, 22, 1, 311-315, 2015.01, Purpose: This study clarifies age differences in clinicopathologic characteristics and risk factor exposure of patients who have undergone esophagectomy for esophageal cancer (EC).
Methods: Clinical results of esophagectomy were compared between 22 patients younger than 50years of age (Group I) and 327 patients older than 50 years of age (Group II) with esophageal squamous cell carcinoma.
Results: The two groups did not significantly differ in clinicopathological characteristics, including prognosis. Postoperative pulmonary complication incidence rates were 4.2% (Group I) and 14.4% (Group II). In Group I, the incidence of multiple ECs was 36.4%, and association with head and neck cancer was 31.8%, which were significantly higher than in Group II (13.4%, p=0.021; and 9.2%, p=0.015, respectively). Furthermore, the patients in Group I with multiple cancers were almost all heavy smokers and/or users of alcohol.
Conclusions: These results suggest that multiple upper aerodigestive tract cancers are associated with heavy exposure to risk factors in patients younger than 50years of age..
187. Shuhei Ito, Eiji Oki, Yuichiro Nakashima, Koji Ando, Yukiharu Hiyoshi, Kippei Ohgaki, Hiroshi Saeki, Masaru Morita, Yoshihisa Sakaguchi, Yoshihiko Maehara, Clinical significance of adjuvant surgery following chemotherapy for patients with initially unresectable stage IV gastric cancer, Anticancer research, 35, 1, 401-406, 2015.01, Background: More effective treatment is necessary to improve the poor prognosis for patients with unresectable gastric cancer. We investigated the efficacy and feasibility of adjuvant surgery following chemotherapy.
Patients and Methods: Records of 70 patients with unresectable stage IV gastric cancer who underwent induction chemotherapy were reviewed retrospectively. Patients who developed an absence of non-curative clinical factors during chemotherapy underwent gastrectomy [adjuvant surgery (AS) group]; the others continued chemotherapy [non-AS group].
Results: Non-AS and AS groups contained 56 (80%) and 14 (20%) patients, respectively. In the AS group, 92.9% of patients had one noncurative clinical factor, while 48.2% of patients in the non-AS group had two or more non-curative clinical factors (p=0.0386). In the AS group, operative outcomes, including the postoperative complication rate (21.4%), were acceptable. The 3-year overall survival rate in the AS group was 65.6% versus 7.7% in the non-AS group (p<0.0001). In patients with one noncurative clinical factor of peritoneal dissemination, the median survival of the AS group was 29.5 months versus 11.4 months in the non-AS group (p=0.0230).
Conclusion: Adjuvant surgery for initially unresectable stage IV gastric cancer was safe and feasible, and may improve the prognosis for patients with one non-curative clinical factor, such as peritoneal dissemination..
188. Yukiharu Hiyoshi, Masaru Morita, Hiroyuki Kawano, Hajime Otsu, Koji Ando, Shuhei Ito, Yuji Miyamoto, Yasuo Sakamoto, Hiroshi Saeki, Eiji Oki, Tetsuo Ikeda, Hideo Baba, Yoshihiko Maehara, Clinical Significance of Surgical Resection for the Recurrence of Esophageal Cancer After Radical Esophagectomy, Annals of Surgical Oncology, 10.1245/s10434-014-3970-5, 22, 1, 240-246, 2015.01, Background: This study aimed to clarify the clinical significance of surgical resection for recurrent lesions after esophagectomy for esophageal cancer.
Methods: Recurrence was detected in 113 of 365 consecutive patients who underwent surgical resection for esophageal cancer, and some treatment was performed for recurrence in 100 of the 113 patients. The treatments were classified into two groups: chemotherapy and/or radiation with surgery (surgery group, n = 14) and chemotherapy and/or radiation without surgery (no surgery group, n = 86). The outcomes were retrospectively analyzed.
Results: Of the 14 patients in the surgery group, 3 underwent repeated resection. Thus, a total of 22 resections were performed for these patients. The resected organs were the lymph nodes in nine patients, the lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, the liver in one patient, the brain in one patient, and the parotid gland in one patient. Among the 22 recurrent cases, 20 involved solitary lesions or multiple lesions located in a small resectable region. When the two groups were compared, the surgery group showed a more favorable prognosis in terms of both survival after esophagectomy (median survival time, 103.3 vs 23.1 months; p = 0.0060) and survival after initial recurrence (92.1 vs 12.2 months; p = 0.0057).
Conclusions: Multimodal treatment provides a significant benefit for patients with recurrence after esophagectomy for esophageal cancer. Surgical intervention should be aggressively included in the treatment strategy when the recurrent lesion is solitary or localized..
189. Hideo Baba, Yoshifumi Baba, Shinji Uemoto, Kazuhiro Yoshida, Akio Saiura, Masayuki Watanabe, Yoshihiko Maehara, Eiji Oki, Yasuharu Ikeda, Hiroyuki Matsuda, Masakazu Yamamoto, Mitsuo Shimada, Akinobu Taketomi, Michiaki Unno, Kenichi Sugihara, Yutaka Ogata, Susumu Eguchi, Seigo Kitano, Kazuo Shirouzu, Yasumitsu Saiki, Hiroshi Takamori, Masaki Mori, Toshihiko Hirata, Go Wakabayashi, Norihiro Kokudo, Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer
Results of a multicenter study, Oncotarget, 10.18632/oncotarget.5227, 6, 32, 34004-34013, 2015.01, Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman's correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression..
190. Shuhei Ito, Masaru Morita, Sho Nanbara, Yu Nakaji, Koji Ando, Yukiharu Hiyoshi, Tatsuro Okamoto, Hiroshi Saeki, Eiji Oki, Hirofumi Kawanaka, Yoshihisa Tanoue, Yoshihiko Maehara, Cardiac tamponade due to bleeding as a potential lethal complication after surgery for esophageal cancer, Anticancer research, 35, 1, 407-412, 2015.01, Background: Cardiac tamponade, due to bleeding in the pericardial space after esophagectomy for esophageal cancer, is an extremely rare complication and may be associated with sudden hemodynamic instability that can lead to death unless there is prompt diagnosis and appropriate treatment.
Case Report: A 76-year-old man underwent subtotal esophagectomy via a cervico-right thoracoabdominal approach and reconstruction with a gastric tube through the retrosternal route. On postoperative day 4, the patient developed hypotension due to cardiac tamponade caused by bleeding into the pericardial space and he had a decreased level of consciousness. Pericardial resection and open drainage via a minimal left anterior thoracotomy was performed that resulted in hemodynamic improvement followed by an uneventful recovery.
Conclusion: Cardiac tamponade due to postoperative bleeding, which is a rare but life-threatening complication, should be considered as a cause of hemodynamic instability in the early postoperative period after esophagectomy..
191. Tomonori Nakanoko, Yoshihiro Kakeji, Koji Ando, Yuichiro Nakashima, Kippei Ohgaki, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiko Maehara, Assessment of surgical treatment and postoperative nutrition in gastric cancer patients older than 80 years, Anticancer research, 35, 1, 511-516, 2015.01, Background: A gastrectomy for gastric cancer is sometimes required in patients older than 80 years due to the continuously increasing age of society. However, if a gastrectomy worsens the postoperative quality of life and daily activity in elderly patients because of poor nutrition, the procedure may not always be a useful treatment strategy.
Patients and Methods: Clinicopathological data of patients with gastric cancer who underwent a gastrectomy at our Department between 1998 and 2008 (N=471) were collected and analyzed. The results of treatment for patients older than 80 years (N=41) were analyzed and compared against those of patients younger than 80 years (N=430).
Results: Patients older than 80 years had a higher frequency of preoperative co-morbidities than patients younger than 80 years. However, there was no statistical difference in postoperative complications regarding nutrition between the two groups.
Conclusion: Older age is not a determinant of poor nutrition following gastrectomy. Gastrectomy for gastric cancer is, therefore, a useful treatment strategy, regardless of ageing..
192. Yoko Zaitsu, Eiji Oki, Koji Ando, Satoshi Ida, Yasue Kimura, Hiroshi Saeki, Masaru Morita, Minako Hirahashi, Yoshinao Oda, Yoshihiko Maehara, Loss of heterozygosity of PTEN (Encoding phosphate and tensin homolog) associated with elevated HER2 expression is an adverse prognostic indicator in gastric cancer, Oncology (Switzerland), 10.1159/000368984, 88, 3, 189-194, 2015.03, Objective: PTEN (the encoding phosphate and tensin homolog) is a well-known cancer suppressor gene and its mutation and loss of heterozygosity (LOH) occurs in various types of carcinomas. This study aimed to examine the association between LOH of PTEN and prognosis in HER2-expressing and nonexpressing gastric cancer patients. Methods: Fresh-frozen tumor samples of 221 gastric cancer patients with a primary diagnosis of gastric carcinoma were examined for LOH of PTEN. The results were compared with pathological parameters and the HER2 status. To elucidate the role of LOH of PTEN, the activation of the PI3K/AKT pathway was examined immunohistochemically using a phosphorylation-specific antibody. Results: LOH of PTEN was observed in 20% of the patients (39 of 195 cases). LOH of PTEN was associated with vascular involvement (25 of 39 cases; p = 0.0083), equivocal to positive staining for HER2 (p = 0.0080), and phospho-Akt expression (p = 0.0067). Patients with HER2-expressing gastric cancer with LOH of PTEN had a significantly worse prognosis (p = 0.0050). Conclusions: Although HER2 expression itself was not a prognostic factor, the combination of HER2 expression and LOH of PTEN exacerbates the malignant potential of gastric cancer through its proliferative function..
193. T. Ikegami, T. Yoshizumi, Y. Soejima, N. Harimoto, S. Itoh, K. Takeishi, H. Uchiyama, H. Kawanaka, Y. I. Yamashita, E. Tsujita, N. Harada, E. Oki, H. Saeki, Y. Kimura, K. Shirabe, Y. Maehara, Triple therapy using direct-acting agents for recurrent hepatitis C after liver transplantation
A single-center experience, Transplantation Proceedings, 10.1016/j.transproceed.2014.10.058, 47, 3, 730-732, 2015.04, Background Hepatitis C viral graft reinfection is almost a universal event after liver transplantation with consequent disease progression. Methods We applied triple therapy (n = 21) with the use of telaprevir (TVR; n = 12) or simeprevir (SVR; n = 9). Results TVR was given at the dose 1,500 mg daily (n = 11) with reduced dose of cyclosporine at 25% to 50%, and SVR was given at the dose 100 mg daily with unadjusted cyclosporine, followed by 12 weeks of dual therapy. The early viral response was achieved in 91.7% (n = 11), end of treatment response rate was 91.7% (n = 11), and sustained viral response rate was 83.3% (n = 10) in the TVR group, and respective rates were 88.9% (n = 8), 77.8% (n = 7), and 77.8% (n = 7) in the SVR group. Although granulocyte colony-stimulating factor was not given in the patients with triple therapy, blood transfusion was performed in 7 cases (58.3%) in the TVR group and 1 case (11.1%) in the SVR group. Interferon-mediated graft dysfunction was observed in 4 cases (33.3%) in the TVR group and 3 cases (33.3%) in the SVR group, respectively. The cumulative viral clearance rates in triple (n = 21) and dual (n = 105) therapy were 95.0% and 18.1% at 12 weeks, and 95.0% and 40.0%, respectively, at 24 weeks (P <.01). Conclusions Although careful monitoring for possible adverse events is required during treatment, triple therapy with the use of direct-acting agents are very effective in treating hepatitis C after liver transplantation..
194. K. Takeishi, T. Ikegami, T. Yoshizumi, S. Itoh, N. Harimoto, N. Harada, E. Tsujita, Y. Kimura, Y. Yamashita, K. Saeki, E. Oki, K. Shirabe, Y. Maehara, Thymoglobulin for steroid-resistant immune-mediated graft dysfunction during simeprevir-based antiviral treatment for post-transplantation hepatitis c
Case report, Transplantation Proceedings, 10.1016/j.transproceed.2014.11.056, 47, 3, 794-795, 2015.04, Introduction Immune-mediated graft dysfunction (IGD), a recently established disease entity with unfavourable outcome, is an antigraft immune reaction during interferon-based antiviral treatment for hepatitis C virus (HCV) infection after liver transplantation (LT). We report a case having steroid-resistant acute cellular rejection (ACR) type IGD, which was successfully treated using thymoglobulin. Case Report A 56-year-old woman with recurrent HCV after LT was commenced on antiviral treatment including simeprevir, pegylated-interferon (IFN) 2a, and ribavirin. A negative serum HCV-RNA was confirmed after 4 weeks. After 12 weeks of therapy, severe liver dysfunction developed, despite a constantly negative HCV-RNA. Liver biopsy revealed portal and periportal inflammatory infiltrates including numerous eosinophils, lymphocytes, and bile duct damages, indicating ACR. IFN therapy was ceased, and she was treated with steroid pulse treatment, followed by high-level immunosuppression maintenance. However, ACR was irremediable. Thereafter she was treated with thymoglobulin (75 mg/d for 5 days). Her serum alanine aminotransaminase and total bilirubin levels decreased immediately, and her liver biopsy specimen showed no activity. During these periods of the treatment, the HCV-RNA became positive and the liver enzyme elevated, but other liver function tests still remained within normal range. Conclusion Thymoglobulin could be the best choice in steroid-resistant IGD during antiviral treatment for post-transplantation recurrent hepatitis C..
195. N. Harimoto, Y. Yoshida, T. Kurihara, K. Takeishi, S. Itoh, N. Harada, E. Tsujita, Y. I. Yamashita, H. Uchiyama, Y. Soejima, T. Ikegami, T. Yoshizumi, H. Kawanaka, T. Ikeda, K. Shirabe, H. Saeki, E. Oki, Y. Kimura, Y. Maehara, Prognostic impact of Des-γ-carboxyl prothrombin in living-donor liver transplantation for recurrent hepatocellular carcinoma, Transplantation Proceedings, 10.1016/j.transproceed.2014.09.178, 47, 3, 703-704, 2015.04, Background Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-γ-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. Methods Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. Results The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration ≥300 ng/mL, DCP concentration ≥300 mAU/mL, tumor number ≥4, tumor size ≥5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP ≥300 mAU/mL (P =.03) and duration from last treatment to LDLT <3 months (P =.01) were independent predictors of RFS. Conclusions DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC..
196. Yoshihiko Maehara, Sho Nishimura, Hiroshi Saeki, Tomonori Nakanoko, Yuta Kasagi, Yasuo Tsuda, Yoko Zaitsu, Koji Ando, Yuichiro Nakashima, Y. U. Imamura, Kippei Ohgaki, Eiji Oki, Saiji Ohga, Katsumasa Nakamura, Masaru Morita, Hyperthermia combined with chemotherapy for patients with residual or recurrent oesophageal cancer after definitive chemoradiotherapy, Anticancer research, 35, 4, 2299-2304, 2015.04, Background/Aim: Definitive chemoradiotherapy (dCRT) is frequently administered in oesophageal cancer. We carried out hyperthermochemotherapy (HCT) for residual or recurrent cases after dCRT for oesophageal cancer. The aim of this study was to elucidate the usefulness of salvage HCT for these patients. Patients and Methods: Salvage HCT after dCRT was performed in 11 patients with residual or recurrent oesophageal cancer. We used an 8-MHz radiofrequency capacitive heating system for hyperthermia. The combined chemotherapy comprised of cisplatin/5-fluorouracil, an oral fluoropyrimidine and irinotecan. Results: There were no severe adverse events caused by hyperthermia. Complete response and stable disease was achieved in three and five patients, respectively; symptoms were improved in the remaining three patients. The median survival time after HCT was 12 (range=3-88) months. Conclusion: HCT is a feasible and potent salvage therapy for patients with residual or recurrent oesophageal cancer after dCRT, unless salvage surgery is indicated..
197. Tetsuo Ikeda, Ryuichi Kumashiro, Eiji Oki, Kenji Taketani, Koji Ando, Shinichi Aishima, Tomohiko Akahoshi, Masaru Morita, Yoshihiko Maehara, Evaluation of techniques to prevent colorectal anastomotic leakage, Journal of Surgical Research, 10.1016/j.jss.2014.11.045, 194, 2, 450-457, 2015.04, Background Anastomotic leakage is a major complication after anterior resection for rectal cancer. The double-stapling technique (DST) is the main method for creating a colorectal anastomosis. However, the rate of anastomotic leakage after DST remains high, and the technical risk factors have not been well established. Materials and methods Five methods of colorectal anastomosis were performed on the porcine rectum and colon: single-stapled double-purse-string (SSDP), DST, side-to-side with a linear stapler (SS-L), side-to-side with a circular stapler (SS-C), and SS-C with hand-sewn reinforcement (n = 6 for each method). In each group, burst pressures were tested, paying special attention to the locations of the first disruptions. The anastomosis line, including staples, was embedded in polyester resin, and polished sections were examined histologically. Results Burst pressures were significantly higher in the SS-L and SS-C than those in the SSDP and DST groups (P < 0.001) and were higher in the SS-C with hand-sewn reinforcement than those in the SS-L and SS-C groups (P < 0.001). Remarkably, in the SSDP, DST, and SS-C groups, the first disruptions occurred on the staple line created by the circular stapler. Conclusions The experimentally strongest colorectal anastomosis created with instruments currently in use was a SS-C. This anastomosis does not overlap staple lines and does not require a purse-string suture. Hand-sewn reinforcement was effective in increasing the anastomotic strength..
198. Hajime Otsu, Eiji Oki, Ayae Ikawa-Yoshida, Hiroyuki Kawano, Koji Ando, Satoshi Ida, Yasue Kimura, Shinichi Aishima, Hiroshi Saeki, Masaru Morita, Shunji Kohnoe, Yoshinao Oda, Yoshihiko Maehara, Correlation of HER2 expression with clinicopathological characteristics and prognosis in resectable gastric cancer, Anticancer research, 35, 4, 2441-2446, 2015.04, Results from the Trastuzumab for Gastric Cancer (ToGA) trial highlighted the clinical significance of trastuzumab in the treatment of HER2 (Human Epidermal Growth Factor Receptor type 2)-positive gastric cancer. However, whether expression of HER2 is related to prognosis of gastric cancer is still controversial. A total of 360 consecutive patients with gastric cancer who underwent surgical resection in our Department from 1994 to 2007 were analyzed. We performed immunohistochemical analysis of HER2 expression. HER2 expression level was classified into four scores (0, 1+, 2+ and 3+). There were 37 (10%) patients with a score of 3+. A score of 3+ was defined as being HER2-positive. Recurrence-free survival was worse in HER2-positive cases (p=0.045). When the analysis was conducted with intestinal types of cancer, RFS was considerably worse in the HER2-positive group (p=0.011). HER2 expression may have potential as a prognostic factor for intestinal cancer types. Further research is warranted..
199. Masaru Morita, Hiroshi Saeki, Tatsuro Okamoto, Eiji Oki, Sei Yoshida, Yoshihiko Maehara, Tracheobronchial fistula during the perioperative period of esophagectomy for esophageal cancer, World journal of surgery, 10.1007/s00268-015-2945-4, 39, 5, 1119-1126, 2015.05, Background: Tracheobronchial (TB) injury and fistula formation during the perioperative period of esophagectomy is a rare but life-threatening complication. Methods: We examined the development of intraoperative TB injury and postoperative TB fistulas in consecutive 763 patients with esophageal cancer who underwent esophagectomy, including 494 patients who underwent transthoracic subtotal esophagectomy. Results: TB injury and fistulas developed in two (0.4 %) and four patients (0.8 %), respectively, who received transthoracic esophagectomy. TB injury developed during the dissection of a tumor invading a major airway. Direct suturing of the laceration and covering it using a muscle flap was effective for one patient, while additional repair with a major pectoral muscle flap was needed in another patient. Postoperative TB fistulas developed due to peri-tracheal infection in two patients, and conservative treatment with drainage was performed. In another two patients, gastro-tracheal fistulas developed due to mechanical compression of staplers on the gastric tube, which was elevated via the posterior mediastinal route. The direct repair of the gastric tube and covering it with a major pectoral muscle flap resulted in the resolution of these fistulas. Conclusion: Careful dissection with direct vision of the esophagus, as well as oversewing of the staplers on the gastric tube, is mandatory for preventing TB injury and fistula formation. Appropriate drainage is effective in cases with peri-tracheal abscesses. If the TB fistula fails to heal within a 4-to 6-week period, conservative management should be abandoned. Direct surgical intervention with coverage by a muscle flap is important for TB fistulas..
200. Eiji Oki, Koji Ando, Hiroshi Saeki, Yuichiro Nakashima, Yasue Kimura, Yukiharu Hiyoshi, Yu Imamura, Kippei Ohgaki, Shuhei Ito, Masaru Morita, Tetsuo Ikeda, Yoshihiko Maehara, The use of a circular side stapling technique in laparoscopic low anterior resection for rectal cancer
Experience of 30 serial cases, International Surgery, 10.9738/INTSURG-D-14-00202.1, 100, 6, 979-983, 2015.06, The double-stapling technique using a circular stapler (CS) to create an end-to-end anastomosis is currently used widely in laparoscopic-assisted rectal surgery. However, a high rate of anastomotic failure has been reported. We report new side-to-side anastomosis creation using a CS, the so-called circular side stapling technique (CST). After excising the rectum at the oral and anal sides of the tumor with a linear stapler, a side-to-side colorectal anastomosis was made on the anterior wall of the rectosigmoid colon and the anterior or posterior wall of the rectum with a CS. Between 2012 and 2013, we recorded 30 serial cases of rectal-sigmoid or rectal cancer that were treated with laparoscopic-assisted surgeries using this method. In the 30 cases, the mean age was 68 ± 12 years, operating time was 288 ± 80 minutes, and blood loss was 66 ± 67 mL. None of the patients suffered from anastomosis leakage or postoperative anastomotic bleeding, and none complained of their stool habits. Three months after the last surgery in this cohort, no anastomosis strictures were reported. Based on these results, we propose an alternative method of side-to-side anastomosis for low anterior resection by using a CS to prevent staple overlap. Our experience indicates that the CST is easy and safe. Therefore, this method is a useful alternative to the current method used in laparoscopic surgery..
201. Satoshi Ida, Nobuyuki Ozaki, Kimi Araki, Kotaro Hirashima, Yoko Zaitsu, Katsunobu Taki, Yasuo Sakamoto, Yuji Miyamoto, Eiji Oki, Masaru Morita, Masayuki Watanabe, Yoshihiko Maehara, Ken Ichi Yamamura, Hideo Baba, Masaki Ohmuraya, SPINK1 status in colorectal cancer, impact on proliferation, and role in colitis-associated cancer, Molecular Cancer Research, 10.1158/1541-7786.MCR-14-0581, 13, 7, 1130-1138, 2015.07, Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer..
202. Kouji Andou, Eiji Oki, Hiroshi Saeki, Yuichiro Nakashima, Yoshihiko Maehara, Long-term treatment with panitumumab monotherapy for recurrent colorectal cancer, International Cancer Conference Journal, 4, 3, 151, 2015.07, With the development of new chemotherapy agents and methods, metastatic colorectal cancer patients can now achieve a survival time of >30 months. Higher line therapies have had a significant influence on the survival of these patients. However, it remains uncertain as to which therapy is the most effective and best tolerated. Herein, we describe the case of a patient with metastatic KRAS wild-type colorectal cancer who received panitumumab monotherapy as a third-line therapy after failure of 5-fluorouracil, irinotecan, oxaliplatin and bevacizumab. This patient had both lymph node and lung recurrence. The patient achieved a partial response time of 15 months. The lymph node and recurrent lung tumor had shrunk by 74 and 100 %, respectively, and the treatment was well tolerated with limited cutaneous toxicity. Panitumumab monotherapy may be an effective and well-tolerated treatment of KRAS wild-type metastatic colorectal cancer patients who have undergone many prior therapies. The present case showed a response to panitumumab monotherapy extending over a period of >1 year..
203. Yuki Bekki, Yasue Kimura, Masaru Morita, Yoko Zaitsu, Hiroshi Saeki, Tatsuro Okamoto, Eiji Oki, Shingo Baba, Yoshinao Oda, Yoshihiko Maehara, Esophageal cancer associated with bilateral hilar lymphadenopathy caused by sarcoid-like reactions
a report of two cases, Esophagus, 10.1007/s10388-014-0454-4, 12, 3, 322-326, 2015.07, Hilar lymph node metastasis of esophageal cancer is considered to be a distant metastasis and is not indicated for surgical resection. However, its diagnosis is difficult when accompanied by inflammatory diseases such as sarcoidosis. We report two patients with esophageal cancer accompanied by bilateral hilar lymphadenopathy or accumulation on [18F]-fluorodeoxyglucose positron emission tomography–computed tomography. The first patient underwent surgery because the enlarged bilateral hilar lymph nodes were considered to be nonmalignant lesions owing to superficial carcinoma and symmetric distribution of the hilar lymph nodes. The second patient received chemotherapy, which caused the main tumor to shrink and decreased [18F]-fluorodeoxyglucose uptake. However, chemotherapy did not affect the hilar lymphadenopathy, which suggests that it was caused by reactive changes rather than metastasis. In both cases, esophagectomy and histological findings revealed that the hilar nodes were caused by sarcoid-like reactions. These findings profoundly influenced our treatment decisions for these patients..
204. Yuki Bekki, Yasue Kimura, Masaru Morita, Yoko Zaitsu, Hiroshi Saeki, Tatsuro Okamoto, Eiji Oki, Shingo Baba, Yoshinao Oda, Yoshihiko Maehara, Esophageal cancer associated with bilateral hilar lymphadenopathy caused by sarcoid-like reactions
A report of two cases, Esophagus, 10.1007/s10388-014-0454-4, 12, 3, 322-326, 2015.07, Hilar lymph node metastasis of esophageal cancer is considered to be a distant metastasis and is not indicated for surgical resection. However, its diagnosis is difficult when accompanied by inflammatory diseases such as sarcoidosis. We report two patients with esophageal cancer accompanied by bilateral hilar lymphadenopathy or accumulation on [18F]-fluorodeoxyglucose positron emission tomography-computed tomography. The first patient underwent surgery because the enlarged bilateral hilar lymph nodes were considered to be nonmalignant lesions owing to superficial carcinoma and symmetric distribution of the hilar lymph nodes. The second patient received chemotherapy, which caused the main tumor to shrink and decreased [18F]-fluorodeoxyglucose uptake. However, chemotherapy did not affect the hilar lymphadenopathy, which suggests that it was caused by reactive changes rather than metastasis. In both cases, esophagectomy and histological findings revealed that the hilar nodes were caused by sarcoid-like reactions. These findings profoundly influenced our treatment decisions for these patients..
205. Takaki Akamine, Koji Ando, Eiji Oki, Hiroshi Saeki, Yuichiro Nakashima, Yu Imamura, Kippei Ohgaki, Yoshihiko Maehara, Acute liver failure due to regorafenib may be caused by impaired liver blood flow
A case report, Anticancer research, 35, 7, 4037-4042, 2015.07, Background/Aim: Regorafenib has been approved for treatment of patients with unresectable or recurrent gastrointestinal stromal tumors resistant to imatinib or sunitinib. However, regorafenib has severe side-effects, including acute liver failure. We describe the case of a patient with multiple liver metastases of a small intestinal stromal tumor who experienced acute liver failure while being treated with regorafenib. Case Report: A 50-year-old patient with an unresectable small intestinal stromal tumor resistant to prior treatment with imatinib and sunitinib was started on regorafenib, but experienced acute liver failure 10 days later. Plasma exchange and steroid pulse treatment improved her liver function. During liver failure, abdominal ultrasonography showed to-and-fro flow in the portal vein. Lactate dehydrogenase concentration was markedly elevated to 1633 U/l. These findings indicate that liver failure in this patient was due to impaired liver blood flow. Conclusion: Regorafenib may impair liver blood flow, inducing acute liver failure..
206. Eiji Oki, Koji Ando, Yuta Kasagi, Yoko Zaitsu, Masahiko Sugiyama, Yuichiro Nakashima, Hideto Sonoda, Kippei Ohgaki, Hiroshi Saeki, Yoshihiko Maehara, Recent advances in multidisciplinary approach for rectal cancer, International Journal of Clinical Oncology, 10.1007/s10147-015-0858-8, 20, 4, 641-649, 2015.08, Surgery is a major treatment option for rectal cancer, and total mesorectal excision has been demonstrated to be advantageous in terms of oncological outcome and thus has been the standard surgical approach. Radiotherapy before or after radical surgery is the optimal treatment to control local recurrence of advanced rectal cancer. To date, in many countries, the combination of neoadjuvant concurrent chemotherapy and radiotherapy is considered the standard therapy. A more recent interest in neoadjuvant therapy has been the use of oxaliplatin or targeted agents for neoadjuvant chemoradiotherapy. However, despite many trials of oxaliplatin and targeted agents, 5-FU-based concurrent chemoradiotherapy has remained the only standard treatment option. Postoperative adjuvant chemotherapy with neoadjuvant chemoradiotherapy or induction chemotherapy with neoadjuvant chemoradiotherapy may further improve patient survival, as some clinical studies recently indicated. In Japan, neoadjuvant therapy is not the standard treatment method, because surgery with lateral lymph node dissection is usually performed and this type of surgery may reduce recurrence rate as does radiation therapy. The phase III study to evaluate the oncological effect of the Japanese standard operation (mesorectal excision, ME) with lateral lymph node dissection in comparison with ME alone for clinical stage II and III lower rectal cancer is currently ongoing..
207. Eiji Oki, Yasunori Emi, Hiroshi Kojima, Jun Higashijima, Takeshi Kato, Yasuhiro Miyake, Masanori Kon, Yutaka Ogata, Kenichi Takahashi, Hideyuki Ishida, Hiroshi Saeki, Yoshihisa Sakaguchi, Takeharu Yamanaka, Toru Kono, Naohiro Tomita, Hideo Baba, Ken Shirabe, Yoshihiro Kakeji, Yoshihiko Maehara, Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial)
a placebo-controlled, double-blind, randomized phase III study, International Journal of Clinical Oncology, 10.1007/s10147-015-0784-9, 20, 4, 767-775, 2015.08, Background: Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG’s potential for reducing peripheral neuropathy in patients with colorectal cancer. Methods: Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Findings: An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908; p = 0.007). Conclusion: Goshajinkigan did not prevent oxaliplatin-associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated..
208. Takafumi Yukaya, Hiroshi Saeki, Yuta Kasagi, Yuichiro Nakashima, Koji Ando, Yu Imamura, Kippei Ohgaki, Eiji Oki, Masaru Morita, Yoshihiko Maehara, Indocyanine Green Fluorescence Angiography for Quantitative Evaluation of Gastric Tube Perfusion in Patients Undergoing Esophagectomy, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2015.04.022, 221, 2, e37-e42, 2015.08.
209. Rintaro Yoshida, Masaru Morita, Fumihiro Shoji, Yuichiro Nakashima, Naoko Miura, Keiji Yoshinaga, Tadashi Koga, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Yoshihiko Maehara, Clinical Significance of SIP1 and E-cadherin in Patients with Esophageal Squamous Cell Carcinoma, Annals of Surgical Oncology, 10.1245/s10434-014-4314-1, 22, 8, 2608-2614, 2015.08, Background: Epithelial-mesenchymal transition (EMT), when epithelial cells convert to mesenchymal cells, influences cancer invasion and metastasis. Smad interacting protein 1 (SIP1) is an EMT trigger, which is inversely correlated with E-cadherin in some carcinomas. To elucidate the role of SIP1 in esophageal squamous cell carcinoma (ESCC), the status of EMT and the clinicopathological features were evaluated. Methods: Immunohistochemical (IHC) analyses of 111 human ESCC tissue specimens for SIP1 and E-cadherin were performed, and the relationships between the expression and clinicopathological features were evaluated. Results: IHC analyses of esophageal tumors showed the expression of SIP1 and E-cadherin to be significantly inversely correlated. Significant correlations between the SIP1 expression and clinicopathological variables such as differentiation, depth of invasion, vascular invasion, and pathological stage were also seen. Conversely, tumors with a weak expression of E-cadherin tended to exhibit greater histological differentiation. Logistic regression analyses revealed a positive SIP1 expression, lymphatic invasion, and vascular invasion to be factors predicting lymph node (LN) metastasis. Univariate survival analyses revealed a positive SIP1 expression predicted a poorer overall survival than a negative expression. Conclusion: These results suggest that SIP1 is correlated with LN metastasis and may therefore be an independent marker for metastasis in patients with ESCC..
210. Mitsuhiro Yasuda, Hiroshi Saeki, Yuichiro Nakashima, Takafumi Yukaya, Satoshi Tsutsumi, Hirotada Tajiri, Yoko Zaitsu, Yasuo Tsuda, Yuta Kasagi, Koji Ando, Yu Imamura, Kippei Ohgaki, Tomohiko Akahoshi, Eiji Oki, Yoshihiko Maehara, Treatment results of two-stage operation for the patients with esophageal cancer concomitant with liver dysfunction, Journal of Medical Investigation, 10.2152/jmi.62.149, 62, 3, 149-153, 2015.09, Purpose: The aim of this study was to clarify the usefulness of two-stage operation for the patients with esophageal cancer who have liver dysfunction. Methods: Eight patients with esophageal cancer concomitant with liver dysfunction who underwent two-stage operation were analyzed. The patients initially underwent an esophagectomy, a cervical esophagostomy and a tube jejunostomy, and reconstruction with gastric tube was performed after the recovery of patients' condition. Results: The average time of the 1st and 2nd stage operation was 410.0 min and 438.9 min, respectively. The average amount of blood loss in the 1st and 2nd stage operation was 433.5 ml and 1556.8 ml, respectively. The average duration between the operations was 29.8 days. The antesternal route was selected for 5 patients (62.5%) and the retrosternal route was for 3 patients (37.5%). In the 1st stage operation, no postoperative complications were observed, while, complications developed in 5 (62.5%) patients, including 4 anastomotic leakages, after the 2nd stage operation. Pneumonia was not observed through two-stage operation. No in-hospital death was experienced. Conclusion: A two-stage operation might prevent the occurrence of critical postoperative complications for the patients with esophageal cancer concomitant with liver dysfunction..
211. Kazuto Harada, Yoshifumi Baba, Takatsugu Ishimoto, Keisuke Kosumi, Ryuma Tokunaga, Daisuke Izumi, Mayuko Ohuchi, Kenichi Nakamura, Yuki Kiyozumi, Junji Kurashige, Shiro Iwagami, Yuji Miyamoto, Yasuo Sakamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Hideo Baba, Suppressor microRNA-145 Is epigenetically regulated by promoter hypermethylation in esophageal squamous cell carcinoma, Anticancer research, 35, 9, 4617-4624, 2015.09, Background/Aim: DNA methylation is a common epigenetic change in cancer. However, microRNA (miRNA) regulation by epigenetic alteration, especially CpG island hypermethylation, remains poorly understood in esophageal squamous cell carcinoma (ESCC). Materials and Methods: miRNAs which were up-regulated after de-methylation with 5- aza-2'-deoxycytidine (5-AZA) were analyzed using the Human miFinder 384HC miScript miRNA PCR Array. The DNA methylation level was evaluated by bisulfite-pyrosequencing assay. Results: In two of the cell lines, 20 miRNAs, including miR-145-5p, were found to be up-regulated by more than three-fold after 5-AZA treatment. The miRNA-145 promoter was significantly more hypermethylated in the cancer tissues than in matched normal adjacent esophageal epithelial mucosa (p=0.0042; paired t-test). Moreover, the miRNA-145- 5p expression levels were significantly lower in cancerous tissues (p=0.0024). Conclusion: miRNA-145 expression in ESCC seems to be regulated by hypermethylation of the miRNA-145 promoter region..
212. Shotaro Korehisa, Kippei Ohgaki, Takafumi Yukaya, Yoko Zaitu, Yasuo Tsuda, Yuta Kasagi, Koji Ando, Yuichiro Nakashima, Yu Imamura, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Laparoscopic total gastrectomy for RGC
Four case reports, Anticancer research, 35, 9, 5023-5026, 2015.09, Surgery for RGC can generally be difficult because of the severity of intra-abdominal adhesion due to past gastrectomy. Laparoscopic gastrectomy for RGC has been reported in some cases, but the adequacy of this procedure is still unclear. Herein we report four cases of RGC that underwent laparoscopic gastrectomy at our Hospital and discuss the benefit of the laparoscopic approach for RGC..
213. Shinichi Kiyonari, Makoto Iimori, Kazuaki Matsuoka, Sugiko Watanabe, Tomomi Morikawa-Ichinose, Daisuke Miura, Shinichiro Niimi, Hiroshi Saeki, Eriko Tokunaga, Eiji Oki, Masaru Morita, Kenji Kadomatsu, Yoshihiko Maehara, Hiroyuki Kitao, The 1,2-diaminocyclohexane carrier ligand in oxaliplatin induces p53-dependent transcriptional repression of factors involved in thymidylate biosynthesis, Molecular cancer therapeutics, 10.1158/1535-7163.MCT-14-0748, 14, 10, 2332-2342, 2015.10, Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity. However, the underlying mechanism of this activity has not been completely elucidated, and it remains unclear whether factors other than downregulation of dUTPase contribute to the synergistic effect of 5-FU and oxaliplatin. In this study, we found that oxaliplatin and dachplatin, platinum-based drugs containing the 1,2-diaminocyclohexane (DACH) carrier ligand, repressed the expression of nuclear isoform of dUTPase (DUT-N), whereas cisplatin and carboplatin did not. Oxaliplatin induced early p53 accumulation, upregulation of primary miR-34a transcript expression, and subsequent downregulation of E2F3 and E2F1. Nutlin-3a, which activates p53 nongenotoxically, had similar effects. Introduction of miR-34a mimic also repressed E2F1 and DUT-N expression, indicating that this miRNA plays a causative role. In addition to DUT-N, oxaliplatin repressed, in a p53-dependent manner, the expression of genes encoding enzymes involved in thymidylate biosynthesis. Consequently, oxaliplatin significantly decreased the level of dTTP in the dNTP pool in a p53-dependent manner. These data indicate that the DACH carrier ligand in oxaliplatin triggers signaling via the p53-miR-34a-E2F axis, leading to transcriptional regulation that ultimately results in accumulation of dUTP and reduced dTTP biosynthesis, potentially enhancing 5-FU cytotoxicity..
214. Hiroyuki Kawano, Masaru Morita, Hajime Otsu, Koji Ando, Yukiharu Hiyoshi, Shuhei Ito, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Pharyngo-laryngo-esophagectomy and reconstruction with a gastric tube for corrosive pharyngoesophagitis, Esophagus, 10.1007/s10388-014-0466-0, 12, 4, 360-364, 2015.10, We herein present the case of a 44-year-old male who was successfully treated with pharyngo-laryngo-esophagectomy for severe corrosive esophagitis associated with pharyngitis. He accidentally ingested an unidentified liquid and subsequently developed esophagitis and progressive pharyngolaryngitis. Since he also developed dyspnea, he initially underwent a tracheotomy at an emergency hospital. Afterward, dysphagia due to hypopharingoesophageal stricture gradually developed, and the patient was referred to our hospital. Therefore, under laparotomy, a feeding tube was inserted into the jejunostomy, and the gastroendoscope inserted via the anterior gastric wall revealed that the gastric mucosa along the greater curvature was intact. Based on this information, it was concluded that the patient could undergo reconstruction with a gastric tube following pharyngo-laryngo-esophagectomy, and this was successfully accomplished 3 months later..
215. Yoshifumi Baba, Takatsugu Ishimoto, Kazuto Harada, Keisuke Kosumi, Asuka Murata, Keisuke Miyake, Yukiharu Hiyoshi, Junji Kurashige, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Yasuo Sakamoto, Naoya Yoshida, Eiji Oki, Ken ichi Iyama, Masayuki Watanabe, Hideo Baba, Molecular Characteristics of Basaloid Squamous Cell Carcinoma of the Esophagus
Analysis of KRAS, BRAF, and PIK3CA Mutations and LINE-1 Methylation, Annals of Surgical Oncology, 10.1245/s10434-015-4445-z, 22, 11, 3659-3665, 2015.10, Background: Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare carcinoma with distinct characteristics, and was recently recognized as a variant of squamous cell carcinoma (SCC). We previously revealed genetic and epigenetic alterations associated with esophageal SCCs in relation to clinical outcome, including mutations in KRAS, BRAF, and PIK3CA, p53 expression, and long interspersed nucleotide element-1 (LINE-1) methylation, a surrogate marker for global DNA methylation level. In this study, we explored these features in BSCC. Methods: A database of 502 esophageal cancers was used to evaluate the clinical and molecular characteristics of BSCC. KRAS, BRAF, and PIK3CA mutations and LINE-1 methylation were analyzed by pyrosequencing. Results: Of 502 tumors, 22 (4.4 %) were pathologically diagnosed as BSCC, and 440 (87 %) as SCC. No prognostic differences between BSCC and SCC cases were identified (p = 0.41). KRAS or BRAF mutations were not observed in BSCCs. While 23 % of SCC tumors harbored a PIK3CA mutation, all BSCC cases were wild-type for PIK3CA (p = 0.002), and there were no differences in p53 expression between BSCCs and SCCs (p = 0.57), as assessed by immunohistochemistry. Furthermore, BSCC tissues exhibited significantly lower levels of LINE-1 methylation than SCC tissues (p < 0.0001). Conclusions: These findings imply that esophageal BSCC and SCC retain different cellular phenotypes with distinct genetic and epigenetic alterations; thus, tailored therapeutic strategies should be developed against each cancer type..
216. Masaki Yamazaki, Atsuhiko Kato, Yoko Zaitsu, Takeshi Watanabe, Makoto Iimori, Shinichi Funahashi, Hiroyuki Kitao, Hiroshi Saeki, Eiji Oki, Masami Suzuki, Intensive immunofluorescence staining methods for low expression protein
Detection of intestinal stem cell marker LGR5, Acta Histochemica et Cytochemica, 10.1267/ahc.15019, 48, 5, 159-164, 2015.10, Leucine-rich repeat-containing G-protein coupled receptor 5, or LGR5, is a molecule that recognizes stem cells in multiple organs and also in colon cancer. Previously, we have developed monoclonal antibodies specific to LGR5 protein that can be used for immunofluorescence staining, but because a very low level of LGR5 protein is expressed, the visualization technique needed to be enhanced. To develop procedures to detect LGR5 protein in various specimens by immunofluorescence staining, we evaluated the Alexalabeled streptavidin biotin (LSAB), the Qdot, and the tyramide methods. The detection sensitivity was highest in the tyramide method followed by the Qdot method, whereas subcellular localization of the protein was most clear in the Qdot method, because the Qdot method gave a high S/N ratio that could show a low background. Thus, the tyramide method is superior to the Q-dot method for intensifying the signal of a low expression protein, and the Qdot method is superior to the tyramide method for identifying the subcellular localization of the target protein. The results of the present study will be helpful in providing more insight into the pathophysiological roles of LGR5-positive cancer stem cells and in developing therapeutic approaches for targeting cancer stem cells..
217. Ryuma Tokunaga, Yasuo Sakamoto, Shigeki Nakagawa, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Hideo Baba, Prognostic nutritional index predicts severe complications, recurrence, and poor prognosis in patients with colorectal cancer undergoing primary tumor resection, Diseases of the colon and rectum, 10.1097/DCR.0000000000000458, 58, 11, 1048-1057, 2015.11, BACKGROUND: The prognostic nutritional index is reportedly related to postoperative outcomes. OBJECTIVE: The aim of this study was to elucidate the clinical importance of the prognostic nutritional index in patients with colorectal cancer who were undergoing primary tumor resection. DESIGN: This is a retrospective study from a single institution. SETTINGS: This study was conducted at a colorectal surgery service in an academic teaching hospital. PATIENTS: The 556 patients with colorectal cancer who were undergoing surgery between March 2005 and August 2014 were eligible for this study. MAIN OUTCOME MEASURES: The preoperative prognostic nutritional index was calculated. Classification and regression tree analysis was performed to determine the prognostic nutritional index cutoff value. The associations of the prognostic nutritional index status with clinicopathological factors and postoperative outcomes were examined using univariate and multivariate analyses. RESULTS: Classification and regression tree analysis demonstrated that 45.5 was the optimal cutoff value. The low status (≤45.5) was correlated with older age, low BMI, low estimated glomerular filtration rate, CEA positivity, carbohydrate antigen 19-9 positivity, preoperative chemotherapy, tumors invading muscular or deeper layers, distant metastasis, poor differentiation, severe postoperative complications, tumor recurrence, and poor survival. In multivariate analysis, the low status was an independent risk factor for severe postoperative complications (OR = 2.06 [95% CI, 1.22-3.50]; p = 0.007) and low overall survival (HR =3.98 [95% CI, 2.38-6.89]; p < 0.001). LIMITATIONS: Our data set was collected retrospectively from a single institution. In addition, our study was only for preoperative prognostic nutritional index status, not considering the postoperative host status. CONCLUSIONS: The preoperative prognostic nutritional index predicts severe complications, recurrence, and poor prognosis in patients with colorectal cancer who are undergoing primary tumor resection. Investigation of the nutritional and immunologic statuses using the prognostic nutritional index could be a useful clinical approach..
218. Koji Ando, Eiji Oki, Hiroshi Saeki, Yuta Kasagi, Yasuo Tsuda, Yoko Zaitsu, Yuichiro Nakashima, Yu Imamura, Kippei Ohgaki, Yoshihiko Maehara, Number of lymph node metastases may indicate the regimen for adjuvant chemotherapy in patients with stage III colorectal cancer, Anticancer research, 35, 11, 6207-6211, 2015.11, Background: Adjuvant chemotherapy (ACT) may prevent recurrence in patients with stage III colorectal cancer (CRC). However, only 10% of patients benefit from ACT and no effective indicators exist to predict which patients are likely to benefit. The present study validated metastatic lymph node (MLN) number as a new indicator for ACT. Patients and Methods: We retrospectively reviewed 173 patients with stage III CRC, who were classified by Union for International Cancer Control (UICC) stage or N category, and analyzed their overall survival (OS) and disease-free survival (DFS) according to stage, number of MLNs and ACT use. Results: Among 173 patients, we found 65 with only one MLN (N1a). For N1a patients treated with ACT, the 5-year OS rate was 100%; the 3-year DFS rate was 92.7% for those treated with oral ACT. Conclusion: The number of MLNs is a simple indicator for ACT in patients with stage III CRC. For patients with only one MLN, oral chemotherapy is a good option..
219. Ryuma Tokunaga, Yu Imamura, Kenichi Nakamura, Tomoyuki Uchihara, Takatsugu Ishimoto, Shigeki Nakagawa, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Shinichiro Oyama, Takashi Shono, Hideaki Naoe, Hiroshi Saeki, Eiji Oki, Masayuki Watanabe, Yutaka Sasaki, Yoshihiko Maehara, Hideo Baba, Carbohydrate antigen 19-9 is a useful prognostic marker in esophagogastric junction adenocarcinoma, Cancer Medicine, 10.1002/cam4.514, 4, 11, 1659-1666, 2015.11, The incidence rate of esophagogastric junction (EGJ) adenocarcinoma has been rapidly increasing worldwide. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are major serum tumor markers in gastrointestinal cancers. However, the role of these markers in EGJ adenocarcinoma has not been thoroughly investigated. A total of 211 patients with EGJ adenocarcinoma who underwent surgery or endoscopic submucosal dissection at two academic institutions, Kumamoto University Hospital or Kyushu University Hospital between January 1996 and March 2014, were eligible for this study. Serum CEA and CA19-9 were examined within 1 month before resection. The cut-off values for CEA and CA19-9 were set at 5.0 ng/mL and 37 U/mL, respectively. The clinicopathological features and prognostic roles of the markers were examined using univariate and multivariate analyses. The positive ratios for preoperative CEA (>5.0 ng/mL) and CA19-9 (>37 U/mL) were 20.3% and 12.9%, respectively. The positive ratio of CEA and CA19-9 was significantly higher in patients with tumors invading muscular or deeper layers (P = 0.002 and <0.001, respectively). Cox proportional hazards model revealed that CA19-9 positivity, but not CEA positivity, was an independent prognostic factor in patients with EGJ adenocarcinoma for cancer-specific survival (multivariate hazard ratio [HR] = 3.89, 95% confidence interval [CI] 1.41-10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03-5.35; P = 0.043). Preoperative serum CA19-9 is a useful prognostic marker in patients with EGJ adenocarcinoma..
220. Hiromitsu Hayashi, Takaaki Higashi, Naomi Yokoyama, Takayoshi Kaida, Keita Sakamoto, Yukiko Fukushima, Takatsugu Ishimoto, Hideyuki Kuroki, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Eiji Oki, Toru Beppu, Hideo Baba, An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression, Cancer Research, 10.1158/0008-5472.CAN-15-0291, 75, 22, 4985-4997, 2015.11, Transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. However, the expression profiles of TAZ/YAP differ depending on the cancer cell type, suggesting that these proteins have different roles during cancer progression, yet no studies have examined the biologic significance of the balance between TAZ and YAP expression levels. Here we examined the functional roles of TAZ/YAP in hepatocellular carcinoma progression. We found that TAZ, but not YAP, was predominantly expressed in HCC. TAZ knockdown under normal conditions attenuated cell growth in HCC cells; however, TAZ knockdown combined with 5-fluorouracil treatment significantly increased chemoresistance compared with control cells. Notably, TAZ knockdown induced compensatory YAP expression and was accompanied by upregulation of CD90, a HCC-specific cancer stem cell marker. Continuous treatment with 5-fluorouracil also induced YAP expression and promoted tumor formation in vivo. Conversely, double knockdown of TAZ/YAP reduced chemoresistance and tumorigenicity. Moreover, YAP knockdown aggravated HCC cell growth to a greater degree than TAZ knockdown, and YAP overexpression was strongly associated with poor prognoses in patients with HCC. Collectively, these studies demonstrate that TAZ and YAP exhibit different functional roles in cancer progression, and a shift to predominant YAP expression upon TAZ depletion conferred cancer stem cell-like properties including chemoresistance and tumorigenicity in HCC. Therefore, targeting of both TAZ/YAP will be required for a complete antitumor response in HCC..
221. Eiji Oki, Yasunori Emi, Yuji Miyamoto, Akira Kabashima, Hidefumi Higashi, Yutaka Ogata, Masahiko Ikebe, Hiroshi Saeki, Shoji Tokunaga, Ken Shirabe, Toru Beppu, Shinji Uchida, Mitsuhisa Takatsuki, Masahiko Sakoda, Susumu Eguchi, Yoshito Akagi, Yoshihiro Kakeji, Hideo Baba, Shoji Natsugoe, Yoshihiko Maehara, Phase II Trial of S-1 and Oxaliplatin Plus Cetuximab for Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases (KSCC1002), Annals of Surgical Oncology, 10.1245/s10434-015-4771-1, 22, 1067-1074, 2015.12, Background: The Kyushu Study Group of Clinical Cancer (KSCC) conducted phase II trials of KSCC1002 (UMIN000001308) concerning liver resectability after first-line treatment of initially unresectable or not optimally resectable colorectal liver metastases in a prospective, multicenter study. Methods: Patients with wild-type KRAS received 4–6 cycles of S-1 and oxaliplatin (SOX) plus cetuximab. Liver resectability was evaluated subsequently with the liver resection rate as the primary endpoint. Results: Of the 33 patients enrolled between March 2010 and July 2013, the median number of administration cycles was 4 (range 0–10). The overall response rate was 63.6 % (95 % confidence interval [CI] 45.1–79.6 %). Liver resection was possible in 16 of 33 (48.5 %) patients, and there were 13 R0 cases (39.4 %). We conducted a central review of liver resectability evaluated by five liver surgeons, and the resectability increased from 18.2 to 66.7 % after chemotherapy, based on imaging. The median overall survival for all 33 cases was 31.6 months (95 % CI 14.8–not reached). The median progression-free survival was 9.7 months (95 % CI 6.2–11.8). Conclusions: SOX plus cetuximab is safe and effective for advanced colorectal cancer with limited liver metastasis, and may lead to high liver resectability..
222. Takuya Matsumoto, Daisuke Matsuda, Kenichi Honma, Yukihiko Aoyagi, Jun Okadome, Koichi Morisaki, Shinichi Tanaka, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, One-stage Procedure for Concomitant Abdominal Aortic Aneurysm and Gastric Cancer, Anticancer research, 35, 12, 6909-6912, 2015.12, BACKGROUND/AIM: A concise surgical strategy for concomitant abdominal aortic aneurysm (AAA) and operable gastric cancer remains unknown. We assessed a one-stage procedure that included endovascular abdominal aortic aneurysm repair (EVAR) and gastric resection.
PATIENTS AND METHODS: Forteen patients who underwent surgery for an infrarenal AAA and gastric cancer between 1990 and 2012 were retrospectively reviewed. Demographic characteristics, aneurysm size, comorbid conditions, length of postoperative hospital stay, complications within 30 days of surgery, and survival in patients in EVAR (n=4) were compared against patients who had an open AAA repair (n=10).
RESULTS: Demographic characteristics, aneurysm size, and comorbid conditions were similar in the EVAR and open-AAA-repair group. The mean length of hospitalization was significantly shorter in the EVAR group (15.2 days vs. 34.9 days; p=0.005), and the rate of postoperative complications was significantly lower (p<0.05). The overall survival rates in the EVAR and open-AAA-repair groups were, respectively, 100% and 80% at 1 year and 75% and 60% at 3 years; the differences between groups were not significant (p=0.788).
CONCLUSION: In patients with concomitant AAA and gastric cancer who are eligible for EVAR, use of a one-stage procedure including EVAR and gastric resection is feasible..
223. Nobuyoshi Takizawa, Yoshihiro Ohishi, Minako Hirahashi, Shunsuke Takahashi, Kazuhiko Nakamura, Masao Tanaka, Eiji Oki, Ryoichi Takayanagi, Yoshinao Oda, Molecular characteristics of colorectal neuroendocrine carcinoma; Similarities with adenocarcinoma rather than neuroendocrine tumor, Human Pathology, 10.1016/j.humpath.2015.08.006, 46, 12, 1890-1900, 2015.12, To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, β-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), β-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P <.01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P <.05, respectively) or NETs (10%, 5%, and 5%, P <.01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P <.01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs..
224. Eiji Oki, Yasunori Emi, Yuji Miyamoto, Akira Kabashima, Hidefumi Higashi, Yutaka Ogata, Masahiko Ikebe, Hiroshi Saeki, Shoji Tokunaga, Ken Shirabe, Toru Beppu, Shinji Uchida, Mitsuhisa Takatsuki, Masahiko Sakoda, Susumu Eguchi, Yoshito Akagi, Yoshihiro Kakeji, Hideo Baba, Shoji Natsugoe, Yoshihiko Maehara, Erratum to Phase II Trial of S-1 and Oxaliplatin Plus Cetuximab for Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases (KSCC1002) (Ann Surg Oncol, (2015), 10.1245/s10434-015-4771-1), Annals of Surgical Oncology, 10.1245/s10434-015-4864-x, 22, 2015.12.
225. Nami Yamashita, Eriko Tokunaga, Hiroyuki Kitao, Megan Hitchins, Yuka Inoue, Kimihiro Tanaka, Yuichi Hisamatsu, Kenji Taketani, Sayuri Akiyoshi, Satoko Okada, Yoshinao Oda, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Epigenetic inactivation of BRCA1 through promoter hypermethylation and its clinical importance in triple-negative breast cancer, Clinical Breast Cancer, 10.1016/j.clbc.2015.06.009, 15, 6, 498-504, 2015.12, Background Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. Patients and Methods Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. Results BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P <.0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P =.02), high nuclear grade (P =.05), low BRCA1 mRNA expression (P <.0001), and loss of BRCA1 protein expression (P =.0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P =.038). Conclusion BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1..
226. Yuji Miyamoto, Eiji Oki, Hiroshi Saeki, Yoshihiko Maehara, Hideo Baba, Recent Advances in Systemic Chemotherapy for Metastatic Colorectal Cancer, Gan to kagaku ryoho. Cancer & chemotherapy, 43, 1, 15-23, 2016.01, The recent development of chemotherapeutic agents and biomarkers have remarkably improved treatment outcomes of metastatic colorectal cancer (mCRC). However, decision making regarding the choice of therapy for mCRC has been complicated by the availability of many different treatment options. In this review, we will discuss the clinical evidence for current systemic treatment, including the key roles of 3 cytotoxic drugs and oral fluoropyrimidines, the appropriate use of anti-VEGF and anti-EGFR therapy, the significance of RAS mutation status as a predictive marker for anti-EGFR therapy, and new agents for salvage therapy (regorafenib and TAS-102 [TFTD])..
227. Yuta Kasagi, Yui Harada, Yosuke Morodomi, Toshiki Iwai, Satoru Saito, Kumi Yoshida, Eiji Oki, Hiroshi Saeki, Kippei Ohgaki, Masahiko Sugiyama, Mitsuho Onimaru, Yoshihiko Maehara, Yoshikazu Yonemitsu, Peritoneal dissemination requires an Sp1-dependent CXCR4/CXCL12 signaling axis and extracellular matrix-directed spheroid formation, Cancer Research, 10.1158/0008-5472.CAN-15-1563, 76, 2, 347-357, 2016.01, Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy..
228. Keisuke Kosumi, Yoshifumi Baba, Akihisa Sakamoto, Takatsugu Ishimoto, Kazuto Harada, Kenichi Nakamura, Junji Kurashige, Yukiharu Hiyoshi, Masaaki Iwatsuki, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Shinjiro Hino, Mitsuyoshi Nakao, Hideo Baba, Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer, International Journal of Cancer, 10.1002/ijc.29714, 138, 2, 428-439, 2016.01, Lysine-specific demethylase-1 (LSD1) removes the methyl groups from mono- and di-methylated lysine 4 of histone H3. Previous studies have linked LSD1 to malignancy in several human tumors, and LSD1 is considered to epigenetically regulate the energy metabolism genes in adipocytes and hepatocellular carcinoma. This study investigates the function of LSD1 in the invasive activity and the metabolism of esophageal cancer cells. We investigated whether LSD1 immunohistochemical expression levels are related to clinical and pathological features, including the maximum standard uptake value in fluorodeoxyglucose positron emission tomography assay. The influence of LSD1 on cell proliferation, invasion and glucose uptake was evaluated in vitro by using specific small interfering RNA for LSD1, and an LSD1 inhibitor. We also evaluated two major energy pathways (glycolytic pathway and mitochondrial respiration) by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) with an extracellular flux analyzer. High LSD1 immunohistochemical expression was significantly associated with high tumor stage, lymphovascular invasion, poor prognosis, and high maximum standard uptake value in esophageal cancer patients. In the in vitro analysis, LSD1 knockdown significantly suppressed the invasive activity and glucose uptake of cancerous cells, reduced their ECAR and increased their OCR and OCR/ECAR. LSD1 may contribute to malignant behavior by regulating the invasive activity and metabolism, activating the glycolytic pathway and inhibiting the mitochondrial respiration of esophageal cancer cells. The results support LSD1 as a potential therapeutic target. What's new? How does the enzyme lysine-specific demethylase-1 (LSD)-1 help esophageal cancer cells survive and spread? New results may shed some light on the molecular goings-on that boost the cancer and suggest a way to shut it down. In this article, the authors blocked LSD-1 expression in vitro using small interfering RNAs. The cells producing less LSD-1 had reduced glucose uptake and decreased invasive activity. When they tested the enzyme's effect on energy metabolism pathways, they found that it appears to activate the cancer cells' glycolytic pathway and suppress mitochondrial respiration. Thus, LSD-1 could be useful as a therapeutic target..
229. Masahiko Sugiyama, Yoshihisa Sakaguchi, Eiji Oki, Eiji Kusumoto, Mitsuhiko Ota, Yasue Kimura, Norifumi Tsutsumi, Tetsuya Kusumoto, Koji Ikejiri, Yoshihiko Maehara, Clinical significance of closure of mesenteric defects in laparoscopic colectomy
A single-institutional cohort study, Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 10.1097/SLE.0000000000000234, 26, 1, 82-85, 2016.01, Background: The effect of closure of mesenteric defects to prevent complications, such as internal hernia, during laparoscopic colectomy remains controversial and is a subject of debate. Purpose: This retrospective single-institution study aimed to clarify the clinical significance of mesenteric defect closure during a laparoscopic colectomy. Methods: We evaluated 58 patients who underwent laparoscopic right-side colectomy or transverse colectomy. The statistical relevance of complications, surgical maneuvers, and clinical factors was examined. Results: The mesenteric defects were closed in 30 patients and not closed in 28 patients. Two patients with ileus and 1 with a deep incisional surgical site infection required a second surgery. The reoperation rate was significantly higher in the nonclosure group than in the closure group (11% vs. 0%, respectively; P=0.033). Consideration: Serious complications requiring reoperation occurred only in the nonclosure group. The procedure for closing the defect did not extend the operation time or increase the bleeding..
230. Hiroyuki Kitao, Kazuaki Matsuoka, Makoto Iimori, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yuji Miyamoto, Hideo Baba, Yoshihiko Maehara, Antitumor Molecular Mechanism of Trifluridine and Tipiracil Hydrochloride (TAS-102
TFTD), Gan to kagaku ryoho. Cancer & chemotherapy, 43, 1, 8-14, 2016.01, Treatment options for patients with metastatic colorectal cancer (mCRC), who are refractory to standard chemotherapy, are limited. In a global multicenter randomized double-blind phase III study (RECOURSE study), TAS-102 (TFTD) administration significantly improved overall survival rate with favorable safety profile in mCRC patients refractory to standard chemotherapy (HR=0.68, p<0.001). TFTD was approved initially in Japan in March 2014 and is currently under review by health authorities in the United States and Europe. TFTD is expected to play an important role in salvage-line treatment for patients with mCRC. In this review, we present the history of its clinical development and the experimental data that elucidate the underlying molecular mechanism of action of TFTD and its key component, trifluridine..
231. Kayo Tokumaru, Eikichi Ihara, Tsutomu Iwasa, Souichi Itaba, Yukishige Andou, Eiji Oki, Nobuyoshi Takizawa, Minako Hirahashi, Yoshinao Oda, Kazuhiko Nakamura, A case of A 3 - mm ileal neuroendocrine tumor with distant lymph node metastasis, GASTROENTEROLOGICAL ENDOSCOPY, 58, 1, 10-14, 2016.01, A 53 - year - old man was referred to our hospital for evaluation and treatment of an ileal neuroendocrine tumor (NET). Colonoscopy revealed a xanthochromic submucosal tumor of 3 mm in diameter in the terminal ileum. It was diagnosed as NET by histological analysis of a biopsy specimen. Preoperative examinations including contrast - enhanced CT, FDG - PET and small - bowel endoscopy did not reveal synchronous or distant metastatic lesions. As a result, the patient was diagnosed as having clinical stage I (cT1, N0, M0) NET. The patient underwent segmental resection of the ileum with D3 lymph node dissection. Despite the small diameter of the tumor, the final pathological diagnosis was grade 2 ileal NET accompanied by metastasis to the ileocolic lymph nodes (#203). Surgical resection and appropriate lymph node dissection should thus be considered for the treatment of ileal NET, regardless of tumor size..
232. Ryuma Tokunaga, Yasuo Sakamoto, Shigeki Nakagawa, Keisuke Miyake, Daisuke Izumi, Keisuke Kosumi, Katsunobu Taki, Takaaki Higashi, Yu Imamura, Takatsugu Ishimoto, Masaaki Iwatsuki, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Hideo Baba, The Prognostic Significance of Histone Lysine Demethylase JMJD3/KDM6B in Colorectal Cancer, Annals of Surgical Oncology, 10.1245/s10434-015-4879-3, 23, 2, 678-685, 2016.02, Background: Jumonji-domain containing 3 (JMJD3) affects transcriptional regulation by demethylating lysine 27 residue of histone 3. We investigated its function and prognostic significance in colorectal cancer (CRC). Methods: The influence of JMJD3 on cell proliferation was assessed using quantitative RT-PCR and western blot on the downstream target gene of JMJD3, in knock-down (KD) experiments and clinical samples from 151 CRC patients. Results: Cells with KD JMJD3 significantly increased proliferation through cell cycle progression and apoptosis suppression. Expression of P15INK4B was remarkably decreased in KD JMJD3 cells; and JMJD3 expression strongly correlated with p15INK4B expression in clinical CRC samples (P < 0.001, r = 0.566). Low JMJD3 also was an independent predictor of poor prognosis (P = 0.042) in surgically resected CRC patients. Conclusions: JMJD3 has prognostic significance in CRC and mediates p15INK4B expression. These results imply that elucidation of the JMJD3 role may lead to a new therapeutic approach for CRC patients..
233. Yu Imamura, Eiji Oki, Kippei Ohgaki, Yuichiro Nakashima, Koji Ando, Satoshi Tsutsumi, Daisuke Tsurumaru, Hiroshi Saeki, Hideo Baba, Yoshihiko Maehara, Real-Time Accurate Identification of Tumor Site Using a Mobile X-Ray Image-Intensifier System during Laparoscopic Gastrectomy, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2015.11.001, 222, 2, e1-e7, 2016.02.
234. Keisuke Miwa, Eiji Oki, Yasunori Emi, Hiroshi Saeki, Tetsuya Kusumoto, Yoshito Akagi, Yutaka Ogata, Hironori Samura, Shoji Tokunaga, Hiroshi Ishikawa, Takaho Tanaka, Susumu Sueyoshi, Hidefumi Higashi, Hiroyuki Matsuda, Tetsuo Touyama, Yoshihiko Maehara, Phase II trial of an alternating regimen consisting of first-line mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer
FIREFOX plus bevacizumab trial (KSCC0801), International Journal of Clinical Oncology, 10.1007/s10147-015-0850-3, 21, 1, 110-117, 2016.02, Objectives: The purpose of this phase II study was to explore the efficacy and safety of an alternating regimen consisting of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (mFOLFOX6) plus bevacizumab, and folinic acid, 5-FU and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer. Methods: Fifty-two patients with metastatic colorectal cancer received an alternating regimen consisting of four cycles of mFOLFOX6 plus bevacizumab followed by four cycles of FOLFIRI plus bevacizumab until disease progression. The primary endpoint was progression-free survival. Results: The median age was 60 years (range 37–75 years). Median progression-free survival was 14.2 months (95 % confidence interval [CI] 10.6–16.3) and median overall survival was 28.4 months (95 % CI 22.6–39.1). The overall response rate was 60.0 % (95 % CI 45.2–73.6). Regarding toxicity, the commonest grade 3–4 hematological adverse events were neutropenia (34.6 %) and leukopenia (7.7 %), and the commonest grade 3–4 non-hematological adverse events were anorexia (13.5 %), fatigue (9.6 %), nausea (9.6 %), and vomiting (9.6 %). Bevacizumab-related grade 3–4 adverse events included hypertension (1.9 %) and thrombosis (1.9 %). Conclusions: An alternating regimen consisting of mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab is an effective and well-tolerated first-line chemotherapy combination for patients with metastatic colorectal cancer..
235. Ryutaro Uchi, Yusuke Takahashi, Atsushi Niida, Teppei Shimamura, Hidenari Hirata, Keishi Sugimachi, Genta Sawada, Takeshi Iwaya, Junji Kurashige, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Kenichi Chiba, Yuichi Shiraishi, Genta Nagae, Kenichi Yoshida, Yasunobu Nagata, Hiroshi Haeno, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Hisae Iinuma, Shin Sasaki, Satoshi Nagayama, Kazutaka Yamada, Shinichi Yachida, Mamoru Kato, Tatsuhiro Shibata, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Yoshinao Oda, Yoshihiko Maehara, Shizuo Komune, Masaki Mori, Yutaka Suzuki, Ken Yamamoto, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Koshi Mimori, Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution, PLoS genetics, 10.1371/journal.pgen.1005778, 12, 2, 2016.02, Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease..
236. Yasue Kimura, Eiji Oki, Koji Ando, Hiroshi Saeki, Tetsuya Kusumoto, Yoshihiko Maehara, Incidence of Venous Thromboembolism Following Laparoscopic Surgery for Gastrointestinal Cancer
A Single-Center, Prospective Cohort Study, World journal of surgery, 10.1007/s00268-015-3234-y, 40, 2, 309-314, 2016.02, Background: The occurrence of venous thromboembolism (VTE), manifesting as deep vein thrombosis or pulmonary embolism, after gastric and colorectal cancer surgery remains poorly characterized. The purpose of this study was to investigate the incidence of VTE following laparoscopic surgery in Japanese patients with gastric and colorectal cancer and identify the associated risk factors. Methods: We prospectively analyzed VTE events after laparoscopic surgery for gastric and colorectal cancer from April 2012 to March 2013 in our institute. Deep vein thrombosis was diagnosed with Doppler ultrasound sonography of the lower limb. Thromboprophylaxis, graduated compression stockings, and intermittent pneumatic compression were used in all patients. Fondaparinux sodium was used in several patients. We examined all patients' plasma D-dimer levels throughout the perioperative period. Results: In total, 101 patients were enrolled in this study; 71 who underwent laparoscopic surgery for gastrointestinal cancer were finally analyzed. Thirteen patients (18.3 %) developed asymptomatic VTE. There were no relationships between the development of VTE and perioperative factors such as cardiovascular disease, operation time, blood loss, postoperative complications, and fondaparinux administration. Neoadjuvant treatment (chemotherapy or chemoradiotherapy) was significantly associated with VTE (p < 0.05). Plasma D-dimer levels were higher 7 days after surgery in patients with than without VTE, although the levels remained high after surgery in all patients. Conclusions: The incidence of VTE among Japanese patients who underwent laparoscopic surgery for gastrointestinal cancer was not low. In particular, clinicians should consider the higher risk of VTE in patients undergoing neoadjuvant therapy..
237. , M. Takatsuki, S. Tokunaga, S. Uchida, M. Sakoda, K. Shirabe, T. Beppu, Y. Emi, E. Oki, S. Ueno, S. Eguchi, Y. Akagi, Y. Ogata, H. Baba, S. Natsugoe, Y. Maehara, Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases
A multicenter study, European Journal of Surgical Oncology, 10.1016/j.ejso.2015.11.007, 42, 2, 184-189, 2016.02, Background/Aim The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. Methods Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. Results In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. Conclusion Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons..
238. Eriko Tokunaga, Nami Yamashita, Hiroyuki Kitao, Kimihiro Tanaka, Kenji Taketani, Yuka Inoue, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Yoshihiko Maehara, Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer, Breast, 10.1016/j.breast.2015.10.006, 25, 62-68, 2016.02, Purpose: INPP4B is considered to function as a putative tumor suppressor through its inhibitory function of Akt. In various malignant tumors, loss of heterozygosity (LOH) at the chromosomal region containing INPP4B and lower expression of INPP4B has been reported. The purpose of this study was to examine the frequency of the INPP4B LOH and its association with the clinicopathological characteristics and prognosis in breast cancer of Japanese women. Methods: The allelic alteration at the INPP4B and PTEN gene loci was analyzed in 277 invasive primary breast carcinomas. The relationships between INPP4B LOH and the clinicopathological features were investigated. Results: Among the 238 informative cases for the evaluation, LOH at the INPP4B gene locus was observed in 43 tumors (18.1%). INPP4B LOH was significantly correlated with ER and PR negativity (p = 0.0009 and p = 0.0029, respectively), higher nuclear grade (p < 0.0001), higher Ki67 labeling index (p = 0.0006), triple-negative (TN) subtype (p = 0.0005) and PTEN LOH (p < 0.0001). INPP4B LOH was significantly associated with poorer prognosis, in terms of the relapse-free survival (RFS) and overall survival (OS). According to the multivariate analyses, INPP4B LOH was not independently associated with the prognosis. Conclusion: The incidence of INPP4B LOH was significantly higher in the TN subtype and positively correlated with PTEN LOH. INPP4B LOH was associated with more aggressive and proliferative phenotype. INPP4B LOH was also associated with poorer prognosis..
239. Makoto Iimori, Sugiko Watanabe, Shinichi Kiyonari, Kazuaki Matsuoka, Ryo Sakasai, Hiroshi Saeki, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara, Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability, Nature communications, 10.1038/ncomms11117, 7, 2016.03, Temporal regulation of microtubule dynamics is essential for proper progression of mitosis and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Here we show that Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the amino terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules. Expression of non-phosphorylatable EB2 induces stable kinetochore microtubule dynamics and delays formation of bipolar metaphase plates in a microtubule binding-dependent manner, and leads to aneuploidy even in unperturbed mitosis. We propose that Aurora B and CDK1 temporally regulate the binding affinity of EB2 for microtubules, thereby ensuring kinetochore microtubule dynamics, proper mitotic progression and genome stability..
240. Hiroshi Saeki, Yuichiro Nakashima, Yoko Zaitsu, Yasuo Tsuda, Yuta Kasagi, Koji Ando, Yu Imamura, Kippei Ohgaki, Shuhei Ito, Yasue Kimura, Akinori Egashira, Eiji Oki, Masaru Morita, Yoshihiko Maehara, Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma, Surgery today, 10.1007/s00595-015-1144-0, 46, 3, 261-267, 2016.03, The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC..
241. Keisuke Kosumi, Yoshifumi Baba, Takatsugu Ishimoto, Kazuto Harada, Kenichi Nakamura, Mayuko Ohuchi, Yuki Kiyozumi, Daisuke Izumi, Ryuma Tokunaga, Katsunobu Taki, Takaaki Higashi, Tatsunori Miyata, Hironobu Shigaki, Junji Kurashige, Yukiharu Hiyoshi, Masaaki Iwatsuki, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Hideo Baba, APOBEC3B is an enzymatic source of molecular alterations in esophageal squamous cell carcinoma, Medical Oncology, 10.1007/s12032-016-0739-7, 33, 3, 1-9, 2016.03, APOBEC3B belongs to the cytidine deaminase apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3) family of enzymes and induces C to T transitions of target DNA by cytidine deamination. Recently, several mutations in various cancers have been linked to APOBEC3B, suggesting a crucial role for this protein in carcinogenesis and cancer development. However, the significance of APOBEC3B in esophageal squamous cell carcinoma (ESCC) remains uncertain. In addition, the APOBEC3B immunoreactivity in cancer tissues is uncertain. Recently, we have demonstrated that PIK3CA mutation and the methylation level of long interspersed nucleotide element 1 (LINE-1) (a surrogate marker of global DNA methylation level) are prognostic markers and have crucial role on malignancy in ESCC patients. This study aims to clarify the impact of APOBEC3B on the clinical, pathological, and molecular features of ESCC. We evaluated APOBEC3B expression in ESCC and investigated the relationships among the immunoreactivity of APOBEC3B, clinical and pathological features, and the molecular features of ESCC (PIK3CA mutation, p53 expression, and LINE-1 methylation level). The immunoreactivity and mRNA level of APOBEC3B were significantly higher in cancer tissues than in noncancerous esophageal mucosae (P = 0.050). APOBEC3B expression was significantly correlated with PIK3CA mutation (P = 0.013), particularly with C to T transitions of PIK3CA (P = 0.041). Moreover, a high expression of APOBEC3B was significantly associated with LINE-1 hypomethylation (P = 0.027). Given the crucial roles of PIK3CA mutation and LINE-1 methylation levels, our findings might provide new insights into the biological mechanisms of ESCC tumorigenesis and progression..
242. Yuichiro Nakashima, Ryota Nakanishi, Masahiko Sugiyama, Kippei Ohgaki, Hideto Sonoda, Hiroshi Saeki, Eiji Oki, Ayumi Matsuyama, Takashi Maeda, Shinichi Tsutsui, Hiroyuki Matsuda, Teruyoshi Ishida, Yoshihiko Maehara, Laparoscopic resection of gastric cancer in a patient with chronic lymphocytic leukemia accompanied by neutropenia, Anticancer research, 36, 4, 1779-1783, 2016.04, Aim: We report an unusual case of early gastric cancer and T-cell-type chronic lymphocytic leukemia accompanied by severe neutropenia that was successfully treated by laparoscopic gastrectomy. Case Report: A 76-year-old female was referred to our Hospital for resection of a gastric adenoma that was suspicious for malignancy. Routine preoperative laboratory studies showed severe neutropenia and increased atypical lymphocytes in the peripheral blood. Bone marrow biopsy confirmed the diagnosis of T-cell chronic lymphocytic leukemia. One day before surgery, granulocyte colony-stimulating factor was administered. Laparoscopic-assisted distal gastrectomy was performed. The patient's postoperative course was uneventful and she was discharged after 10 days. The histopathological findings revealed well-differentiated adenocarcinoma (pT1a, pN0, and stage IA). Conclusion: Laparoscopic gastrectomy may be considered a primary approach in patients with neutropenia because it is associated with lower risk of postoperative infection and a lower mortality rate compared to open resection..
243. Ryuma Tokunaga, Yu Imamura, Kenichi Nakamura, Takatsugu Ishimoto, Shigeki Nakagawa, Keisuke Miyake, Yu Nakaji, Yasuo Tsuda, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Hiroshi Saeki, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Yoshinao Oda, Adam J. Bass, Yoshihiko Maehara, Hideo Baba, Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma, Oncotarget, 10.18632/oncotarget.7782, 7, 15, 19748-19761, 2016.04, Background: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and methods: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusion: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma..
244. Yutaka Ogata, Mototsugu Shimokawa, Takaho Tanaka, Yasunori Emi, Eiji Oki, Hiroshi Saeki, Noriaki Sadanaga, Tetsuya Kusumoto, Tetsuo Touyama, Masami Kimura, Hideo Baba, Yoshito Akagi, Kazuo Shirouzu, Yoshihiko Maehara, A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC 0902), International Journal of Clinical Oncology, 10.1007/s10147-015-0895-3, 21, 2, 335-343, 2016.04, Background: This study was designed to evaluate the efficacy and safety of XELOX plus bevacizumab in a Japanese metastatic colorectal cancer population that included elderly patients. Methods: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated metastatic colorectal cancer, presence of measurable lesions, age ≥20 years; Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELOX (130 mg/m2 oxaliplatin on day 1 plus 1,000 mg/m2 capecitabine b.i.d. on days 1–14) every 3 weeks. The primary endpoint was confirmed objective response rate. Results: The study included 47 patients (male/female 30/17; median age 69 years; age range 38–81 years with 10 patients ≥75 years; PS 0/1/2, 40/5/2) enrolled between May 2010 and March 2011. Responses were assessed in 46 eligible patients. The objective response rate was 52.2 % (95 % confidence interval [CI] 37.0–67.1). The median progression-free survival and overall survival were 10.0 months (95 % CI 7.8–12.3) and 34.6 months (95 % CI 19.9–not estimable), respectively. Frequently encountered grade 3 and 4 adverse events in this study were aspartate aminotransferase elevation (23.4 %), alanine aminotransferase elevation (21.3 %), anorexia (12.8 %), neutropenia (10.6 %), fatigue (8.5 %) and anemia (6.4 %). Grade 3 or 4 peripheral neuropathy was not observed. Conclusion: First-line treatment with XELOX plus bevacizumab showed a promising response rate and an acceptable tolerability profile in the clinical practice of Japanese metastatic colorectal cancer patients that included elderly patients. Registry: UMIN-CTR, ID number: UMIN000003915, URL:https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004706&language=E.
245. Hiroyuki Kitao, Yosuke Morodomi, Shinichiro Niimi, Mamoru Kiniwa, Kazuhiko Shigeno, Kazuaki Matsuoka, Yuki Kataoka, Makoto Iimori, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, The antibodies against 5-bromo-2′-deoxyuridine specifically recognize trifluridine incorporated into DNA, Scientific reports, 10.1038/srep25286, 6, 2016.05, Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2′-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA. These antibodies are useful for several biological applications, such as fluorescence-activated cell sorting, fluorescent immunostaining and immunogold detection for electron microscopy. These techniques confirmed that FTD is mainly incorporated in the nucleus during S phase in a concentration-dependent manner. In addition, FTD was also detected by immunohistochemical staining in paraffin-embedded HCT-116 xenograft tumors after intraperitoneal administration of FTD. Intriguingly, FTD was hardly detected in surrounding matrices, which consisted of fibroblasts with marginal expression of the nucleoside transporter genes SLC29A1 and SLC29A2. Thus, applications using anti-BrdU antibodies will provide powerful tools to unveil the underlying mechanism of FTD action and to predict or evaluate the efficacy and adverse effects of TAS-102 clinically..
246. Daisuke Tsurumaru, Mitsutoshi Miyasaka, Yusuke Nishimuta, Yoshiki Asayama, Akihiro Nishie, Satoshi Kawanami, Eiji Oki, Minako Hirahashi, Hiroshi Honda, Differentiation of early gastric cancer with ulceration and resectable advanced gastric cancer using multiphasic dynamic multidetector CT, European Radiology, 10.1007/s00330-015-3938-2, 26, 5, 1330-1337, 2016.05, Objectives: Early gastric cancer with ulceration (EGC-U) mimics advanced gastric cancer (AGC), as EGC-Us and ACGs often have similar endoscopic appearance to ulceration. The purpose of this retrospective study was to determine whether multiphasic dynamic multidetector CT (MDCT) can help differentiate EGC-Us from AGCs. Methods: Patients with EGC-Us with ulcer stages Ul-III or IV and AGCs with tumour stages T2 to T4a were enrolled. MDCT images were obtained 40 s (arterial phase), 70 s (portal phase) and 240 s (delayed phase) after injection of non-ionic contrast material. Two readers independently measured the attenuation values of the lesions by placing regions of interest. We compared the EGC-Us and AGCs using the mean attenuation values in each phase and peak enhancement phase. We analysed the diagnostic performance of CT for differentiating EGC-Us from AGCs. Results: Forty cases (16 EGC-Us and 24 AGCs) were analysed. The mean attenuation values of the EGC-Us were significantly lower than those of the AGCs in both the arterial and portal phases (all p < 0.0001 for each reader). The peak enhancement was significantly different between the EGC-Us and AGCs for both readers (Reader 1, p = 0.0131; Reader 2, p = 0.0006). Conclusion: Multiphasic dynamic contrast-enhanced MDCT can help differentiate EGC-Us from AGCs. Key Points: • Early gastric cancer with ulceration and advanced gastric cancer have similar endoscopic appearances. • EGC-U shows significantly lower attenuation values in both arterial and portal phases. • Multiphasic dynamic contrast-enhanced MDCT differentiates EGC-U from AGC..
247. Yuichiro Nakashima, Hiroshi Saeki, Takafumi Yukaya, Satoshi Tsutsumi, Ryota Nakanishi, Masahiko Sugiyama, Kippei Ohgaki, Hideto Sonoda, Eiji Oki, Yoshihiko Maehara, Blood Flow Assessment with Indocyanine Green Fluorescence Angiography for Pedicled Omental Flap on Cervical Esophagogastric Anastomosis after Esophagectomy, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2016.01.048, 222, 5, e67-e69, 2016.05.
248. Hiroyuki Kitao, Shinichi Kiyonari, Makoto Limori, Shinichiro Niimi, Yuki Kataoka, Shingo Akiyama, Keitaro Edahiro, Ryota Nakanishi, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Shingo Kanaji, Yoshihiro Kakeji, Yoshihiko Maehara, The molecular aspect of the antitumor effect of oxaliplatin in combination with 5-FU, Japanese Journal of Cancer and Chemotherapy, 43, 6, 707-714, 2016.06, Platinum-based chemotherapeutic drugs as a component of combination chemotherapy are widely used in the treatment of cancer. In particular, oxaliplatin (L-OHP), one such platinum-based chemotherapeutic drug, has a synergistic effect in combination with 5-FU and Leucovorin for the treatment of advanced colorectal cancer. However, the underlying molecular mechanism of this synergistic effect has not been fully clarified yet. In this review, we summarize several updates about the in vitro action of oxaliplatin in human tumor cells and discuss the underlying mechanism of its synergistic effect with 5-FU..
249. Hiroyuki Kitao, Shinichi Kiyonari, Makoto Iimori, Shinichiro Niimi, Yuki Kataoka, Shingo Akiyama, Keitaro Edahiro, Ryota Nakanishi, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Shingo Kanaji, Yoshihiro Kakeji, Yoshihiko Maehara, The Molecular Aspect of the Antitumor Effect of Oxaliplatin in Combination with 5-FU, Gan to kagaku ryoho. Cancer & chemotherapy, 43, 6, 707-714, 2016.06, Platinum-based chemotherapeutic drugs as a component of combination chemotherapy are widely used in the treatment of cancer. In particular, oxaliplatin(L-OHP), one such platinum-based chemotherapeutic drug, has a synergistic effect in combination with 5-FU and Leucovorin for the treatment of advanced colorectal cancer. However, the underlying molecular mechanism of this synergistic effect has not been fully clarified yet. In this review, we summarize several updates about the in vitro action of oxaliplatin in human tumor cells and discuss the underlying mechanism of its synergistic effect with 5-FU..
250. Yukiko Kohno, Hidetaka Yamamoto, Minako Hirahashi, Yoshiteru Kumagae, Masafumi Nakamura, Eiji Oki, Yoshinao Oda, Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia, Human Pathology, 10.1016/j.humpath.2016.01.006, 52, 145-152, 2016.06, The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of inducible nitric oxide synthase; 8-hydroxy-deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition type. Age 62 years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P =.0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer..
251. Shingo Kanaji, Eiji Oki, Hiroshi Saeki, Hiroyuki Kitao, Yoshihiko Maehara, Yoshihiro Kakeji, Oxaliplatin -- A 10-Year Trajectory, Gan to kagaku ryoho. Cancer & chemotherapy, 43, 6, 715-722, 2016.06, Oxaliplatin(Elplat(®)iv infusion solution)is a third-generation 1,2-DACH-platinum derivative. A number of international clinical trials have investigated the effects of this drug for each of its four indications. Building on the results of these earlier studies, much research has also been carried out in Japan in terms of developing and accumulating evidence on oxaliplatin. This report reviews the trajectory of its use over the last 10-years and considers its future potential..
252. Shingo Kanaji, Eiji Oki, Hiroshi Saeki, Hiroyuki Kitao, Yoshihiko Maehara, Yoshihiro Kakeji, Oxaliplatin - A 10-year trajectory, Japanese Journal of Cancer and Chemotherapy, 43, 6, 715-722, 2016.06, Oxaliplatin (Elplat® iv infusion solution) is a third-generation 1,2-DACH-platinum derivative. A number of international clinical trials have investigated the effects of this drug for each of its four indications. Building on the results of these earlier studies, much research has also been carried out in Japan in terms of developing and accumulating evidence on oxaliplatin. This report reviews the trajectory of its use over the last 10-years and considers its future potential..
253. Yuichi Hisamatsu, Eiji Oki, Hajime Otsu, Koji Ando, Hiroshi Saeki, Eriko Tokunaga, Shinichi Aishima, Masaru Morita, Yoshinao Oda, Yoshihiko Maehara, Effect of EGFR and p-AKT Overexpression on Chromosomal Instability in Gastric Cancer, Annals of Surgical Oncology, 10.1245/s10434-016-5097-3, 23, 6, 1986-1992, 2016.06, Background: Molecular profiling in gastric cancer (GC) is important for diagnosis and treatment. In this study, we investigated signal transduction pathways that might induce chromosomal instability in GC. Methods: Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and p-AKT expression were analyzed using immunohistochemistry, and chromosomal instability was assessed by DNA aneuploidy using laser scanning cytometry, in a total of 202 GC cases. Results: The rate of EGFR expression and p-AKT expression was 70.3 and 34.2 %, respectively, in GC patients. In total, 57.5 % of GC patients exhibited DNA aneuploidy, and p-AKT positively correlated with EGFR and HER2 (p = 0.0127 and p = 0.00031, respectively). Patients with EGFR overexpressing GC showed shorter disease-specific survival than the other cases (hazard ratio 2.00, 95 % confidence interval 1.19–3.53; p = 0.0104). Moreover, EGFR and p-AKT expression was significantly correlated with DNA aneuploidy (p = 0.0002 and p = 0.0302, respectively). Conclusions: Our data showed that both EGFR and p-AKT overexpression were clearly associated with DNA aneuploidy. Aneuploidy could be a useful marker for therapies that target EGFR..
254. Shenghong Yang, Yu Imamura, Russell W. Jenkins, Israel Canadas, Shunsuke Kitajima, Amir Aref, Arthur Brannon, Eiji Oki, Adam Castoreno, Zehua Zhu, Tran Thai, Jacob Reibel, Zhirong Qian, Shuji Ogino, Kwok Kwong, Hideo Baba, Alec C. Kimmelman, Marina Pasca Di Magliano, David A. Barbie, Autophagy inhibition dysregulates TBK1 signaling and promotes pancreatic inflammation, Cancer Immunology Research, 10.1158/2326-6066.CIR-15-0235, 4, 6, 520-530, 2016.06, Autophagy promotes tumor progression downstreamof oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IkB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro. Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNg signaling and involves JAK pathway activation. Treatment with the TBK1/IKKe/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting..
255. Shotaro Korehisa, Hiroshi Saeki, Yuichiro Nakashima, Yu Nakaji, Satoshi Tsutsumi, Takafumi Yukaya, Hirotada Tajiri, Yuta Kasagi, Hideto Sonoda, Masahiko Sugiyama, Kippei Ohgaki, Eiji Oki, Minako Hirahashi, Hidetaka Yamamoto, Yoshihiko Maehara, Mixed spindle and epithelioid cell type gastrointestinal stromal tumor of the esophagus
a case report, Esophagus, 10.1007/s10388-016-0525-9, 13, 3, 301-305, 2016.07, Fewer than 1 % of gastrointestinal stromal tumors (GISTs) are of the esophagus. This report describes a 63-year-old female diagnosed with mixed spindle/epithelioid cell GIST of the esophagus. She was admitted to our hospital with symptoms of nausea and hematemesis. Preoperative imaging showed a huge submucosal tumor in the lower thoracic and abdominal esophagus. Pathologic examination of an endoscopic biopsy sample suggested squamous cell carcinoma. She underwent subtotal esophagectomy and reconstruction with a gastric tube. Postoperative pathological diagnosis revealed a mixed spindle/epithelioid cell type GIST. The tumor measured 8 × 6 cm, with 30–50 mitotic counts per high power field, immunohistochemical positivity for C-kit (CD117) and CD34 and high risk by modified Fletcher classification. Adjuvant chemotherapy with imatinib mesylate was started 3 months after surgery. Preoperative pathological examination, including staining for CD117 and CD34, of biopsy samples of apparently stromal tumors may be required to rule out rare subtypes of GIST..
256. Hajime Otsu, Makoto Iimori, Koji Ando, Hiroshi Saeki, Shinichi Aishima, Yoshinao Oda, Masaru Morita, Keitaro Matsuo, Hiroyuki Kitao, Eiji Oki, Yoshihiko Maehara, Gastric Cancer Patients with High PLK1 Expression and DNA Aneuploidy Correlate with Poor Prognosis, Oncology (Switzerland), 10.1159/000445952, 91, 1, 31-40, 2016.07, Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients. Gastric cancer specimens were analyzed from 207 consecutive patients. Patients were classified into two groups according to tumor PLK1 expression and DNA content, and an analysis of their clinical outcomes was carried out. Prognoses of patients with PLK1-high tumors were worse than those of patients with PLK1-low tumors, but the differences were not statistically significant. In cell lines, overexpression of PLK1 induced centrosome amplification and multipolar spindles, potentially leading to DNA aneuploidy. Indeed, high expression of PLK1 was also associated with DNA aneuploidy in clinical gastric cancer specimens. Patients with both high PLK1 expression and DNA aneuploidy had poor recurrencefree survival, whereas PLK1 expression and DNA ploidy status alone were not significantly associated with outcome. Here, we provide clinical evidence that high expression of PLK1 could have detrimental effects in tumors with DNA aneuploidy, which may increase the risk of recurrence in gastric cancer patients..
257. Yoshihiko Maehara, Eiji Oki, Hiroshi Saeki, Eriko Tokunaga, Hiroyuki Kitao, Makoto Iimori, Shinichiro Niimi, Yuki Kataoka, Yasunori Emi, Yoshihiro Kakeji, Hideo Baba, Tetsuhiko Shirasaka, Evolving 5-fluorouracil therapy to achieve enhanced efficacy-past and current efforts of researchers, Japanese Journal of Cancer and Chemotherapy, 43, 7, 845-854, 2016.07, 5-fluorouracil (5-FU) therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation (BCM) with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur (FT), followed by tegafur-uracil (UFT) and tegafurgimeracil-potassium oxonate (S-1) as combined products based on BCM. In the current standard treatment for gastrointestinal cancers, anticancer 5-FU derivatives serve as a platform for combination regimens with other cytotoxic agents or molecular-targeted drugs. To provide further improvements in anticancer therapy outcomes, novel molecular-targeted agents, immune checkpoint inhibitors, and other drugs are being developed, but 5-FU remains an attractive target that shows further potential for increased efficacy. In the future, the evolution of anticancer therapy with 5-FU derivatives is expected to continue via a variety of approaches..
258. Sho Nishimura, Eiji Oki, Satoshi Tsutsumi, Yasuo Tsuda, Masahiko Sugiyama, Yuichiro Nakashima, Hideto Sonoda, Kippei Ohgaki, Hiroshi Saeki, Yoshihiko Maehara, Clinical significance of totally laparoscopic distal gastrectomy
A comparison of short-term outcomes relative to open and laparoscopic-assisted distal gastrectomy, Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 10.1097/SLE.0000000000000308, 26, 5, 372-376, 2016.07, Background: Laparoscopic distal gastrectomy has become an established minimally invasive treatment for gastric cancer since it was first reported in 1994. Materials and Methods: We retrospectively assessed the clinical outcomes of 248 patients who had undergone open distal gastrectomy (ODG), laparoscopic-assisted distal gastrectomy (LADG), and totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. Results and Conclusions: TLDG showed superiority in terms of blood loss, reconstruction options, and postoperative recovery compared with ODG and LADG. Especially, the mean operating time in the TLDG group was significantly shorter than that of the LADG group (P=0.003). Book-binding technique used in TLDG was one of the reasons of this result. The only inferior aspect of TLDG was the longer operating time compared with ODG; TLDG had no disadvantages compared with LADG. Although the operating time and long-term outcome remain problems, we suggest that TLDG has the potential to serve as an optimal operative method..
259. E. Oki, A. Murata, K. Yoshida, K. Maeda, K. Ikejiri, Y. Munemoto, K. Sasaki, C. Matsuda, M. Kotake, T. Suenaga, H. Matsuda, Y. Emi, Y. Kakeji, H. Baba, C. Hamada, S. Saji, Y. Maehara, A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1
ACTS-RC), Annals of Oncology, 10.1093/annonc/mdw162, 27, 7, 1266-1272, 2016.07, Backgrounds: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. Patients and methods: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. Results: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96].Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. Conclusion: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection..
260. Yuji Miyamoto, Akihito Tsuji, Hiroaki Tanioka, Soichiro Maekawa, Hirofumi Kawanaka, Masaki Kitazono, Eiji Oki, Yasunori Emi, Hidetsugu Murakami, Yutaka Ogata, Hiroshi Saeki, Mototsugu Shimokawa, Shoji Natsugoe, Yoshito Akagi, Hideo Baba, Yoshihiko Maehara, S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer
a multicenter phase II study in Japan (KSCC1102), International Journal of Clinical Oncology, 10.1007/s10147-015-0943-z, 21, 4, 705-712, 2016.08, Background: Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC. Methods: Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 80 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m2 and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS). Results: Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7–37.9), and the disease control rate was 76.5 % (95 % CI 58.8–89.3). The median PFS was 5.6 months (95 % CI 3.8–7.0). The median overall survival was 16.4 months (95 % CI 8.1–20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred. Conclusions: The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC..
261. Shuhei Ito, Shinji Okano, Masaru Morita, Hiroshi Saeki, Satoshi Tsutsumi, Hiroshi Tsukihara, Yuichiro Nakashima, Koji Ando, Yu Imamura, Kippei Ohgaki, Eiji Oki, Hiroyuki Kitao, Koshi Mimori, Yoshihiko Maehara, Expression of PD-L1 and HLA Class I in Esophageal Squamous Cell Carcinoma
Prognostic Factors for Patient Outcome, Annals of Surgical Oncology, 10.1245/s10434-016-5376-z, 23, 508-515, 2016.08, Background: Programmed cell death 1 ligand 1 (PD-L1) and human leukocyte antigen (HLA) class I molecules on malignant cell surfaces are pivotal for tumor immunity. The clinical significance of their expression in patients with esophageal squamous cell carcinoma (ESCC) remains to be determined. Methods: PD-L1 and HLA class I protein expression was investigated by immunohistochemical staining of resected specimens from 90 ESCC patients who underwent radical surgery without preoperative therapy. The relationships between the expression of PD-L1 and HLA class I and clinicopathologic factors and patient prognosis were assessed. Results: High expression of PD-L1 and HLA class I were observed in 17 (18.9 %) and 35 (38.9 %) of 90 cases, respectively. High PD-L1 expression was correlated with the depth of tumor invasion (P = 0.0379), lymph node metastasis (P = 0.0031), recurrence (P = 0.0085), and poor overall survival (OS) (5-year survival rate; low/high: 60.9/28.4 %, P = 0.0110). Among those patients with high expression of HLA class I, high PD-L1 expression was correlated with significantly poorer recurrence-free survival (median survival time, low/high: 102.5/3.1 months, P = 0.0016) and poorer OS (median survival time, low/high: 102.5/13.1 months, P = 0.0027). Multivariate analysis showed that combined high PD-L1/high HLA class I expression was an independent prognostic factor for recurrence-free survival (hazard ratio 2.88, 95 % confidence interval 1.02–7.04, P = 0.0455) and OS (hazard ratio 2.95, 95 % confidence interval 1.03–7.50, P = 0.0447). Conclusions: High PD-L1 expression was a significant independent prognostic factor in ESCC patients with high HLA class I expression..
262. Masaru Morita, Hiroshi Saeki, Yu Nakaji, Yoko Zaitsu, Minako Hirahashi, Takayuki Ohguri, Eiji Oki, Yasushi Toh, Yoshinao Oda, Yoshihiko Maehara, Conversion to neuroendocrine carcinoma from squamous cell carcinoma of the esophagus after definitive chemoradiotherapy, Anticancer research, 36, 8, 4045-4049, 2016.08, Background/Aim: Neuroendocrine carcinoma (NEC) of the esophagus is rare and aggressive. We herein report a case of a patient who showed NEC conversion from squamous cell carcinoma (SCC) of the esophagus in the recurrent lesion after definitive chemoradiotherapy. Case Report: The patient was a 57-year-old Japanese male with mid-thoracic esophageal carcinoma diagnosed as SCC with invasion of the submucosal layer. After definitive chemoradiotherapy, the esophageal tumor completely disappeared. Two months later, local recurrence was recognized at the same location and salvage surgery was performed. An immunohistochemical examination of the resected specimen revealed that most of the recurrent tumor had neuroendocrine (NE) differentiation, although a retrospective review of the initial biopsy specimen showed no involvement of NE differentiation. Conclusion: This case is significant not only in bringing attention to the possibility of NEC conversion from SCC after chemoradiotherapy, but also in discussing tumors originating in the esophagus..
263. Takao Takahashi, Yasunori Emi, Eiji Oki, Kazuma Kobayashi, Akihito Tsuji, Mototsugu Shimokawa, Takaho Tanaka, Yoshito Akagi, Yutaka Ogata, Hideo Baba, Kazuhiro Yoshida, Shoji Natsugoe, Yoshihiko Maehara, Study Group of Clinical Cancer (KSCC) Kyushu Study Group of Clinical Cancer (KSCC), Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study), Cancer chemotherapy and pharmacology, 10.1007/s00280-016-3109-4, 78, 3, 585-593, 2016.09, Purpose: Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines. Methods: The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m2, followed by weekly infusion at 250 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2 orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status. Results: Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3–4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia. Conclusions: Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer..
264. Masakazu Sugiyama, Eiji Oki, Yu Nakaji, Satoshi Tsutsumi, Naomi Ono, Ryota Nakanishi, Masahiko Sugiyama, Yuichiro Nakashima, Hideto Sonoda, Kippei Ohgaki, Nami Yamashita, Hiroshi Saeki, Shinji Okano, Hiroyuki Kitao, Masaru Morita, Yoshinao Oda, Yoshihiko Maehara, High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer, Cancer Science, 10.1111/cas.13075, 107, 11, 1705-1716, 2016.11, The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged-1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E-cadherin and their associations with clinicopathologic characteristics, overall survival (OS) and relapse-free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate or strong in 32%, 36% and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type and lymphatic invasion independently correlated with OS and RFS. The combination of high JAG1 expression and low E-cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E-cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E-cadherin expression. In vitro studies suggested that RAS-MEK-MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. High expression of JAG1 is regulated by various pathways and is associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining cell survival in CRC..
265. Hidetoshi Nitta, Takayuki Shimose, Yasunori Emi, Takahisa Imamura, Koji Ohnishi, Tetsuya Kusumoto, Manabu Yamamoto, Kengo Fukuzawa, Ikuo Takahashi, Hidefumi Higashi, Akihito Tsuji, Yoshito Akagi, Eiji Oki, Yoshihiko Maehara, Hideo Baba, Study Group of Clinical Cancer (KSCC) ancillary study Kyushu Study Group of Clinical Cancer (KSCC) ancillary study, Expression of the anaphylatoxin C5a receptor in gastric cancer
implications for vascular invasion and patient outcomes, Medical Oncology, 10.1007/s12032-016-0834-9, 33, 11, 2016.11, The C5a receptor (C5aR) expressed in various types of cancers is involved in C5a-induced cancer cell invasion. However, its role in gastric cancer has not yet been fully elucidated. Therefore, we studied the clinical significance of C5aR expression in gastric cancer. The association of C5aR expression in gastric cancer, determined by immunostaining using the anti-C5aR antibody, with clinicopathological parameters and outcomes was evaluated in 148 patients. Further, the association of C5aR expression in liver metastatic sites with clinicopathological parameters was investigated in a separate cohort of 58 patients who underwent hepatectomy. High tumoral C5aR expression (n = 45, 30.4 %) was significantly related to tumor location, cancer invasion depth, vascular and lymphatic invasion, and tumor stage. The 5-year recurrence-free and overall survival rates of patients with high tumoral C5aR expression were significantly lower than those of patients with low tumoral C5aR expression (50.9 vs. 84.2 %, P = 0.002 and 58.8 vs. 86.1 %, P = 0.007, respectively). The incidence of liver metastasis was significantly higher in patients with high tumoral C5aR expression (13.3 %) than in those with low tumoral C5aR expression (3.9 %; P = 0.04). C5aR expression at liver metastatic sites was associated with the C5aR expression status at the primary site (P = 0.0004), vascular invasion at the primary site (P = 0.04), and tumor size at the metastatic site (P = 0.01). C5aR expression in gastric cancer was associated with cancer progression, liver metastasis, and poor prognosis. Therefore, C5aR may represent a prognostic factor and therapeutic target in gastric cancer..
266. Kimihiro Tanaka, Eriko Tokunaga, Yuka Inoue, Nami Yamashita, Hiroshi Saeki, Shinji Okano, Hiroyuki Kitao, Eiji Oki, Yoshinao Oda, Yoshihiko Maehara, Impact of Expression of Vimentin and Axl in Breast Cancer, Clinical Breast Cancer, 10.1016/j.clbc.2016.06.015, 16, 6, 520-526.e2, 2016.12, The receptor tyrosine kinase Axl has been reported to be a downstream effector of epithelial-to-mesenchymal transition and to be regulated by vimentin expression in preclinical models. Coexistence of vimentin-positive and Axl-high expression was significantly associated with triple-negative breast cancer and poor prognosis. Vimentin and Axl expression might contribute to the aggressive phenotype in breast cancer patients. Background The association between Axl and vimentin protein expression has been observed in several cell lines. However, the clinical importance of Axl and vimentin expression in breast cancer have not been fully determined. Patients and Methods The expressions of Axl and vimentin were evaluated by immunohistochemistry in a total of 343 patients with invasive ductal carcinoma. The relationships between expression of Axl and vimentin and clinicopathologic characteristics and prognosis were analyzed. Results Axl expression was classified into high (n = 170) and low (n = 173) expression groups. Axl expression alone was not associated with any clinicopathologic factor or prognosis. Coexistence of vimentin-positive and Axl-high expression was observed in 10.5% (n = 36). Vimentin-positive and Axl-high tumors were associated with triple-negative breast cancers (P = .0396) and with poor prognosis in terms of both recurrence-free survival (P = .0126) and overall survival (P = .0005) compared to the other groups, including vimentin-positive and Axl-low tumors, vimentin-negative and Axl-high tumors, and vimentin-negative and Axl-low tumors. Multivariate analysis showed that coexistence of vimentin-positive and Axl-high expression was an independent poor prognostic factor for recurrence-free survival (hazard ratio, 2.78; 95% confidence interval, 1.23-5.68; P = .0158) and overall survival (hazard ratio, 3.72; 95% confidence interval, 1.51-8.47; P = .0059). Conclusion Coexistence of vimentin-positive and Axl-high expression is a poor prognostic factor for primary breast cancer. Vimentin and Axl expression might contribute to the aggressive phenotype in breast cancer..
267. Masayuki Nagahashi, Toshifumi Wakai, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Ryoma Yagi, Nobuaki Sato, Yuko Kitagawa, Hiroyuki Uetake, Kazuhiro Yoshida, Eiji Oki, Shin ei Kudo, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Julie Tse, Meaghan Russell, Joerg Heyer, Winslow Powers, Ruobai Sun, Jennifer E. Ring, Kazuaki Takabe, Alexei Protopopov, Yiwei Ling, Shujiro Okuda, Stephen Lyle, Genomic landscape of colorectal cancer in Japan
Clinical implications of comprehensive genomic sequencing for precision medicine, Genome Medicine, 10.1186/s13073-016-0387-8, 8, 1, 2016.12, Background: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC). Methods: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC. Results: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy. Conclusions: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities..
268. Eriko Tokunaga, Nami Yamashita, Kimihiro Tanaka, Yuka Inoue, Sayuri Akiyoshi, Hiroshi Saeki, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara, Expression of APOBEC3B mRNA in primary breast cancer of Japanese women, PloS one, 10.1371/journal.pone.0168090, 11, 12, 2016.12, Recent studies have identified the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) as a source of mutations in various malignancies. APO-BEC3B is overexpressed in several human cancer types, including breast cancer. In this study, we analyzed APOBEC3B mRNA expression in 305 primary breast cancers of Japanese women using quantitative reverse transcription-PCR, and investigated the relationships between the APOBEC3B mRNA expression and clinicopathological characteristics, prognosis, and TP53 mutations. The expression of APOBEC3B mRNA was detected in 277 tumors and not detected in 28 tumors. High APOBEC3B mRNA expression was significantly correlated with ER- and PR-negativity, high grade and high Ki67 index. The APOBEC3B mRNA expression was highest in the triple-negative and lowest in the hormone receptorpositive/HER2-negative subtypes. The TP53 gene was more frequently mutated in the tumors with high APOBEC3B mRNA expression. High APOBEC3B mRNA expression was significantly associated with poor recurrence-free survival in all cases and the ER-positive cases. These findings were almost consistent with the previous reports from the Western countries. In conclusion, high APOBEC3B mRNA expression was related to the aggressive phenotypes of breast cancer, high frequency of TP53 mutation and poor prognosis, especially in ER-positive tumors..
269. Mitsutoshi Miyasaka, Daisuke Tsurumaru, Yusuke Nishimuta, Yoshiki Asayama, Satoshi Kawanami, Eiji Oki, Minako Hirahashi, Hiroshi Honda, Diagnosis of early colorectal cancer invasion depth by quantitative evaluation of the basal indentation in CT colonography, Japanese Journal of Radiology, 10.1007/s11604-016-0586-7, 34, 12, 786-794, 2016.12, Objective: To investigate the feasibility of diagnosing the invasion depth of early colorectal cancer (CRC) by quantitatively evaluating the basal indentation (BI)—i.e., the intestinal lateral deformity—in CT colonography (CTC). Materials and methods: 34 early CRCs (13 Tis CRCs and 21 T1 CRCs) in 32 patients who underwent a preoperative CTC were retrospectively examined. Two radiologists calculated the depth of the BI on a computed tomographic air-contrast enema (CT enema) image, the depth of the BI due to the geometric function (BI-G) on a cross-sectional multiplanar reconstruction (CS-MPR) image, and the ratio of the BI to the BI-G (i.e., the “BI ratio”) for each lesion. The BI ratios of the Tis and T1 CRCs were compared. Results: The BI ratios were significantly higher in the T1 CRCs than in the Tis CRCs (p < 0.0001). The optimum cutoff value of the BI ratio for differentiating the T1 CRCs from the Tis CRCs was 1.64, with a sensitivity, specificity, and area under the curve of 90.5 %, 100 %, and 0.974, respectively. Conclusions: We have demonstrated for the first time that quantitatively evaluating the BI can improve the accuracy of diagnosis of early CRC invasion depth..
270. Kensuke Kudou, Tetsuro Komatsu, Jumpei Nogami, Kazumitsu Maehara, Akihito Harada, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Yasuyuki Ohkawa, The requirement of Mettl3-promoted MyoD mRNA maintenance in proliferative myoblasts for skeletal muscle differentiation, Open Biology, 10.1098/rsob.170119, 7, 9, 2017.01, Myogenic progenitor/stem cells retain their skeletal muscle differentiation potential by maintaining myogenic transcription factors such as MyoD. However, the mechanism of how MyoD expression is maintained in proliferative progenitor cells has not been elucidated. Here, we found that MyoD expression was reduced at the mRNA level by cell cycle arrest in S and G2 phases, which in turn led to the absence of skeletal muscle differentiation. The reduction of MyoD mRNA was correlated with the reduced expression of factors regulating RNA metabolism, including methyltransferase like 3 (Mettl3), which induces N6-methyladenosine (m6A) modifications of RNA. Knockdown of Mettl3 revealed that MyoD RNA was specifically downregulated and that this was caused by a decrease in processed, but not unprocessed, mRNA. Potential m6A modification sites were profiled by m6A sequencing and identified within the 50 untranslated region (UTR) of MyoD mRNA. Deletion of the 50 UTR revealed that it has a role in MyoD mRNA processing. These data showed that Mettl3 is required for MyoD mRNA expression in proliferative myoblasts..
271. Yuta Kasagi, Eiji Oki, Koji Ando, Shuhei Ito, Tomohiro Iguchi, Masahiko Sugiyama, Yuichiro Nakashima, Kippei Ohgaki, Hiroshi Saeki, Koshi Mimori, Yoshihiko Maehara, The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers, Oncology (Switzerland), 10.1159/000452143, 92, 1, 48-54, 2017.01, Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC..
272. Yu Nakaji, Eiji Oki, Ryota Nakanishi, Koji Ando, Masahiko Sugiyama, Yuichiro Nakashima, Nami Yamashita, Hiroshi Saeki, Yoshinao Oda, Yoshihiko Maehara, Prognostic value of BRAF V600E mutation and microsatellite instability in Japanese patients with sporadic colorectal cancer, Journal of Cancer Research and Clinical Oncology, 10.1007/s00432-016-2275-4, 143, 1, 151-160, 2017.01, Purpose: In colorectal cancer (CRC), the BRAF V600E mutation is an important biomarker for poor prognosis, while high microsatellite instability (MSI-H) indicates good prognosis. Using a commercial BRAF V600E-specific antibody, we investigated the BRAF V600E mutation according to immunohistochemistry (IHC) and the MSI status in Japanese patients with CRC. Methods: In this retrospective study, tissue samples from 472 Japanese patients with CRC, stratified for MSI, were analyzed to determine the prognostic value of BRAF V600E, as assessed using IHC. Mutations in 254 patients were evaluated using the direct sequencing method to check for concordance. Results: The frequency of MSI-H was 9.3 % (44/472), and BRAF V600E mutation was detected immunohistochemically in 8.7 % patients (41/472). The sensitivity and specificity for detection of BRAF V600E mutations by IHC were 100 % (17/17) and 98.7 % (234/237), respectively. BRAF V600E mutations were significantly correlated with the anatomical tumor site (P = 0.0035), histological type (P < 0.0001), and MSI status (P < 0.0001). Consistent with other published series, patients with BRAF V600E mutation exhibited a significantly shorter overall survival (hazard ratio = 1.500, P = 0.0432). In particular, the microsatellite stable/BRAF mutation group had inferior prognosis compared with the MSI-H/BRAF wild-type group (hazard ratio = 2.621, P = 0.0004). Conclusions: IHC using a BRAF V600E-specific antibody was useful for diagnosis and concurred with direct sequencing results. CRC cases could be stratified by combining BRAF V600E mutation and MSI status as a prognostic factor in Japanese patients..
273. Shingo Akiyama, Hiroshi Saeki, Yuichiro Nakashima, Makoto Iimori, Hiroyuki Kitao, Eiji Oki, Yoshinao Oda, Yusaku Nakabeppu, Yoshihiro Kakeji, Yoshihiko Maehara, Prognostic impact of MutT homolog-1 expression on esophageal squamous cell carcinoma, Cancer Medicine, 10.1002/cam4.979, 6, 1, 258-266, 2017.01, MutT homolog-1 (MTH1) is a pyrophosphatase that acts on oxidized nucleotides and hydrolyzes 8-oxo-2’-deoxyguanosine triphosphate in deoxynucleoside triphosphate pool to prevent its incorporation into nuclear and mitochondrial DNA, result in reduce cytotoxicity in tumor cells. MTH1 is overexpressed in various cancers and is considered as a therapeutic target. Environmental factors such as cigarette smoking and alcohol consumption are critical risk factors for the development and progression of esophageal squamous cell carcinoma (ESCC), suggesting that oxidative stress contributes to the pathogenesis of ESCC. We examined the expression of MTH1 and the accumulation of 8-oxo-2’-deoxyguanosine (8-oxo-dG) in 84 patients with ESCC who underwent curative resection without neoadjuvant therapy. MTH1 mRNA level was quantified by performing quantitative reverse transcription-PCR. Immunohistochemical analysis of paraffin-embedded cancer tissues was performed to determine MTH1 protein expression and 8-oxo-dG accumulation. MTH1 mRNA expression was higher in cancerous tissues than in the corresponding normal epithelium (P < 0.0001). Immunohistochemical analysis showed that high MTH1 expression was significantly associated with deeper tumor invasion and venous invasion, advanced cancer stage, and poor overall survival (P = 0.0021) and disease-specific survival (P = 0.0013) compared with low MTH1 expression. Furthermore, high MTH1 expression was an independent predictor of poor disease-specific survival (P = 0.0121). In contrast, 8-oxo-dG accumulation was not associated with any clinicopathological factor and poor prognosis. These results suggest that MTH1 overexpression is a predictor of ESCC progression and poor prognosis and that MTH1 can serve as a therapeutic target for treating patients with ESCC..
274. , Hironaga Satake, Masaaki Iwatsuki, Yoshikazu Uenosono, Takeshi Shiraishi, Hiroaki Tanioka, Hiroshi Saeki, Keishi Sugimachi, Dai Kitagawa, Mototsugu Shimokawa, Eiji Oki, Yasunori Emi, Yoshihiro Kakeji, Akihito Tsuji, Yoshito Akagi, Shoji Natsugoe, Hideo Baba, Yoshihiko Maehara, Phase II trial of capecitabine plus modified cisplatin (mXP) as first-line therapy in Japanese patients with metastatic gastric cancer (KSCC1104), Cancer chemotherapy and pharmacology, 10.1007/s00280-016-3204-6, 79, 1, 147-153, 2017.01, Purpose: Capecitabine plus cisplatin (XP) is a standard therapy for metastatic gastric cancer (mGC). However, while results from previous phase III trials suggested that the cisplatin dosage should be reduced in Japanese patients, no clinical data exist to support this. Here, we conducted a multicenter study to evaluate the efficacy and safety of modified XP (mXP) in Japanese patients with mGC. Methods: Patients with previously untreated mGC received mXP (cisplatin 60 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1–14) every 3 weeks. The primary endpoint was the Response Evaluation Criteria in Solid Tumors-confirmed overall response rate (ORR). A sample size of 40 was planned for a threshold ORR of 30% and an expected value of 50%, with a one-sided α of 0.05 and a beta of approximately 0.2. Results: Forty-two patients were enrolled. One patient did not fulfill the eligibility criteria; therefore, a total of 41 patients were assessed. The results were as follows: complete response in 2 patients, partial response in 16, stable disease in 14, progressive disease in 8, and no evaluation in 1. The confirmed ORR was 43.9% (95% confidence interval 28.7–59.1%). The median progression-free survival and median overall survival were 4.6 and 11.3 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (37.5%), anemia (24.4%), anorexia (24.4%), and nausea (12.2%). Conclusions: First-line chemotherapy with mXP in Japanese patients with mGC did not reach its primary objective. However, it did show a promising response rate and an acceptable tolerability profile..
275. Kohei Shitara, Keisho Chin, Takaki Yoshikawa, Hitoshi Katai, Masanori Terashima, Seiji Ito, Motohiro Hirao, Kazuhiro Yoshida, Eiji Oki, Mitsuru Sasako, Yasunori Emi, Toshimasa Tsujinaka, Phase II study of adjuvant chemotherapy of S-1 plus oxaliplatin for patients with stage III gastric cancer after D2 gastrectomy, Gastric Cancer, 10.1007/s10120-015-0581-1, 20, 1, 175-181, 2017.01, Background: The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated a survival benefit by adjuvant S-1 monotherapy in patients who had undergone curative resection of stage II/III gastric cancer, but there is still a need to improve the efficacy of treatment of stage III disease. We investigated the tolerability and safety of S-1 and oxaliplatin as adjuvant chemotherapy for stage III gastric cancer. Methods: Japanese patients with stage III gastric cancer who had undergone D2 or more extensive lymphadenectomy were enrolled. In the first cycle, S-1 (40–60 mg/m2 twice daily) alone was given orally for 2 weeks of a 3-week cycle. From the second cycle, S-1 was administered as in the first cycle and oxaliplatin (100 mg/m2) was infused intravenously on day 1. Treatment was continued for 8 cycles. The primary end point was the treatment completion rate for eight cycles. Results: Sixty-three patients were enrolled and 62 patients were included in analysis. The treatment completion rate was 74.2 %, which was higher than the expected completion rate of 72.0 %. The median relative dose intensities were 77.1 % for S-1 and 72.6 % for oxaliplatin, with 41.9 and 61.7 % patients requiring dose reduction of S-1 and oxaliplatin, respectively. Neutropenia was the only grade 3 or higher adverse event with an incidence 10 % or greater (32.3 %). There was no grade 3 or higher peripheral sensory neuropathy or treatment-related death. Conclusions: S-1 and oxaliplatin therapy is suggested to be manageable and safe with optimal dose reduction and delay in selected patients for stage III gastric cancer after D2 gastrectomy, and warrants further evaluation in larger studies..
276. Eriko Yamaguchi, Tsutomu Iwasa, Eikichi Ihara, Yosuke Tomita, Akira Aso, Eiji Oki, Kayoko Nakano, Minako Hirahashi, Kazuhiko Nakamura, Gastric neuroendocrine tumor with hypergastrinemia, Journal of Japanese Society of Gastroenterology, 114, 2, 248-255, 2017.01, A man in his 60s was referred to our institution for the evaluation of a gastric neuroendocrine tumor (G-NET) located in the fornix and that measured 13mm in size. Blood test results revealed hypergastrinemia (up to 3376pg/ml). Additional tests, including esophagogastroduodenoscopy, computed tomography, and intragastric pH monitoring, indicated that hypergastrinemia was not associated with type A autoimmune gastritis or gastrinoma The patient was positive for the immunoglobulin G antibody against Helicobacter pylori, suggesting type B chronic atrophic gastritis as the cause for the condition. This report describes a rare case of G-NET with hypergastrinemia following type B chronic atrophic gastritis. Evaluation of similar cases is necessary to determine if H. pylori-associated chronic atrophic gastritis is frequently associated with G-NET..
277. Hiroshi Saeki, Satoshi Tsutsumi, Takafumi Yukaya, Hirotada Tajiri, Ryosuke Tsutsumi, Sho Nishimura, Yu Nakaji, Kensuke Kudou, Shingo Akiyama, Yuta Kasagi, Yuichiro Nakashima, Masahiko Sugiyama, Hideto Sonoda, Kippei Ohgaki, Eiji Oki, Ryuji Yasumatsu, Torahiko Nakashima, Masaru Morita, Yoshihiko Maehara, Clinicopathological features of cervical esophageal cancer retrospective analysis of 63 consecutive patients who
Underwent surgical resection, Annals of surgery, 10.1097/SLA.0000000000001599, 265, 1, 130-136, 2017.01, Objective: The objectives of this retrospective study were to elucidate the clinicopathological features and recent surgical results of cervical esophageal cancer. Summary Background Data: Cervical esophageal cancer has been reported to have a dismal prognosis. Accurate knowledge of the clinical characteristics of cervical esophageal cancer is warranted to establish appropriate therapeutic strategies. Methods: The clinicopathological features and treatment results of 63 consecutive patients with cervical esophageal cancer (Ce group) who underwent surgical resection from 1980 to 2013 were analyzed and compared with 977 patients with thoracic or abdominal esophageal cancer (T/A group) who underwent surgical resection during that time. Results: Among the patients who received curative resection, the 5-year overall and disease-specific survival rates of the Ce patients were significantly better than those of the T/A patients (overall: 77.3% vs 46.5%, respectively, P = 0.0067; disease-specific: 81.9% vs 55.8%, respectively, P = 0.0135). Although total pharyngo-laryngo-esophagectomy procedures were less frequently performed in the recent period, the rate of curative surgical procedures was markedly higher in the recent period (2000-1013) than that in the early period (1980-1999) (44.4% vs 88.9%, P = 0.0001). The 5-year overall survival rate in the recent period (71.5%) was significantly better than that in the early period (40.7%, P = 0.0342). Conclusions: Curative resection for cervical esophageal cancer contributes to favorable outcomes compared with other esophageal cancers. Recent surgical results for cervical esophageal cancer have improved, and include an increased rate of curative resection and decreased rate of extensive surgery..
278. Sho Nambara, Takaaki Masuda, Taro Tobo, Shinya Kidogami, Hisateru Komatsu, Keishi Sugimachi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Koshi Mimori, Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma, Oncology Letters, 10.3892/ol.2017.6341, 14, 2, 1795-1801, 2017.01, The present authors previously identified a novel candidate tumor suppressor gene, zinc finger protein 750 (ZNF750), in esophageal squamous cell carcinoma (ESCC) (1). The present study aimed to clarify the clinical significance of ZNF750 expression in ESCC. The association between ZNF750 DNA mutation status and the mRNA expression was examined by whole exome sequence analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR). The expression of ZNF750 in 76 patients with ESCC (Kyushu University Beppu Hospital) was measured using immunohistochemistry and RT-qPCR. Using this dataset, the association between ZNF750 mRNA expression and clinicopathological factors was examined. Additionally, survival analysis was performed using datasets from the Kyushu University Beppu Hospital and The Cancer Genome Atlas (TCGA). The biological effects of ZNF750 expression were explored using gene set enrichment analysis (GSEA) and were validated using datasets from the Cancer Cell Line Encyclopedia (CCLE) and the Kyushu University Beppu Hospital. ZNF750 expression analyses demonstrated that ZNF750 mRNA expression was lower in patients with the DNA mutations compared with those without the mutations (P<0.05), and ZNF750 expression was downregulated in tumor tissues compared with normal tissues (P<0.00005). In the clinicopathological analysis, the low ZNF750 expression group exhibited a higher incidence of undifferentiated histology (P<0.05) compared with the high expression group. The low ZNF750 expression group exhibited a poorer prognosis in the Kyushu and TCGA datasets (P<0.0005 and P<0.05, respectively). GSEA indicated that ZNF750 expression was significantly correlated with epithelial differentiation in ESCC. This was confirmed using the datasets from CCLE and the Kyushu University Beppu Hospital by analyzing the levels of small proline rich protein 1A mRNA, an epithelial differentiation-associated gene. In conclusion, the results of the present study suggested that ZNF750 serves a role as a tumor suppressor; potentially via regulating epithelial differentiation and that it may be a promising biomarker of poor outcomes in ESCC..
279. Masahiko Sugiyama, Eiji Oki, Kippei Ogaki, Masaru Morita, Yoshihisa Sakaguchi, Satoshi Koga, Hiroshi Saeki, Yoshihiko Maehara, Clinical Outcomes of Esophagojejunostomy in Totally Laparoscopic Total Gastrectomy
A Multicenter Study, Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 10.1097/SLE.0000000000000435, 27, 4, e87-e91, 2017.01, Purpose: To examine the short-term outcomes of intracorporeal anastomosis during totally laparoscopic total gastrectomy retrospectively at multiple institutions. Patients and Methods: We collected data of the patients who had undergone totally laparoscopic total gastrectomy at 4 institutions. All patients received an intracorporeal esophagojejunostomy. Results: Of the 215 patients evaluated, 147 underwent functional end-to-end anastomosis (FEEA) as the intracorporeal esophagojejunostomy (FEEA group), and 68 patients received a circular stapler anastomosis (Circular group). The rate of tumor invasion to the esophagus was significantly higher in the Circular group than in the FEEA group (33% vs. 6%, respectively; P<0.0001). Univariate and multivariate analyses revealed that the circular stapler anastomosis and high preoperative BMI were statistically significant risk factors for postoperative leakage. However, the rates of complications and mortality were not significantly different between groups. Consideration: Our results showed that each type of esophagojejunostomy is safe and feasible for patients with gastric cancer with acceptable morbidity and mortality..
280. Ryuma Tokunaga, Yasuo Sakamoto, Shigeki Nakagawa, Mayuko Ohuchi, Daisuke Izumi, Keisuke Kosumi, Katsunobu Taki, Takaaki Higashi, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Hideo Baba, CONUT
a novel independent predictive score for colorectal cancer patients undergoing potentially curative resection, International Journal of Colorectal Disease, 10.1007/s00384-016-2668-5, 32, 1, 99-106, 2017.01, Background: Controlling nutritional status (CONUT) score, calculated from serum albumin and total cholesterol concentrations and total lymphocyte count, is reportedly valuable for nutritional assessment. This study investigated whether CONUT score was predictive of outcomes in colorectal cancer (CRC) patients undergoing surgical resection. Methods: Preoperative CONUT scores were retrospectively evaluated in 417 CRC patients who underwent potentially curative resection at Kumamoto University Hospital from March 2005 to August 2014. Patients were divided into four groups based on preoperative CONUT scores: normal, light, moderate, and severe. The associations of CONUT score with clinicopathological factors, patient survival, and postoperative complications were examined. Results: CONUT score correlated significantly with age (P < 0.001), body mass index (P = 0.005), carcinoembryonic antigen (P = 0.002), and carbohydrate antigen 19-9 (P = 0.005) concentrations. Overall survival (OS) rate was significantly lower in patients with moderate/severe than light or normal CONUT scores. CONUT score was independently prognostic of OS [moderate/severe vs. normal, hazard ratio = 5.92, 95 % confidence interval (CI) 2.30–14.92; P < 0.001)]. Patients with moderate/severe CONUT scores were at greater risk for complications, especially for severe complications. Multivariate analysis showed that CONUT score was independently predictive of severe complications (moderate/severe vs. normal, odds ratio = 4.51, 95 % CI 1.89–10.74; P < 0.001). Conclusions: CONUT score may predict survival and postoperative severe complications in CRC patients undergoing potentially curative resection. Management of CRC patients may need consideration of host nutritional status..
281. Sho Nambara, Takaaki Masuda, Miki Nishio, Shotaro Kuramitsu, Taro Tobo, Yushi Ogawa, Qingjiang Hu, Tomohiro Iguchi, Yousuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Keishi Sugimachi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Akira Suzuki, Koshi Mimori, Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer, Oncotarget, 10.18632/oncotarget.22587, 8, 64, 107666-107677, 2017.01, Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression..
282. Y. Baba, H. Saeki, Y. Nakashima, E. Oki, H. Shigaki, N. Yoshida, M. Watanabe, Y. Maehara, Hideo Baba, Review of chemotherapeutic approaches for operable and inoperable esophageal squamous cell carcinoma, Diseases of the Esophagus, 10.1111/dote.12521, 30, 2, 2017.02, The predominant histological types of esophageal cancer are adenocarcinoma and squamous cell carcinoma. Since these two histological types present as different diseases in terms of their epidemiology, pathologenesis, and tumor biology, separate therapeutic approaches should be developed against each type. While surgical resection remains the dominant therapeutic intervention for patients with operable esophageal squamous cell carcinoma (ESCC), their high rates of tumor recurrence have prompted investigation of multimodality therapies that combine surgery with chemotherapy, radiotherapy, and chemoradiotherapy. In Japan, preoperative chemotherapy with cisplatin (CDDP) plus 5-fluorouracil (5-FU) followed by radical esophagectomy has been accepted as the standard therapeutic approach for resactable clinical Stage II/III ESCC. Similarly, the CDDP and 5-FU regimen has been accepted as the first-line treatment for metastatic and unresectable ESCCs in Japan. Thus, in Japan chemotherapy is an indispensable component of therapy for both resectable and unresectable ESCCs. This review discusses the current knowledge, rationale, and available data regarding chemotherapy for resectable and unresectable ESCCs..
283. Hiroshi Saeki, Satoshi Tsutsumi, Hirotada Tajiri, Takafumi Yukaya, Ryosuke Tsutsumi, Sho Nishimura, Yu Nakaji, Kensuke Kudou, Shingo Akiyama, Yuta Kasagi, Ryota Nakanishi, Yuichiro Nakashima, Masahiko Sugiyama, Kippei Ohgaki, Hideto Sonoda, Eiji Oki, Yoshihiko Maehara, Prognostic significance of postoperative complications after curative resection for patients with esophageal squamous cell carcinoma, Annals of surgery, 10.1097/SLA.0000000000001692, 265, 3, 527-533, 2017.03, Objective: The objective of this study was to elucidate the impact of postoperative complications on long-term survival after curative resection for esophageal squamous cell carcinoma. Background: The relation between postoperative complications and long-term survival after curative surgery for esophageal squamous cell carcinoma is controversial; thus, this issue should be resolved with a large-scale, well-designed study. Methods: Clinicopathological features and survival of 580 consecutive patients who received curative resection for esophageal squamous cell carcinoma were investigated according to the development of postoperative pulmonary complications and anastomotic leakage. Results: The 5-year survival rates of patients with pStage 0, I, and II disease with postoperative complications (n = 116) were significantly poorer than those of patients without postoperative complications (n = 288) (overall 69.6% vs 46.9%, P < 0.0001; disease-specific; 76.7% vs 58.9%, P < 0.0022), whereas no differences were found in patients with pStage III and IV disease (n = 176). In the univariate and multivariate analyses for disease-specific survival, pT3, pT4, pN positivity, and development of postoperative complications were significant prognostic factors in all patients. Also, when the analysis was limited to the pStage 0, I, and II patients, development of postoperative complications, and pT3, pT4, and pN positivity, were found to be independent poor prognostic factors in multivariate analyses (hazard ratio: 1.56, 95% confidence interval, 1.01-2.41, P = 0.0476). Conclusions: The development of postoperative complications is an independent disease-specific poor prognostic factor after curative resection for patients with less-advanced esophageal squamous cell carcinoma..
284. Nozomu Fuse, Hideaki Bando, Keisho Chin, Seiji Ito, Takaki Yoshikawa, Akira Tsuburaya, Masanori Terashima, Yoshiyuki Kawashima, Tetsu Fukunaga, Masahiro Gotoh, Yasunori Emi, Kazuhiro Yoshida, Eiji Oki, Seiji Takahashi, Hiroshi Kuriki, Kumi Sato, Mitsuru Sasako, Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer
a phase II study, Gastric Cancer, 10.1007/s10120-016-0606-4, 20, 2, 332-340, 2017.03, Background: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. Methods: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1–14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. Results: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9–72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4–78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77–91 %). No new safety signals were identified. Conclusions: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection..
285. Yuka Inoue, Nami Yamashita, Eriko Tokunaga, Kimihiro Tanaka, Hiroki Ueo, Hiroshi Saeki, Eiji Oki, Hidetaka Yamamoto, Yoshihiko Maehara, A locally advanced breast cancer that achieved pCR with pertuzumab, trastuzumab and docetaxel
Case report, Anticancer research, 10.21873/anticanres.11530, 37, 4, 1917-1921, 2017.04, We herein report a case of locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer that achieved a pathological complete response (pCR) with pertuzumab, trastuzumab and docetaxel therapy. A 70-year-old female presented with an elastic hard mass, 5.0 cm in diameter with broad redness and edema of the skin in her right breast. Swollen lymph nodes were also recognized in the right axilla. The pathological diagnosis was invasive ductal carcinoma and its biological character was estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, HER2 3+ and Ki-67 index 60%. The patient was finally diagnosed with primary unresectable, locally advanced breast cancer and started on pertuzumab, trastuzumab and docetaxel combination therapy. The tumor subsequently reduced in size and, after 4 cycles of this therapy, she underwent surgery. The histopathological examination of the postoperative specimen showed pCR in both the primary tumor and axillary lymph nodes..
286. Hirotada Tajiri, Takehito Uruno, Takahiro Shirai, Daisuke Takaya, Shigeki Matsunaga, Daiki Setoyama, Mayuki Watanabe, Mutsuko Kukimoto-Niino, Kounosuke Oisaki, Miho Ushijima, Fumiyuki Sanematsu, Teruki Honma, Takaho Terada, Eiji Oki, Senji Shirasawa, Yoshihiko Maehara, Dongchon Kang, Jean François Côté, Shigeyuki Yokoyama, Motomu Kanai, Yoshinori Fukui, Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1, Cell Reports, 10.1016/j.celrep.2017.04.016, 19, 5, 969-980, 2017.05, Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion..
287. Ryutaro Uchi, Yusuke Takahashi, Atsushi Niida, Teppei Shimamura, Hidenari Hirata, Keishi Sugimachi, Genta Sawada, Takeshi Iwaya, Junji Kurashige, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Kenichi Chiba, Yuichi Shiraishi, Genta Nagae, Kenichi Yoshida, Yasunobu Nagata, Hiroshi Haeno, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Hisae Iinuma, Shin Sasaki, Satoshi Nagayama, Kazutaka Yamada, Shinichi Yachida, Mamoru Kato, Tatsuhiro Shibata, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Yoshinao Oda, Yoshihiko Maehara, Shizuo Komune, Masaki Mori, Yutaka Suzuki, Ken Yamamoto, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Koshi Mimori, Erratum
Correction: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution (PLoS genetics (2016) 12 2 (e1005778)), PLoS genetics, 10.1371/journal.pgen.1006798, 13, 5, e1006798, 2017.05, [This corrects the article DOI: 10.1371/journal.pgen.1005778.]..
288. Yasushi Tsuji, Hideo Baba, Koji Takeda, Michiya Kobayashi, Eiji Oki, Masahiro Gotoh, Kazuhiro Yoshida, Mototsugu Shimokawa, Yoshihiro Kakeji, Keisuke Aiba, Chemotherapy-induced nausea and vomiting (CINV) in 190 colorectal cancer patients
a prospective registration study by the CINV study group of Japan, Expert Opinion on Pharmacotherapy, 10.1080/14656566.2017.1317746, 18, 8, 753-758, 2017.05, Objectives: Chemotherapy is an indispensable therapeutic approach for colorectal cancer both in the adjuvant and metastatic setting. Although chemotherapy-induced nausea and vomiting (CINV) is one of the most crucial adverse events, many aspects of CINV in patients with colorectal cancer remain unclear. Methods: This multicenter, prospective, observational study analyzed the data of 190 colorectal cancer patients scheduled for moderately emetogenic chemotherapy (MEC). The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy. Results: All 190 patients received MEC and 99% of patients received antiemetic therapy in compliance with guidelines. Acute CINV was well controlled. 13 (6.8%) patients suffered from acute nausea and 4 (2.1%) experienced acute vomiting, whereas the prevalence of delayed CINV was relatively high. Delayed nausea occurred in 71 (37.4%) patients and delayed vomiting in 24 (12.6%). History of motion sickness was a significant independent risk factor for delayed nausea (Odd ratio 3.89, 95% confidence interval 1.49–10.19, p = 0.0056). Conclusions: The compliance with CINV guidelines in colorectal cancer chemotherapy was quite high and led to good control of chemotherapy-induced vomiting in Japan. However, the incidence of delayed nausea remained high in patients receiving MEC..
289. Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Kouji Iwasaki, Jumpei Soeda, Masamitsu Hihara, Takeharu Yamanaka, Atsushi Ochiai, Kei Muro, Rationale for and Design of the PARADIGM Study
Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer, Clinical Colorectal Cancer, 10.1016/j.clcc.2017.01.001, 16, 2, 158-163, 2017.06, Background It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC. Patients and Methods Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020..
290. Satoshi Tsutsumi, Hiroshi Saeki, Yuichiro Nakashima, Shuhei Ito, Eiji Oki, Masaru Morita, Yoshinao Oda, Shinji Okano, Yoshihiko Maehara, Programmed death-ligand 1 expression at tumor invasive front is associated with epithelial-mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma, Cancer Science, 10.1111/cas.13237, 108, 6, 1119-1127, 2017.06, Programmed death-ligand 1 (PD-L1) plays a crucial role in the host immune system in cancer progression. The gene promoter region of PD-L1 also contains a binding site for ZEB1, a transcription factor related to epithelial-mesenchymal transition (EMT). The purpose of this study was to clarify the relationship between PD-L1 and EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). PD-L1 and ZEB1 expression at the tumor invasive front was examined by immunohistochemistry in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy, and their expression and clinicopathological factors were compared. ZEB1 and PD-L1 expression was determined in TE8 cells, which demonstrate the EMT phenotype, following ZEB1 knockdown by siZEB1. TE5, TE6 and TE11 cells with non-EMT phenotype were also used for studies of TGF-β1-dependent EMT induction and ZEB1 and PD-L1 expression. In cases of high PD-L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ lymphocyte infiltration were observed. High PD-L1 expression was also associated with worse overall and relapse-free survival. A correlation was observed between PD-L1 and ZEB1 expression. In TE8 cells, siZEB1 suppressed PD-L1 and promoted E-cadherin mRNA and protein expression. TGF-β1 induced EMT and surface expression of PD-L1 in TE5, TE6 and TE11 cell lines. PD-L1 expression at the ESCC invasive front was related to ZEB1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC..
291. Sho Nishimura, Eiji Oki, Koji Ando, Makoto Iimori, Yu Nakaji, Yuichiro Nakashima, Hiroshi Saeki, Yoshinao Oda, Yoshihiko Maehara, High ubiquitin-specific protease 44 expression induces DNA aneuploidy and provides independent prognostic information in gastric cancer, Cancer Medicine, 10.1002/cam4.1090, 6, 6, 1453-1464, 2017.06, Chromosomal instability (CIN), characterized by aneuploidy, is a major molecular subtype of gastric cancer. The deubiquitinase USP44 is an important regulator of APC activation in the spindle checkpoint and leads to proper chromosome separation to prevent aneuploidy. Aberrant expression of USP44 leads CIN in cells; however, the correlation between USP44 and DNA aneuploidy in gastric cancer is largely unknown. We analyzed USP44 expression in 207 patients with gastric cancer by immunohistochemistry and found that the proportion of USP44 expression was higher in gastric cancer tumors (mean, 39.6%) than in gastric normal mucosa (mean, 14.6%) (P < 0.0001). DNA aneuploidy was observed in 124 gastric cancer cases and high USP44 expression in cancer strongly correlated with DNA aneuploidy (P = 0.0005). The overall survival was significantly poorer in the high USP44 expression group compared with the low USP44 group (P = 0.033). Notably, USP44 expression had no prognostic impact in the diploid subgroup; however, high USP44 expression was a strong poor prognostic factor for progression-free survival (P = 0.018) and overall survival (P = 0.036) in the aneuploid subgroup. We also confirmed that stable overexpression of USP44 induced somatic copy-number aberrations in hTERT-RPE-1 cells (50.6%) in comparison with controls (6.6%) (P < 0.0001). Collectively, our data show USP44 has clinical impact on the induction of DNA aneuploidy and poor prognosis in the CIN gastric cancer subtype..
292. , Kazuhito Minami, Masaru Morita, Yasunori Emi, Masahiro Okamoto, Eiji Tanaka, Shigeyuki Nagata, Tetsuo Touyama, Kippei Ohgaki, Takaho Tanaka, Hiroshi Okumura, Toyokuni Suenaga, Shoji Tokunaga, Eiji Oki, Yoshihiro Kakeji, Yoshito Akagi, Hideo Baba, Shoji Natsugoe, Yoshihiko Maehara, Final report of KSCC0803
feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japan, International Journal of Clinical Oncology, 10.1007/s10147-017-1088-z, 22, 3, 505-510, 2017.06, Background: The impact of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected colon cancer was unclear. We previously planned and conducted a prospective feasibility study (KSCC0803) and reported on the safety of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer. The purpose of the current study was to assess the survival results from that study. Methods: The study subjects were Japanese patients with resected stage III colon cancer. The protocol adjuvant regimen consisted of oral capecitabine 1250 mg/m2 twice daily on days 1–14 of a 3-week cycle for a total of eight cycles. The 3- and 5-year disease free survival (DFS) rates and overall survival (OS) rates were analyzed in the eligible cohort. Results: Ninety-seven patients were registered between September 2008 and August 2009 and treated with the protocol regimen. The median follow-up time was 60.7 months. The 3- and 5-year DFS rates were 71.2% [95% confidence interval (CI): 61.7–79.8%] and 69.7% (95% CI: 59.4–77.8%), respectively. The 3- and 5-year OS rates were 92.6% (95% CI: 85.2–96.4%) and 84.5% (95% CI: 75.1–90.5%), respectively. Conclusions: The survival results in this study are in line with those of previously reported, reliable, studies. The safety and tolerability of the protocol regimen have already been confirmed. Oral capecitabine is acceptable as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer..
293. Daisuke Tsurumaru, Mitsutoshi Miyasaka, Toshio Muraki, Yoshiki Asayama, Akihiro Nishie, Eiji Oki, Minako Hirahashi, Tomoyuki Hida, Hiroshi Honda, Diffuse-type gastric cancer
specific enhancement pattern on multiphasic contrast-enhanced computed tomography, Japanese Journal of Radiology, 10.1007/s11604-017-0631-1, 35, 6, 289-295, 2017.06, Purpose: To evaluate the enhancement pattern of diffuse-type gastric cancers (DGCs) on multiphasic contrast-enhanced computed tomography gastrography (CECTG). Methods and materials: We studied 21 consecutive clinically diagnosed DGC patients who underwent CECTG. Gastric distension was obtained using effervescent granules. CT images were obtained 40 s (arterial phase) and 240 s (delayed phase) after injection of a nonionic contrast material. Two radiologists reviewed the CT images and analyzed layers and enhancement patterns. The readers evaluated the enhancement degree (mild, moderate, or marked) and calculated CT attenuation values by placing circular regions of interest (ROIs) within each layer of the lesion. The CT findings of 11 operated cases were correlated with pathological results. Results: Most lesions were double-layered in the arterial phase, with a moderately enhanced inner layer and a mildly enhanced outer layer, and single-layered in the delayed phase. The mean attenuation value of the inner layer (146 ± 32.8 HU) was significantly higher than that of the outer layer (80.4 ± 15.5 HU) in the arterial phase (p = 0.0001). In the pathological analysis, wall stratification was preserved in nine cases and not preserved in two cases. Conclusion: Most DGCs showed a double-layered pattern in the arterial phase and a single-layered pattern with moderate enhancement in the delayed phase..
294. Takeshi Kato, Takayuki Yoshino, Kei Muro, Kentaro Yamazaki, Tatsuro Yamaguchi, Eiji Oki, Shigeyoshi Iwamoto, Akihito Tsuji, Goro Nakayama, Yasunori Emi, Tetsuo Touyama, Masato Nakamura, Masahito Kotaka, Hideaki Bando, Yoshinori Kagawa, Hiroya Taniguchi, Takeharu Yamanaka, Akiyoshi Kanazawa, A phase II study of FOLFOXIRI with bevacizumab in untreated metastatic colorectal cancer patients
A UGT1A1 genotype and safety results (QUATTRO study), Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdx263.023, 28, iii9-iii10, 2017.06.
295. Kensuke Kudou, Hiroshi Saeki, Yuichiro Nakashima, Keitaro Edahiro, Shotaro Korehisa, Daisuke Taniguchi, Ryosuke Tsutsumi, Sho Nishimura, Yu Nakaji, Shingo Akiyama, Hirotada Tajiri, Ryota Nakanishi, Junji Kurashige, Masahiko Sugiyama, Eiji Oki, Yoshihiko Maehara, Prognostic Significance of Sarcopenia in Patients with Esophagogastric Junction Cancer or Upper Gastric Cancer, Annals of Surgical Oncology, 10.1245/s10434-017-5811-9, 24, 7, 1804-1810, 2017.07, Background: The association between sarcopenia and postoperative outcomes for patients with gastrointestinal malignancies remains controversial. This study aimed to assess the impact of sarcopenia on short- and long-term outcomes after surgery for esophagogastric junction cancer (EGJC) or upper gastric cancer (UGC). Methods: The study reviewed 148 patients with EGJC or UGC who underwent surgical resection. The patients were categorized into the sarcopenia group or the non-sarcopenia group according to their skeletal muscle index calculated using abdominal computed tomography images. The study compared clinicopathologic factors, postoperative complications, and prognosis between the two groups. Results: Sarcopenia was present in 19 patients (32.2%) with EGJC and 23 patients (25.8%) with UGC. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly poorer in the sarcopenia group than in the non-sarcopenia group (OS 85.5 vs 54.8%, P = 0.0010; RFS 78.7 vs 51.7%, P = 0.0054). The development of postoperative complications did not differ significantly between the two groups. Both the uni- and multivariate analyses showed that N stage (P < 0.0001) and sarcopenia (P = 0.0024 and 0.0293, respectively) were independent poor prognostic factors for OS. Conclusions: Sarcopenia was strongly associated with a poor long-term prognosis for patients with EGJC or UGC who underwent surgery. The results suggest that special attention might be needed during the development of treatment strategies for patients with sarcopenia who intend to undergo operations for EGJC and UGC..
296. Sho Nambara, Tomohiro Iguchi, Eiji Oki, Patrick Tan, Yoshihiko Maehara, Koshi Mimori, Overexpression of CXCR7 Is a novel prognostic indicator in gastric cancer, Digestive surgery, 10.1159/000452977, 34, 4, 312-318, 2017.07, Background: Among several candidate genes that promote peritoneal dissemination extracted by comprehensive expression analysis of both in vivo selected metastatic cell lines and patients with gastric cancer, we focused on the chemokine (C-X-C motif) receptor (CXCR7) and explored its clinicopathological significance in gastric cancer. Methods:CXCR7 expression was evaluated by microarray data in the Singapore cohort (n = 196) and by immunohistochemistry and reverse transcription quantitative real-time polymerase chain reaction in the Japanese cohort (n = 195). The biological function of CXCR7 in gastric cancer was explored using gene set enrichment analysis (GSEA). Results: CXCR7 expression was upregulated in tumor tissues compared to normal tissues. High CXCR7 mRNA expression was associated with peritoneal dissemination and poor prognosis in the Singapore cohort. Consistent with this, the high CXCR7 mRNA expression group showed significantly poorer prognosis and a more aggressive disease course than the low expression group in the Japanese cohort. High CXCR7 mRNA expression and peritoneal dissemination were clinically relevant. GSEA revealed that CXCR7 was significantly enriched in gene expression signatures associated with tumor progression. Conclusions:CXCR7 may be a prognostic indicator and therapeutic target for gastric cancer with peritoneal dissemination..
297. Takatsugu Ishimoto, Keisuke Miyake, Tannistha Nandi, Masakazu Yashiro, Nobuyuki Onishi, Kie Kyon Huang, Suling Joyce Lin, Ramnarayanan Kalpana, Su Ting Tay, Yuka Suzuki, Byoung Chul Cho, Daisuke Kuroda, Kota Arima, Daisuke Izumi, Masaaki Iwatsuki, Yoshifumi Baba, Eiji Oki, Masayuki Watanabe, Hideyuki Saya, Kosei Hirakawa, Hideo Baba, Patrick Tan, Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells, Gastroenterology, 10.1053/j.gastro.2017.03.046, 153, 1, 191-204.e16, 2017.07, Background & Aims Fibroblasts that interact with cancer cells are called cancer-associated fibroblasts (CAFs), which promote progression of different tumor types. We investigated the characteristics and functions of CAFs in diffuse-type gastric cancers (DGCs) by analyzing features of their genome and gene expression patterns. Methods We isolated CAFs and adjacent non-cancer fibroblasts (NFs) from 110 gastric cancer (GC) tissues from patients who underwent gastrectomy in Japan from 2008 through 2016. Cells were identified using specific markers of various cell types by immunoblot and flow cytometry. We selected pairs of CAFs and NFs for whole-exome and RNA sequencing analyses, and compared expression of specific genes using quantitative reverse transcription PCR. Protein levels and phosphorylation were compared by immunoblot and immunofluorescence analyses. Rhomboid 5 homolog 2 (RHBDF2) was overexpressed from a transgene in fibroblasts or knocked down using small interfering RNAs. Motility and invasiveness of isolated fibroblasts and GC cell lines (AGS, KATOIII, MKN45, NUGC3, NUGC4, OCUM-2MD3 and OCUM-12 cell lines) were quantified by real-time imaging analyses. We analyzed 7 independent sets of DNA microarray data from patients with GC and associated expression levels of specific genes with patient survival times. Nude mice were given injections of OCUM-2MD3 in the stomach wall; tumors and metastases were collected and analyzed by immunohistochemistry. Results Many of the genes with increased expression in CAFs compared with NFs were associated with transforming growth factor beta 1 (TGFB1) activity. When CAFs were cultured in extracellular matrix, they became more motile than NFs; DGC cells incubated with CAFs were also more motile and invasive in vitro than DGC cells not incubated with CAFs. When injected into nude mice, CAF-incubated DGC cells invaded a greater number of lymphatic vessels than NF-incubated DGC cells. We identified RHBDF2 as a gene overexpressed in CAFs compared with NFs. Knockdown of RHBDF2 in CAFs reduced their elongation and motility in response to TGFB1, whereas overexpression of RHBDF2 in NFs increased their motility in extracellular matrix. RHBDF2 appeared to regulate oncogenic and non-canonical TGFB1 signaling. Knockdown of RHBDF2 in CAFs reduced cleavage of the TGFB receptor 1 (TGFBR1) by ADAM metallopeptidase domain 17 (ADAM17 or TACE) and reduced expression of genes that regulate motility. Incubation of NFs with in interleukin 1 alpha (IL1A), IL1B or tumor necrosis factor, secreted by DGCs, increased fibroblast expression of RHBDF2. Simultaneous high expression of these cytokines in GC samples was associated with shorter survival times of patients. Conclusions In CAFs isolated from human DGCs, we observed increased expression of RHBDF2, which regulates TGFB1 signaling. Expression of RHBDF2 in fibroblasts is induced by inflammatory cytokines (such as IL1A, IL1B, and tumor necrosis factor) secreted by DGCs. RHBDF2 promotes cleavage of TGFBR1 by activating TACE and motility of CAFs in response to TGFB1. These highly motile CAFs induce DGCs to invade extracellular matrix and lymphatic vessels in nude mice..
298. Nami Yamashita, Eriko Tokunaga, Hidetaka Yamamoto, Chikako Shimizu, Kenji Taketani, Yuka Inoue, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, The local recurrence of breast cancer with squamous metaplasia and obvious histological heterogeneity, Anticancer research, 10.21873/anticanres.11949, 37, 9, 5249-5254, 2017.09, Case Report: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39-year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. Conclusion: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance..
299. Yoshihiko Maehara, Ken Shirabe, Shunji Kohnoe, Yasunori Emi, Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Masataka Ikeda, Michiya Kobayashi, Tadatoshi Takayama, Shoji Natsugoe, Masashi Haraguchi, Kazuhiro Yoshida, Masanori Terashima, Mitsuru Sasako, Hiroki Yamaue, Norihiro Kokudo, Katsuhiko Uesaka, Shinji Uemoto, Tomoo Kosuge, Yoshiki Sawa, Mitsuo Shimada, Yuichiro Doki, Masakazu Yamamoto, Akinobu Taketomi, Masahiro Takeuchi, Kouhei Akazawa, Takeharu Yamanaka, Mototsugu Shimokawa, Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery
results of a multicenter, randomized, prospective, phase II clinical trial, Surgery today, 10.1007/s00595-017-1480-3, 47, 9, 1060-1071, 2017.09, Background: The use of absorbable sutures in wound closure has been shown to reduce the incidence of surgical site infection (SSI); however, there is no evidence that the intra-abdominal use of absorbable rather than silk sutures reduces the incidence of SSI after gastrointestinal surgery. We report the findings of a phase II trial, designed to evaluate the impact of the intra-abdominal use of absorbable sutures on the incidence of SSI. Methods: At 19 Japanese hospitals, 1147 patients undergoing elective gastrectomy, colorectal surgery, hepatectomy, or pancreaticoduodenectomy (PD) were randomly assigned to absorbable or silk intra-abdominal suture groups. The primary efficacy endpoint was the incidence of SSI. The secondary efficacy endpoints were the locations of SSI, time to resolution of SSI, length of hospital stay, and the incidence of bile leakage in hepatectomy and pancreatic fistula. Results: The incidence of SSI was 11.3%, 15.5%, 11.3%, and 36.9% after gastrectomy, colorectal surgery, hepatectomy, and PD, respectively. The incidence of SSI was higher in the absorbable suture group than in the silk suture group for all the surgical procedures, but the difference was not significant. Conclusion: The intra-abdominal use of absorbable sutures did not have enough of an effect on the reduction of SSI in this phase II trial to justify the planning of a large-scale phase III trial..
300. Yoshiaki Fujimoto, Yuichiro Nakashima, Shun Sasaki, Tomoko Jogo, Kosuke Hirose, Keitaro Edahiro, Shotaro Korehisa, Daisuke Taniguchi, Kensuke Kudou, Yu Nakaji, Ryota Nakanishi, Koji Ando, Hiroshi Saeki, Eiji Oki, Minako Fujiwara, Yoshinao Oda, Yoshihiko Maehara, Chemoradiotherapy for solitary skeletal muscle metastasis from oesophageal cancer
Case report and brief literature review, Anticancer research, 10.21873/anticanres.12005, 37, 10, 5687-5691, 2017.10, Background: The incidence of skeletal muscle metastasis from oesophageal cancer is very low, and the treatment strategy has not been established. Case Report: A 77-year-old man underwent oesophagectomy following neoadjuvant chemotherapy for oesophageal squamous cell carcinoma (CT-pT3 N0 M0, CT-pStage II). Fourteen months after surgery, he became aware of a subcutaneous tumour in his left forearm. Computed tomography and fluorodeoxyglucose positron-emission tomography revealed a 65×75 mm intramuscular nodular lesion with a standardized uptake value of 8.5. Further examination by biopsy strongly suggested this was a solitary metastasis from oesophageal cancer. The patient received chemoradiotherapy with two cycles of 5- fluorouracil combined with cisplatin and radiation. Clinical complete response was confirmed by imaging 7 months after chemoradiation and no recurrence has occurred at 20 months since chemoradiation. Conclusion: Radiotherapy or chemoradiotherapy can be an alternative locoregional therapy to surgery for solitary skeletal muscle metastasis..
301. Hiroshi Ichikawa, Masayuki Nagahashi, Yoshifumi Shimada, Takaaki Hanyu, Takashi Ishikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Hiroshi Yabusaki, Satoru Nakagawa, Nobuaki Sato, Yuki Hirata, Yuko Kitagawa, Toshiyuki Tanahashi, Kazuhiro Yoshida, Ryota Nakanishi, Eiji Oki, Dana Vuzman, Stephen Lyle, Kazuaki Takabe, Yiwei Ling, Shujiro Okuda, Kohei Akazawa, Toshifumi Wakai, Actionable gene-based classification toward precision medicine in gastric cancer, Genome Medicine, 10.1186/s13073-017-0484-3, 9, 1, 2017.10, Background: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. Methods: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status. Results: Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N=9), MSI (N=17), chromosomal instability (N=119), and genomically stable subtype (N=62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N=32), while the others (N=175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N=25), CDKN2A, and CDKN2B (N=10), KRAS (N=10), BRCA2 (N=9), and ATM cluster (N=12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster. Conclusions: This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC..
302. , Koji Ando, Yasunori Emi, Toyokuni Suenaga, Masahiro Hamanoue, Soichiro Maekawa, Yasuo Sakamoto, Seiichiro Kai, Hironaga Satake, Takayuki Shimose, Mototsugu Shimokawa, Hiroshi Saeki, Eiji Oki, Kenji Sakai, Yoshito Akagi, Hideo Baba, Yoshihiko Maehara, A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101), International Journal of Clinical Oncology, 10.1007/s10147-017-1140-z, 22, 5, 913-920, 2017.10, Background: This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC). Methods: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 b.i.d. on days 1–14) every 3 weeks. The primary endpoint was the objective tumor response rate. Results: A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1–70.2%). The median progression-free survival was 9.6 months (95% CI 5.1–11.1 months) and the median overall survival was 23.1 months (95% CI 11.3–36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism. Conclusions: A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC..
303. Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yusuke Muneoka, Ryoma Yagi, Yosuke Tajima, Takuma Okamura, Masato Nakano, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Tetsu Hayashida, Hiromasa Takaishi, Yuko Kitagawa, Eiji Oki, Tsuyoshi Konishi, Fumio Ishida, Shin ei Kudo, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Takashi Ishikawa, Kohei Akazawa, Kazuaki Takabe, Toshifumi Wakai, Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer, Oncotarget, 10.18632/oncotarget.20510, 8, 55, 93567-93579, 2017.11, Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than rightsided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC..
304. Eiji Oki, Shinji Okano, Hiroshi Saeki, Yuichiro Umemoto, Koji Teraishi, Yu Nakaji, Koji Ando, Yoko Zaitsu, Nami Yamashita, Masahiko Sugiyama, Yuichiro Nakashima, Kippei Ohgaki, Yoshinao Oda, Yoshihiko Maehara, Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma, Oncology (Switzerland), 10.1159/000479231, 93, 6, 387-394, 2017.12, Objectives: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. Materials and Methods: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. Results: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. Conclusions: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1..
305. Ryota Nakanishi, Hiroyuki Kitao, Mamoru Kiniwa, Yosuke Morodomi, Makoto Iimori, Junji Kurashige, Masahiko Sugiyama, Yuichiro Nakashima, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication, Scientific reports, 10.1038/s41598-017-17282-5, 7, 1, 2017.12, Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients..
306. Yasuo Tsuda, Makoto Iimori, Yuichiro Nakashima, Ryota Nakanishi, Koji Ando, Kippei Ohgaki, Hiroyuki Kitao, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent-induced mitotic arrest, Scientific reports, 10.1038/s41598-017-17002-z, 7, 1, 2017.12, Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity..
307. Daisuke Tsurumaru, Mitsutoshi Miyasaka, Toshio Muraki, Akihiro Nishie, Yoshiki Asayama, Eiji Oki, Yoshinao Oda, Hiroshi Honda, Histopathologic diversity of gastric cancers
Relationship between enhancement pattern on dynamic contrast-enhanced CT and histological type, European Journal of Radiology, 10.1016/j.ejrad.2017.10.018, 97, 90-95, 2017.12, Purpose To evaluate the diagnostic value of contrast-enhanced computed tomography gastrography (CE-CTG) to predict the histological type of gastric cancer. Materials and methods We analyzed 47 consecutive patients with resectable advanced gastric cancer preoperatively evaluated by multiphasic dynamic contrast-enhanced CT. Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. The histological types of gastric cancers were assigned to three groups as differentiated-type, undifferentiated-type, and mixed-type. We compared the peak enhancement phase of the three types and compared the CT attenuation values in each phase. Results The peak enhancement was significantly different between the three types of gastric cancers for both readers (reader 1, p = 0.001; reader 2, p = 0.009); most of the undifferentiated types had peak enhancement in the delayed phase. The CT attenuation values of undifferentiated type were significantly higher than those of differentiated or mixed type in the delayed phase according to both readers (reader 1, p = 0.002; reader 2, p = 0.004). Conclusion CE-CTG could provide helpful information in diagnosing the histological type of gastric cancers preoperatively..
308. Yoshihiko Maehara, Ken Shirabe, Shunji Kohnoe, Yasunori Emi, Eiji Oki, Yoshihiro Kakeji, Hideo Baba, Masataka Ikeda, Michiya Kobayashi, Tadatoshi Takayama, Shoji Natsugoe, Masashi Haraguchi, Kazuhiro Yoshida, Masanori Terashima, Mitsuru Sasako, Hiroki Yamaue, Norihiro Kokudo, Katsuhiko Uesaka, Shinji Uemoto, Tomoo Kosuge, Yoshiki Sawa, Mitsuo Shimada, Yuichiro Doki, Masakazu Yamamoto, Akinobu Taketomi, Masahiro Takeuchi, Kouhei Akazawa, Takeharu Yamanaka, Mototsugu Shimokawa, Erratum to
Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial (Surgery Today, (2017), 47, 9, (1060-1071), 10.1007/s00595-017-1480-3), Surgery today, 10.1007/s00595-017-1589-4, 47, 12, 1539-1540, 2017.12, In the original publication, the article category was published as “Review Article”. The correct category should read as “Original Article”..
309. Hiroshi Saeki, Yasunori Emi, Eiji Oki, Shoji Tokunaga, Yoshihiro Kakeji, Yoshito Akagi, Hideo Baba, Eishi Baba, Yoshihiko Maehara, Study protocol of a phase II clinical trial (KSCC1501A) examining oxaliplatin + S-1 for treatment of HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy, BMC Cancer, 10.1186/s12885-017-3937-6, 18, 1, 2018.01, Background: Oxaliplatin + S-1 is a recognized treatment regimen in Japan, but there are no Japanese clinical data on an oxaliplatin dose of 130mg/m2. The current research involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130mg/m2 to treat HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy in Japan. Methods/design: The primary endpoint of this trial will be the response rate, and the secondary endpoints will be the safety profile of oxaliplatin + S-1, progression-free survival, the response rate in subjects under the age of 75, overall survival, time to treatment failure, duration of treatment, time to failure of strategy, and dose intensity. The threshold response rate is 45% and the expected response rate is 60%. Assuming that a one-tailed score test will be performed with an α of 0.05, 68 patients are needed to ensure a statistical power of 80%. Planned enrollment is 70 subjects and the total duration of this trial is expected to be 3years. Discussion: Since replacing cisplatin with oxaliplatin should provide the same level of therapeutic efficacy while limiting adverse events and simplifying treatment, oxaliplatin + S-1 may be increasingly used to treat gastric cancer in Japan. Verifying the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130mg is an important task that the current trial has set out to achieve. Trial registration: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000017550) on May 29, 2015. The details are available at the following web address: http://www.umin.ac.jp/ctr/..
310. Yuji Miyamoto, Eiji Oki, Yasunori Emi, Shoji Tokunaga, Mototsugu Shimokawa, Yutaka Ogata, Yoshito Akagi, Yasuo Sakamoto, Takaho Tanaka, Hiroshi Saeki, Yoshihiko Maehara, Hideo Baba, Low visceral fat content is a negative predictive marker for bevacizumab in metastatic colorectal cancer, Anticancer research, 10.21873/anticanres.12249, 38, 1, 491-499, 2018.01, Aim: This study aimed to clarify the predictive impact of visceral fat on response to bevacizumab in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Pretreatment computed tomography was used to measure visceral fat area (VFA) and patients with mCRC receiving first-line chemotherapy with/without bevacizumab were divided by median VFA value into two groups: high VFA and low VFA. Results: In the bevacizumab-treated group, patients with low VFA had significantly shorter overall survival (OS) than patients with high VFA in univariate (median=21.1 vs. 38.9 months; hazard ratio=1.70, 95% confidence interval=1.06-2.70, p=0.03) and multivariate analysis (hazard ratio=1.85, 95% confidence interval=1.15-3.03, p=0.01). No significant differences were seen in OS between groups treated with chemotherapy alone. The VFA had a marginally significant modifying effect on the relationship between bevacizumab and OS (p for interaction=0.07). Conclusion: Our findings provide the first evidence that a low VFA might be a negative predictive marker for response to bevacizumab in patients with mCRC..
311. Kayoko Nakano, Hidetaka Yamamoto, Minako Fujiwara, Yutaka Koga, Shinichi Tsuruta, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda, Clinicopathologic and molecular characteristics of synchronous colorectal carcinoma with mismatch repair deficiency, American Journal of Surgical Pathology, 10.1097/PAS.0000000000000947, 42, 2, 172-182, 2018.01, Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/ MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient..
312. Ryota Nakanishi, Eiji Oki, Shun Sasaki, Kosuke Hirose, Tomoko Jogo, Keitaro Edahiro, Shotaro Korehisa, Daisuke Taniguchi, Kensuke Kudo, Junji Kurashige, Masahiko Sugiyama, Yuichiro Nakashima, Kippei Ohgaki, Hiroshi Saeki, Yoshihiko Maehara, Sarcopenia is an independent predictor of complications after colorectal cancer surgery, Surgery today, 10.1007/s00595-017-1564-0, 48, 2, 151-157, 2018.02, Purpose: The significance of sarcopenia after colorectal cancer (CRC) resection has only been discussed with relatively small samples or short follow-up periods. This study aimed to clarify the clinical significance of sarcopenia in a large-sample study. Methods: We retrospectively analyzed the relationship between sarcopenia and clinical factors, surgical outcomes, and the survival in 494 patients who underwent CRC surgery between 2004 and 2013. Sarcopenia was defined based on the sex-specific skeletal muscle mass index measured by preoperative computed tomography. Results: Sarcopenia was associated with sex (higher rate of male, P < 0.0001), and low body mass index (P < 0.0001), but not age or tumor stage. Sarcopenia was associated with higher incidence of all postoperative complications (P = 0.02), especially for patients with Clavien–Dindo classification grade ≥2 (CDC; P = 0.0007). Postoperative hospital stays were significantly longer for sarcopenic patients than for non-sarcopenic patients (P = 0.02). In a multivariate analysis, sarcopenia was an independent predictor for postoperative complications (P = 0.01, odds ratio 1.82, 95% confidence interval 1.13–3.00). Among postoperative complications (CDC grade ≥2), sarcopenia was correlated with non-surgical-site infections (P = 0.03). Sarcopenia was not correlated with the overall or recurrence-free survival. Conclusions: Sarcopenia was an independent predictive factor for postoperative complications after CRC surgery..
313. Hiroyuki Kitao, Makoto Iimori, Yuki Kataoka, Takeshi Wakasa, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, DNA replication stress and cancer chemotherapy, Cancer Science, 10.1111/cas.13455, 109, 2, 264-271, 2018.02, DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS..
314. Shotaro Korehisa, Eiji Oki, Makoto Iimori, Yu Nakaji, Mototsugu Shimokawa, Hiroshi Saeki, Shinji Okano, Yoshinao Oda, Yoshihiko Maehara, Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability, International Journal of Cancer, 10.1002/ijc.31107, 142, 4, 822-832, 2018.02, Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front..
315. Qingjiang Hu, Takaaki Masuda, Kuniaki Sato, Taro Tobo, Sho Nambara, Shinya Kidogami, Naoki Hayashi, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Koshi Mimori, Identification of ARL4C as a Peritoneal Dissemination-Associated Gene and Its Clinical Significance in Gastric Cancer, Annals of Surgical Oncology, 10.1245/s10434-017-6292-6, 25, 3, 745-753, 2018.03, Background: In gastric cancer (GC), peritoneal dissemination (PD) occurs frequently and is incurable. In this study, we aimed to identify PD-associated genes in GC. Methods: We identified a PD-associated gene using three GC datasets: highly disseminated peritoneal GC cell lines, the Singapore dataset and The Cancer Genome Atlas (TCGA) dataset. We assessed the clinicopathological significance of the gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and performed immunohistochemical analysis for the gene in our patient cohort. We also performed survival analyses of the gene in our patient cohort, the Singapore dataset and the GSE62254 datasets. Moreover, gene set enrichment analysis (GSEA) was performed using the Singapore and TCGA datasets. Finally, in vitro experiments such as invasion/migration assays, immunofluorescence staining of actin filaments, epidermal growth factor (EGF) treatment analysis, and gene expression analysis were conducted using three gene-knockdown GC cell lines (AGS, 58As9, MKN45). Results: ADP-ribosylation factor-like 4c (ARL4C) was identified as a PD-associated gene, and immunohistochemical analysis showed that ARL4C was overexpressed in GC cells. High ARL4C expression was associated with the depth of invasion (p < 0.01) and PD (p < 0.05) and was a poor prognostic factor (p < 0.05) in our patient cohort, the Singapore dataset and the GSE62254 dataset. ARL4C expression positively correlated with the epithelial–mesenchymal transition (EMT) gene set in GSEA. Moreover, ARL4C knockdown reduced invasion/migration capacity, SLUG expression, and the formation of lamellipodia or filopodia in AGS and 58As9 cells. Finally, EGF treatment increased ARL4C expression in MKN45 cells. Conclusions: ARL4C was associated with PD and was a poor prognostic factor in GC, possibly through promoting invasive capacity by activation of both EMT and motility..
316. Hideaki Bando, Hideki Shimodaira, Kazumasa Fujitani, Atsuo Takashima, Kensei Yamaguchi, Norisuke Nakayama, Takehiro Takahashi, Eiji Oki, Mizutomo Azuma, Tomohiro Nishina, Shuichi Hironaka, Yoshito Komatsu, Kohei Shitara, A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer, European Journal of Cancer, 10.1016/j.ejca.2017.11.032, 91, 86-91, 2018.03, Background Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility and does not need premedication to avoid infusion-related reactions associated with solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated advanced gastric cancer. Patients and methods Patients with unresectable advanced gastric cancer refractory to first-line chemotherapy were administered nab-paclitaxel 100 mg/m2 intravenously on days 1, 8 and 15, plus ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary end-point was Independent Review Committee (IRC)–assessed overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and quality of life (QOL). Results Forty-five patients were enrolled; 43 received the study treatment. The ORR assessed by the IRC was 54.8% (90% confidence interval [CI] 41.0–68.0) and the primary end-point was met. The DCR was 92.9% (95% CI 80.5–98.5). The IRC-assessed median PFS was 7.6 months (95% CI 5.4–8.1). The median OS was not reached at the data cutoff. The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (76.7%), decreased white blood cell count (27.9%), anaemia (11.6%), decreased appetite (7.0%), febrile neutropenia (4.7%), hypertension (4.7%) and proteinuria (4.7%). No treatment-related deaths occurred. No QOL deterioration was observed during study treatment. Conclusion Nab-paclitaxel plus ramucirumab combination therapy shows promising activity and manageable toxicities and could be a useful second-line treatment option for patients with previously treated advanced gastric cancer..
317. Hideto Sonoda, Eiji Oki, Mitsuru Tanaka, Toshiro Matsui, Takeshi Onodera, Kiyoshi Toko, Yuji Satoh, Yoshihiko Maehara, Research of the cancer-odor, Japanese Journal of Cancer and Chemotherapy, 45, 6, 911-915, 2018.06, Early detection and resection of cancer is the most effective in the treatment of solid cancer. Development of a new cancer detection method is expected to become a breakthrough to solve various problems for early detection. It has been reported that there is the specific odors of cancer by using bio olfaction such as dogs, and it has been recognized that there is the odors of cancer. Cancer cells acquire malignant traits as a result of metabolic changes originating from genetic mutation. The cancer specific odorous substances may be considered to be the end products of their metabolic changes. Omics researches such as genomics, proteomics, and metabolomics have been extensively performed to comprehensively analyze changes in DNA, RNA, protein, metabolism and its products specific to cancer for the purpose of developing a new cancer detection marker. It is thought that the research on the odor of cancer is also on the line of omics research. It is difficult to identify cancer-specific odorants buried in various environmental substances. However, it is expected that human will be able to acquire the technology, from the fact that they can be recognized by biological olfaction. We are continuing the research with the dream that identification of the odorous substances as a new cancer detection marker and sensor development for it will lead to the happiness of colleagues in the world..
318. T. Yoshino, T. Yamanaka, T. Denda, Y. Tsuji, K. Shinozaki, Y. Komatsu, Y. Kobayashi, J. Furuse, H. Okuda, M. Asayama, K. Akiyoshi, Y. Kagawa, T. Kato, E. Oki, T. Ando, Y. Hagiwara, Y. Ohashi, K. Shitara, REVERCE
Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan: Quality of life analysis, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy150.009, 29, v95, 2018.06.
319. T. Kato, H. Satake, K. Oba, Y. Kagawa, H. Yasui, M. Nakamura, T. Watanabe, T. Matsumoto, K. Hirata, K. Muro, Y. Komatsu, T. Yoshino, K. Yamazaki, H. Mishima, M. Kotaka, A. Tsuji, Y. Kakeji, E. Oki, N. Nagata, J. Sakamoto, Multicenter phase Ib/II study of biweekly TAS-102 with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study) - Trial in progress, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy151.293, 29, v83, 2018.06.
320. Tatsuro Okamoto, Kazuki Takada, Seijiro Sato, Gouji Toyokawa, Tetsuzo Tagawa, Fumihiro Shoji, Ryota Nakanishi, Eiji Oki, Terumoto Koike, Masayuki Nagahashi, Hiroshi Ichikawa, Yoshifumi Shimada, Satoshi Watanabe, Toshiaki Kikuchi, Kouhei Akazawa, Stephen Lyle, Kazuaki Takabe, Shujiro Okuda, Kenji Sugio, Toshifumi Wakai, Masanori Tsuchida, Yoshihiko Maehara, Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung, Annals of Surgical Oncology, 10.1245/s10434-018-6401-1, 25, 6, 1564-1571, 2018.06, Background: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. Methods: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. Results: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). Conclusions: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor..
321. Yuichiro Nakashima, Hiroshi Saeki, Ryota Nakanishi, Masahiko Sugiyama, Junji Kurashige, Eiji Oki, Yoshihiko Maehara, Assessment of Sarcopenia as a Predictor of Poor Outcomes after Esophagectomy in Elderly Patients with Esophageal Cancer, Annals of surgery, 10.1097/SLA.0000000000002252, 267, 6, 1100-1104, 2018.06, Objective: The objective of the study was to elucidate the impact of sarcopenia in elderly patients with esophageal cancer on postoperative complications and long-term survival after surgery for esophageal cancer. Summary Background Data: Sarcopenia, defined as loss of skeletal muscle mass with age, has been identified as a poor prognostic factor for malignancies. This retrospective study investigated the effect of sarcopenia on surgical outcomes among young and elderly patients with esophageal cancer. Methods: Data were collected for 341 consecutive patients who underwent esophagectomy for esophageal cancer. Patients were assigned to 2 groups according to age (younger than 65 years and 65 years or older) and the presence of sarcopenia. Results: Sarcopenia was present in 170 of 341 patients (49.9%) with esophageal cancer and in 74 of 166 elderly patients (44.6%). The incidence of anastomotic leak and in-hospital death was significantly higher in the elderly sarcopenia group than in the elderly nonsarcopenia group (31.5% vs 15.2%, P = 0.015, 6.8 vs 0.0%, P = 0.037, respectively), and the overall survival rate in patients with sarcopenia correlated with a significantly poor prognosis in the elderly group (P < 0.001). Multivariate analysis revealed that sarcopenia was a risk factor for an anastomotic leak (P = 0.034) and was an unfavorable prognostic factor for survival (P < 0.001). Those correlations between sarcopenia and surgical outcomes were not observed in the young group. Conclusions: Sarcopenia and worse surgical outcomes were significantly associated patients with in esophageal cancer aged 65 years and older but not in those younger than 65 years..
322. K. Yamazaki, H. Yasui, K. Yamaguchi, Y. Kagawa, Y. Kuboki, T. Yoshino, M. Gamoh, Y. Komatsu, H. Satake, M. Goto, H. Tanioka, E. Oki, M. Kotaka, A. Makiyama, T. Denda, J. Soeda, K. Shibya, M. Iwata, K. Oba, T. Kato, A phase I/II study of panitumumab combined with TAS-102 in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) refractory to standard chemotherapy
APOLLON study, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy151.252, 29, v71, 2018.06.
323. Y. Kagawa, T. Kato, H. Bando, K. Akagi, T. Denda, T. Nishina, Y. Komatsu, E. Oki, T. Kudo, T. Yamanaka, T. Yoshino, A multicentre, prospective clinical evaluation study for analyzing RAS mutational status utilizing plasma circulating tumor DNA in patients with metastatic colorectal cancer, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy149.004, 29, v101-v102, 2018.06.
324. Gabrielle S. Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E. Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O'Day, Rachel Rendak, Wei Li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K. Rustgi, Kwok Kin Wong, J. Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A. Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J. Bass, Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition letter, Nature medicine, 10.1038/s41591-018-0022-x, 24, 7, 968-977, 2018.07, The role of KRAS, when activated through canonical mutations, has been well established in cancer 1 . Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas 2-4 . KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition..
325. Takayuki Yoshino, Eiji Oki, Hiroaki Nozawa, Takako Eguchi-Nakajima, Hiroya Taniguchi, Satoshi Morita, Naruhito Takenaka, Daisuke Ozawa, Kuniaki Shirao, Rationale and design of the TRUSTY study
A randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy, ESMO Open, 10.1136/esmoopen-2018-000411, 3, 5, 2018.08, Background Trifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the TRiflUridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC. Patients and methods Eligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022. Clinical trial registration JapicCTI-173618 (JapicCTI)..
326. Koji Ando, Yara Hamade Tohme, Adithi Srinivasiah, Julian Taylor-Parker, Yevgeniya Harrington, Ankur K. Shah, Eiji Oki, Mohan Brahmandam, Ajit K. Bharti, Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors, Journal of Histochemistry and Cytochemistry, 10.1369/0022155418766503, 66, 8, 549-561, 2018.08, Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology. However, no phosphospecific IHC test is used in oncology clinics. Human topoisomerase I (topoI) inhibitors, camptothecin and its analogues (CPT), are used extensively to treat various solid tumors. Depending on tumor type, the response rate is only 13–32%. We have demonstrated that the deregulated kinase cascade is at the core of CPT resistance. DNA-PKcs, a kinase central to the DNA–double-strand break (DSB) response pathway, phosphorylates topoI at serine 10 (topoI-pS10), and cells with higher basal levels of topoI-pS10 degrade topoI rapidly and are resistant to this class of drug. The higher basal level of topoI phosphorylation is due to continual activation of DNA-PKcs, and one potential mechanism of this pathway activation is failure of upstream effector phosphatases such as phosphatase and tensin homolog (PTEN). Based on this understanding, we have developed an IHC-based test (P-topoIDx) that can stratify the responder and non-responder patient population..
327. Yuka Inoue, Nami Yamashita, Hiroyuki Kitao, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Eriko Tokunaga, Yoshihiko Maehara, Clinical Significance of the Wild Type p53-Induced Phosphatase 1 Expression in Invasive Breast Cancer, Clinical Breast Cancer, 10.1016/j.clbc.2017.11.008, 18, 4, e643-e650, 2018.08, The nuclear expression of wild type p53-induced phosphatase 1 (Wip1) protein was found to be positive in 21 patients (10.4%) out of 201 breast cancer patients in our study. The protein phosphatase magnesium dependent 1 delta DNA copy number was significantly correlated with Wip1 protein expression, which was positively correlated with p21 expression. Tumors with positive Wip1 expression and negative p21 expression showed the poorest prognosis of all tumors examined. Background: Wild type p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), inhibits p53. PPM1D amplification has been reported in breast cancer. Breast cancer can sometimes develop without a tumor protein 53 (TP53) mutation. In these cases, the p53 pathway might be disrupted by alternative mechanisms, and Wip1 is reported to be a key molecule involved. Materials and Methods: Primary invasive ductal carcinoma specimens were obtained from 201 cases, for which archival tissue samples for immunohistochemistry were available. We evaluated Wip1 and p21 protein expression (201 cases), Wip1 mRNA expression (63 cases), PPM1D DNA copy number (71 cases) and TP53 status (36 cases) using available samples among the 201 cases, and analyzed their relationships with clinicopathological factors and prognosis. Results: The nuclear expression of Wip1 protein was positive in 21 cases (10.4%). The PPM1D DNA copy number was significantly correlated with Wip1 protein expression. All cases with PPM1D amplification by single-nucleotide polymorphism comparative genomic hybridization array showed positive nuclear Wip1 expression. Wip1 protein expression was positively correlated with p21 expression. The tumors with positive Wip1 and negative p21 expression showed the poorest prognosis among all tumor types. Conclusion: The protein expression of Wip1 might be regulated by PPM1D amplification, independent of TP53 status. Positive Wip1 and negative p21 expression was associated with the poorest prognosis and suggests the loss of p53 function..
328. Hiroshi Saeki, Yuichiro Nakashima, Kensuke Kudou, Shun Sasaki, Tomoko Jogo, Kosuke Hirose, Keitaro Edahiro, Shotaro Korehisa, Daisuke Taniguchi, Ryota Nakanishi, Nobuhide Kubo, Koji Ando, Akira Kabashima, Eiji Oki, Yoshihiko Maehara, Neoadjuvant Chemoradiotherapy for Patients with cT3/Nearly T4 Esophageal Cancer
Is Sarcopenia Correlated with Postoperative Complications and Prognosis?, World journal of surgery, 10.1007/s00268-018-4554-5, 42, 9, 2894-2901, 2018.09, Background: Since the clinical impact of sarcopenia on multimodal therapy for patients with esophageal cancer is not well understood, this study was conducted to determine the influence of sarcopenia on the efficacy of neoadjuvant chemoradiotherapy (NACRT) for locally advanced esophageal cancer. Methods: The skeletal muscle index was quantified at the level of the third lumbar vertebra on computed tomography images, and sarcopenia was defined as a skeletal muscle index that was less than the average for each gender. We compared treatment outcomes in patients with cT3 and nearly T4 thoracic esophageal squamous cell carcinoma between the sarcopenia group (n = 85) and the non-sarcopenia group (n = 72). Results: The 5-year survival rates were 33.4% in the non-sarcopenia group and 31.5% in the sarcopenia group; these differences were not significant. The prognosis of the patients with sarcopenia was worse than that of the patients without sarcopenia in the surgery-alone group, but there was no difference between patients with and without sarcopenia in the NACRT group. Conclusions: NACRT could be a useful option for patients with locally advanced esophageal squamous cell carcinoma, even for those with sarcopenia, without increasing the incidence of morbidity and mortality..
329. Nobuyuki Shimizu, Eiji Oki, Yutaka Tanizawa, Yutaka Suzuki, Susumu Aikou, Chikara Kunisaki, Takashi Tsuchiya, Ryoji Fukushima, Yuichiro Doki, Shoji Natsugoe, Yasunori Nishida, Masaru Morita, Naoki Hirabayashi, Fumihiko Hatao, Ikuo Takahashi, Yasuhiro Choda, Yoshiaki Iwasaki, Yasuyuki Seto, Effect of early oral feeding on length of hospital stay following gastrectomy for gastric cancer
a Japanese multicenter, randomized controlled trial, Surgery today, 10.1007/s00595-018-1665-4, 48, 9, 865-874, 2018.09, Purpose: This multicenter, randomized controlled study evaluates the safety of early oral feeding following gastrectomy, and its effect on the length of postoperative hospital stay. Methods: The subjects of this study were patients who underwent distal gastrectomy (DG) or total gastrectomy (TG) for gastric cancer between January 2014 and December 2015. Patients were randomly assigned to the early oral feeding group (intervention group) or the conventional postoperative management group (control group) for each procedure. We evaluated the length of postoperative hospital stay and the incidence of postoperative complications in each group. Results: No significant differences in length of postoperative stay were found between the intervention and control groups of the patients who underwent DG. The incidence of postoperative complications was significantly greater in the DG intervention group. In contrast, the length of postoperative stay was significantly shorter in the TG intervention group, although the TG group did not attain the established target sample size. Conclusion: Early oral feeding did not shorten the postoperative hospital stay after DG. The higher incidence of postoperative complications precluded the unselected adoption of early oral feeding for DG patients. Further confirmative studies are required to definitively establish the potential benefits of early oral feeding for TG patients..
330. S. Yuki, K. Shinozaki, T. Kashiwada, T. Kusumoto, M. Iwatsuki, H. Satake, S. Tokunaga, Y. Emi, A. Makiyama, Y. Kawamoto, Y. Komatsu, M. Shimokawa, H. Saeki, E. Oki, H. Baba, Y. Maehara, Updated analysis of a phase II study of SOX plus trastuzumab for the patients with HER2 positive advanced or recurrent gastric cancer
KSCC/HGCSG/CCOG/PerSeUS1501B, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy282.052, 29, viii225, 2018.10.
331. T. Kawakami, K. Yamazaki, E. Oki, M. Shimokawa, N. Takahashi, M. Yokota, S. Tokunaga, T. Esaki, M. Gamoh, A. Maeda, Y. Tsuji, A. Sakai, K. Hatanaka, Y. Shimada, M. Shiozawa, Y. Komatsu, H. Okuda, M. Ohue, Y. Maehara, Treatment pattern and outcomes of trifluridine/tipiracil therapy for metastatic colorectal cancer in the real-world data from the JFMC50 study, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy281.013, 29, viii155, 2018.10.
332. K. Kobayashi, M. Iwatsuki, H. Orita, S. Hidaka, T. Arigami, T. Kusumoto, H. Satake, E. Oki, K. Satoshi, K. Tobimatsu, M. Shimokawa, H. Saeki, A. Makiyama, Y. Kakeji, S. Natsugoe, H. Baba, S. Eguchi, Y. Maehara, Phase II study of S-1 and oxaliplatin as neo-adjuvant chemotherapy for locally advanced gastric and esophago-gastric cancer (KSCC1601), Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy282.054, 29, viii225-viii226, 2018.10.
333. E. Oki, H. Samura, H. Okumura, T. Ohchi, H. Orita, K. Kobayashi, T. Kinjo, S. Mori, T. Touyama, K. Ohgaki, H. Kawanaka, A. Makiyama, N. Ureshino, M. Kotaka, T. Shimose, H. Saeki, T. Nishimaki, H. Baba, Y. Maehara, Initial report of a phase I/II study of S-1 and irinotecan (IRIS) in combination with cetuximab in patients with wild-type RAS metastatic colorectal cancer, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy281.040, 29, viii166, 2018.10.
334. Y. Emi, T. Yamanaka, K. Muro, H. Uetake, E. Oki, T. Takahashi, Y. Katayose, K. Yoshida, M. Sakamoto, S. Aishima, K. Ishida, J. Imura, M. Unno, I. Hyodo, N. Tomita, K. Sugihara, Y. Maehara, Histopathologic evaluation of patients with liver-limited metastatic colorectal cancer receiving mFOLFOX6 plus bevacizumab or mFOLFOX6 plus cetuximab
The ATOM trial, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy281.036, 29, viii164, 2018.10.
335. Kei Muro, Yasunori Emi, Takeharu Yamanaka, Hiroyuki Uetake, Eiji Oki, Takao Takahashi, Yoshiharu Sakai, Toshiyoshi Fujiwara, Yuh Katayose, Kazuhiro Yoshida, Michiaki Unno, Ichinosuke Hyodo, Naohiro Tomita, Kenichi Sugihara, Yoshihiko Maehara, ATOM trial
a randomized phase II study of mFOLFOX6+Bmab vs. mFOLFOX6+Cmab for not-optimary resectable KRAS wt mCRC, Annals of Oncology, 10.1093/annonc/mdy374, 29, vii51, 2018.10.
336. Atsuo Takashima, Hideaki Bando, Hideki Shimodaira, Kazumasa Fujitani, Kensei Yamaguchi, Norisuke Nakayama, Takehiro Takahashi, Eiji Oki, Mizutomo Azuma, Tomohiro Nishina, Shuichi Hironaka, Yoshito Komatsu, Kohei Shitara, A phase II study of nab-PTX in combination with RAM in patients with pre-treated AGC
results of final analysis, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy375.005, 29, vii67, 2018.10.
337. Y. Kagawa, H. Satake, T. Kato, K. Oba, H. Yasui, M. Nakamura, T. Watanabe, K. Hirata, K. Muro, Y. Komatsu, T. Yoshino, K. Yamazaki, H. Mishima, M. Kotaka, A. Tsuji, Y. Kakeji, E. Oki, N. Nagata, S. Junichi, Phase Ib/II study of biweekly TAS-102 with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study)
Phase Ib results, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy431.021, 29, ix34-ix35, 2018.11.
338. Sei Shu, Makoto Iimori, Takeshi Wakasa, Koji Ando, Hiroshi Saeki, Yoshinao Oda, Eiji Oki, Yoshihiko Maehara, The balance of forces generated by kinesins controls spindle polarity and chromosomal heterogeneity in tetraploid cells, Journal of cell science, 10.1242/jcs.231530, 132, 24, 2019.01, Chromosomal instability, one of the most prominent features of tumour cells, causes aneuploidy. Tetraploidy is thought to be an intermediate on the path to aneuploidy, but the mechanistic relationship between the two states is poorly understood. Here, we show that spindle polarity (e.g. bipolarity or multipolarity) in tetraploid cells depends on the level of functional phosphorylated Eg5, a mitotic kinesin, localised to the spindle. Multipolar spindles are formed in cells with high levels of phosphorylated Eg5. This process is suppressed by inhibition of Eg5 or expression of a non-phosphorylatable Eg5 mutant, as well as by changing the balance between opposing forces required for centrosome separation. Tetraploid cells with high levels of functional Eg5 give rise to a heterogeneous aneuploid population through multipolar division, whereas cells with low levels of functional Eg5 continue to undergo bipolar division and remain tetraploid. Furthermore, Eg5 protein levels correlate with ploidy status in tumour specimens. We provide a novel explanation for the tetraploid intermediate model, i.e. spindle polarity and subsequent tetraploid cell behaviour are determined by the balance of forces generated by mitotic kinesins at the spindle..
339. J. Watanabe, T. Sato, Y. Kagawa, E. Oki, Y. Kuboki, M. Ikeda, H. Ueno, T. Kato, T. Kusumoto, T. Masuishi, K. Yamaguchi, A. Kanazawa, T. Nishina, H. Uetake, T. Yamanaka, T. Yoshino, SUNRISE-DI study
decision impact of the 12-gene recurrence score (12-RS) assay on adjuvant chemotherapy recommendation for stage II and IIIA/B colon cancer, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdz154.016, 30, iv132, 2019.07.
340. Eiji Oki, Yasunori Emi, Takeharu Yamanaka, Hiroyuki Uetake, Kei Muro, Takao Takahashi, Takeshi Nagasaka, Etsuro Hatano, Hitoshi Ojima, Dai Manaka, Tetsuya Kusumoto, Yu Katayose, Toshiyoshi Fujiwara, Kazuhiro Yoshida, Michiaki Unno, Ichinosuke Hyodo, Naohiro Tomita, Kenichi Sugihara, Yoshihiko Maehara, Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial), British journal of cancer, 10.1038/s41416-019-0518-2, 121, 3, 222-229, 2019.07, Background: Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET). Methods: The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS). Results: Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2–13.3 months) in the BEV group and 14.8 months (95% CI 9.7–17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively. Conclusion: Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions. Trial registration: This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209)..
341. K. Muro, H. Uetake, K. Tsuchihara, K. Shitara, K. Yamazaki, M. Ota, E. Oki, T. Sato, T. Naitoh, Y. Komatsu, T. Kato, K. Yamanaka, I. Mori, J. Soeda, M. Hihara, T. Yamanaka, K. Akagi, A. Ochiai, T. Yoshino, PARADIGM study
A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdz155.033, 30, iv10, 2019.07.
342. Daisuke Tsurumaru, Yusuke Nishimuta, Toshio Muraki, Yoshiki Asayama, Akihiro Nishie, Eiji Oki, Hiroshi Honda, CT gastrography “wall-carving technique” of gastric cancer
impact of contrast enhancement based on layer depth, Japanese Journal of Radiology, 10.1007/s11604-019-00845-z, 37, 8, 597-604, 2019.08, Purpose: Wall-carving technique (WC) is a special volume rendering technique of three-dimensional CT gastrography that can illustrate the enhancement of gastric wall at an arbitrary depth. We conducted the present study to evaluate the impact of contrast enhancement based on layer depth on WC of gastric cancer and to correlate them with pathological findings. Methods: The subjects of this retrospective study consisted of 36 patients with advanced gastric cancer (22 men, 14 women; age range, 39–90 years; median, 67 years) who underwent contrast-enhanced CT before surgery. WC images of arterial phase were divided into first and second layer. Two radiologists in consensus evaluated the contrast enhancement of WC images for each layer and correlated with pathologic factors. Results: Twenty-six (72%) of the gastric cancers showed a well-enhanced lesion in the first layer at the arterial phase on WC images, and 18 (50%) showed a well-enhanced lesion in the second layer. The study of second layers showed that the well-enhanced group had significantly more cases of differentiated type histology and intermediate stroma than the normally to poorly enhanced group (p = 0.008 and 0.0026). Conclusion: The contrast enhancement on WC of gastric cancer showed a significant relationship with pathological factors based on layer depth..
343. Yoshihiko Maehara, Yuji Soejima, Tomoharu Yoshizumi, Naoyuki Kawahara, Eiji Oki, Hiroshi Saeki, Tomohiko Akahoshi, Toru Ikegami, Yo ichi Yamashita, Tadashi Furuyama, Keishi Sugimachi, Noboru Harada, Tetsuzo Tagawa, Norifumi Harimoto, Shinji Itoh, Hideto Sonoda, Koji Ando, Yuichiro Nakashima, Yoshihiro Nagao, Nami Yamashita, Yuta Kasagi, Takafumi Yukaya, Takeshi Kurihara, Ryosuke Tsutsumi, Shinkichi Takamori, Shun Sasaki, Tetsuo Ikeda, Yoshikazu Yonemitsu, Takasuke Fukuhara, Hiroyuki Kitao, Makoto Iimori, Yuki Kataoka, Takeshi Wakasa, Masami Suzuki, Koji Teraishi, Yasuto Yoshida, Masaki Mori, The evolution of surgical treatment for gastrointestinal cancers, International Journal of Clinical Oncology, 10.1007/s10147-019-01499-7, 24, 11, 1333-1349, 2019.11, Introduction: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. Materials and methods, and results: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. Conclusion: We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival..
344. Nobuhide Kubo, Hirohumi Kawanaka, Shoji Hiroshige, Hirotada Tajiri, Akinori Egashira, Hideya Takeuchi, Toshifumi Matsumoto, Eiji Oki, Tokujiro Yano, Sarcopenia discriminates poor prognosis in elderly patients following emergency surgery for perforation panperitonitis, Annals of Gastroenterological Surgery, 10.1002/ags3.12281, 3, 6, 630-637, 2019.11, Aim: Sarcopenia has been reported as a prognostic predictor in various conditions; however, it has not been examined in patients with perforation panperitonitis. Methods: A total of 103 consecutive patients with perforation panperitonitis who underwent emergency surgery from 2008 to 2016 were retrospectively evaluated. Skeletal muscle index (SMI) was measured as the cross-sectional area (cm2) of skeletal muscle in the L3 region on computed tomography images normalized for height (cm2/m2). Sarcopenia was defined as an SMI of ≤43.75 and ≤41.10 cm2/m2 in men and women, respectively. The impact of sarcopenia on postoperative outcomes was investigated. Results: Sarcopenia was present in 50 (48.5%) patients. Severe complications (Clavien-Dindo grade ≥IIIb) and in-hospital mortality were more frequently observed in patients with than without sarcopenia (28.0% vs 9.4%, P =.015) (20.0% vs 5.7%, P =.029) respectively. Multivariate analysis showed that age, sarcopenia, and renal dysfunction were independent risk factors for severe complications and in-hospital mortality. The optimal cut-off levels of age and SMI for predicting these were ≥79 years and SMI <38 cm2/m2, respectively. Among the patients aged ≥79 years, those with SMI <38 cm2/m2 had a severe complication rate of 71% and an in-hospital mortality rate of 57%, whereas the rate of those with SMI ≥38 cm2/m2 was 22% (P =.011) and 11% (P =.008), respectively. Conclusion: Sarcopenia is a predictive factor of severe complications and in-hospital mortality following emergency surgery for perforation panperitonitis, especially in elderly patients. Estimation of sarcopenia may identify patients eligible or not eligible for emergency surgery among elderly patients..
345. Hiroya Matsuoka, Koji Ando, Qingjiang Hu, Yoko Zaitsu, Yasuo Tsuda, Yuichi Hisamatsu, Yuichiro Nakashima, Yasue Kimura, Eiji Oki, Masaki Mori, Postoperative C-reactive protein/albumin ratio is a biomarker of risk of recurrence and need for adjuvant chemotherapy for stage III colorectal cancer, International Journal of Clinical Oncology, 10.1007/s10147-020-01672-3, 2020.01, Background: Adjuvant chemotherapy is generally recommended for patients with stage III colorectal cancer. Even with adjuvant chemotherapy, 20–30% of such patients develop recurrences; the risk factors for recurrence are currently unclear. The preoperative systemic inflammation index has been linked to poor prognoses in patients with colorectal cancer; however, the relationship between postoperative systemic inflammation index and recurrence is unclear. We aimed to evaluate the association between preoperative and postoperative systemic inflammation indexes and recurrence in patients with stage III colorectal cancer. Methods: The following laboratory data of 133 patients with stage III colorectal cancer were analyzed: preoperative and postoperative C-reactive protein/albumin ratios (CAR); neutrophil to lymphocyte ratios (NLR); and platelet to lymphocyte ratios (PLR) and their relationships with recurrence analyzed. Results: The optimal cutoff values for systemic inflammation indexes were determined by examining receiver operating characteristic curves. Multivariate analyses indicated that N-stage, postoperative complications, preoperative NLR, and postoperative CAR were independent predictors of recurrence-free survival (RFS). Postoperative CAR was also an independent predictor of overall survival (OS). Patients with postoperative CAR ≥ 0.035 who did not receive adjuvant chemotherapy had shorter RFS and OS than those who did. There were no significant differences in RFS and OS between patients with postoperative CAR < 0.035 who did and did not receive adjuvant chemotherapy. Conclusions: Postoperative CAR is strongly associated with poor prognosis in patients with stage III colorectal cancer and is a useful biomarker for determining whether adjuvant chemotherapy should be administered..
346. Yoshiaki Fujimoto, Ryota Nakanishi, Mamoru Nukatsuka, Kazuaki Matsuoka, Koji Ando, Takeshi Wakasa, Hiroyuki Kitao, Eiji Oki, Yoshihiko Maehara, Masaki Mori, Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil, Cancer chemotherapy and pharmacology, 10.1007/s00280-020-04072-6, 2020.01, Purpose: Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model. Methods: Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed. Results: FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days. Conclusion: These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity..
347. Eiji Shinto, Eiji Oki, Mototsugu Shimokawa, Shigeki Yamaguchi, Megumi Ishiguro, Masaru Morita, Tetsuya Kusumoto, Naohiro Tomita, Yojiro Hashiguchi, Masafumi Tanaka, Shinobu Ohnuma, Sachiyo Tada, Tomoko Matsushima, Kazuo Hase, A Validation Study for Recurrence Risk Stratification of Stage II Colon Cancer Using the 55-Gene Classifier, Oncology (Switzerland), 10.1159/000506369, 2020.01, Introduction: DNA microarrays, such as the consensus molecular subtype (CMS) classification using >600 genes, are used to predict cancer patient prognosis. We recently constructed a simple 55-gene classifier (55GC) system to risk stratify colon cancer (CC). Objective: Here, we validate the 55GC specifically for stage II CC and compare it with CMS categories. Methods: Tissue sections from 232 stage II CC patients who underwent curative surgery without adjuvant chemotherapy between 2009 and 2012 were subjected to DNA microarray analysis. Results: Based on the 55GC, patients were classified into microsatellite instability-like (27%), chromosomal instability-like (41%), and stromal (32%) subtypes with 5-year relapse-free survival (RFS) rates of 88.5, 83.3, and 71.2%, respectively (stromal vs. others: p = 0.0049). Multivariate analysis by Cox's proportional hazard model revealed that the stromal subtype, pT4, and the number of lymph nodes examined (<12) were independent poor prognostic factors. The overall concordance rate between 55GC and CMS was 72%, and 5-year RFS rates of patients with CMS1, CMS2, CMS3, and CMS4 cancers were 100, 85.5, 92.3, and 73.0%, respectively (p = 0.0113). Conclusions: We conclude that the 55GC is a useful and reproducible grading system for stage II CC recurrence risk stratification..
348. Toshikazu Moriwaki, Shota Fukuoka, Toshiki Masuishi, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Yukimasa Hatachi, Takeshi Suto, Naotoshi Sugimoto, Masanobu Enomoto, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Akihito Tsuji, Kenji Tsuchihashi, Daisuke Sakai, Hideki Ueno, Takao Tamura, Kimihiro Yamashita, Yasuhiro Shimada, Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer
an exploratory analysis of the REGOTAS study, International Journal of Clinical Oncology, 10.1007/s10147-019-01600-0, 25, 4, 614-621, 2020.04, Background: Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit. Methods: Patients included in the REGOTAS study, which comprised 489 patients (regorafenib group: 199; FTD/TPI group: 290 patients), were evaluated. OS was analyzed using multivariate Cox proportional model. The prognostic score was calculated using the worst four individual factors weighted by hazard ratio, and the total scores were categorized as low-, moderate-, and high-OS benefit. Results: The worst four factors in the regorafenib group were AST > 40 IU/dL (point, + 3), CRP ≥ 1.0 mg/dL (+ 2), number of metastatic organ site ≥ 3 (+ 2), and duration from initiation of 1st-line chemotherapy < 18 months (+ 2), while they were AST (+ 2), CRP (+ 2), CA19-9 > 37.0 U/mL (+ 2), and ECOG PS ≥ 1 (+ 2) in the FTD/TPI group. These corresponded to a total prognostic score of > 5, 2–4, and 0 points in the regorafenib group and 8, 2–6, and 0 points in the FTD/TPI group. The median OS in the low, moderate, and high OS benefit group was 3.3 (95% CI 3.0–3.7), 8.1 (95% CI 6.4–9.7), and 12.6 months (95% CI 10.6–14.6) in the regorafenib group and 2.8 (95% CI 2.0–3.5), 7.5 (95% CI 6.6–8.3), and 15.4 months (95% CI 9.7–21.2) in the FTD/TPI group. Conclusion: These prognostic scores are useful for identifying patients with mCRC who will obtain survival benefits from these drugs..
349. Hideaki Bando, Yoshinori Kagawa, Takeshi Kato, Kiwamu Akagi, Tadamichi Denda, Tomohiro Nishina, Yoshito Komatsu, Eiji Oki, Toshihiro Kudo, Hiroshi Kumamoto, Takeharu Yamanaka, Takayuki Yoshino, Correction
A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer (British Journal of Cancer, (2019), 120, 10, (982-986), 10.1038/s41416-019-0457-y), British journal of cancer, 10.1038/s41416-020-0766-1, 122, 8, 2020.04, An amendment to this paper has been published and can be accessed via a link at the top of the paper..
350. Khurum Khan, Stefano Cascinu, David Cunningham, Sun Young Kim, Eiji Oki, Tara Seery, Lin Shen, Salvatore Siena, Christophe Tournigand, Nazim Serdar Turhal, Alain Hendlisz, Imaging and clinical correlates with regorafenib in metastatic colorectal cancer, Cancer Treatment Reviews, 10.1016/j.ctrv.2020.102020, 86, 2020.06, In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment..
351. , Koji Ando, Yasunori Emi, Nobutomo Miyanari, Akihito Tsuji, Kenji Sakai, Terumitsu Sawai, Hiroshi Imamura, Shinichiro Mori, Shoji Tokunaga, Eiji Oki, Hiroshi Saeki, Yoshihiro Kakeji, Yoshito Akagi, Hideo Baba, Yoshihiko Maehara, Masaki Mori, Efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) for treating patients with stage III colon cancer (KSCC1303)
final analysis of 3-year disease-free survival, International Journal of Clinical Oncology, 10.1007/s10147-020-01646-5, 25, 6, 1115-1122, 2020.06, Background: Adjuvant chemotherapy is an accepted treatment to improve survival rates in patients with stage III colon cancer, and regimens including oxaliplatin have been shown to be superior to those containing 5-FU alone. The purpose of this study was to examine the efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) as adjuvant chemotherapy for patients with stage III colon cancer following curative resection. Methods: Patients with colon cancer who underwent curative resection were enrolled and received oral S-1 40–60 mg twice daily on days 1–14 every 3 weeks plus intravenous oxaliplatin 130 mg/m2 on day 1 for eight courses. The primary endpoint was 3-year disease-free survival rate. Secondary endpoints were the rate of treatment completion, adverse events, relative dose intensity, and overall survival. Results: Between February 2014 and December 2014, 89 patients were enrolled. One patient was excluded from the analysis because of ineligibility, and the remaining 88 patients were included. The rate of protocol treatment completion was 72.3%. The relative dose intensity of S-1 and oxaliplatin was 72% and 76.3%, respectively. Hematological severe adverse events (Grade 3/4) were neutropenia (21.3%) and thrombocytopenia (15.7%). The most frequent symptom was diarrhea (Grade 3/4: 5.6%). The incidence of grade 2 neuropathy has decreased from 8.1 to 2.7% after 3 years of the therapy. Three-year disease-free survival rate was 73.9% (95% CI 63.8–81.9), and 3-year overall survival rate was 94.3% (95% CI 86.8–97.6) Conclusions: C-SOX is a safe and feasible adjuvant chemotherapy regimen in patients with stage III colon cancer undergoing curative resection..
352. Taisuke Narazaki, Motoaki Shiratsuchi, Mariko Tsuda, Yasuhiro Tsukamoto, Hiroki Muta, Toru Masuda, Daisaku Kimura, Akiko Takamatsu, Ryota Nakanishi, Eiji Oki, Minako Fujiwara, Yoshinao Oda, Yasuhiro Nakashima, Yoshihiro Ogawa, Intestinal Behçet's Disease with Primary Myelofibrosis Involving Trisomy 8, Acta Haematologica, 10.1159/000501019, 142, 4, 253-256, 2019.11, Behçet's disease (BD) is a disorder characterized by systemic inflammation of multiple organs, including the intestines. Several studies have reported a relationship between myelodysplastic syndrome and BD, and trisomy 8 was frequently seen, especially in intestinal BD. However, the association of BD with primary myelofibrosis (PMF) has not been well documented. A 58-year-old Japanese female was diagnosed with PMF in 2014. The symptoms of PMF resolved with ruxolitinib. However, she developed fever and intestinal perforation due to multiple ulcers in the terminal ileum in 2017. Intestinal perforation recurred 1 month later, and the dose of ruxolitinib was tapered. After discontinuation of ruxolitinib, she presented with recurrent oral aphthous ulcers and uveitis. Subsequently, intestinal perforation recurred, and she was diagnosed with intestinal BD. Trisomy 8 was identified in her peripheral blood. She underwent steroid therapy, azathioprine, and infliximab. This case suggests relationships between PMF, trisomy 8, and BD..
353. Tetsuya Hamaguchi, Tadamichi Denda, Toshihiro Kudo, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Fumio Nagashima, Toshikazu Moriwaki, Taito Esaki, Takeo Sato, Michio Itabashi, Eiji Oki, Toru Sasaki, Marielle Chiron, Takayuki Yoshino, Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer, Cancer Science, 10.1111/cas.14198, 110, 11, 3565-3572, 2019.11, Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P <.001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868..
354. Takayuki Yoshino, Takeharu Yamanaka, Eiji Oki, Masahito Kotaka, Dai Manaka, Tetsuya Eto, Junichi Hasegawa, Akinori Takagane, Masato Nakamura, Takeshi Kato, Yoshinori Munemoto, Shintaro Takeuchi, Hiroyuki Bando, Hiroki Taniguchi, Makio Gamoh, Manabu Shiozawa, Tsunekazu Mizushima, Shigetoyo Saji, Yoshihiko Maehara, Atsushi Ohtsu, Masaki Mori, Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer
The ACHIEVE Phase 3 Randomized Clinical Trial, JAMA Oncology, 10.1001/jamaoncol.2019.2572, 5, 11, 1574-1581, 2019.11, Importance: Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer. Objective: To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. Design, Setting, and Participants: An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018. Interventions: Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival. Results: Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P <.001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P =.04) and 6-month arms (21.0% vs 34.1%; P =.02). Conclusions and Relevance: The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease..
355. Kosuke Hirose, Eiji Oki, Takayuki Shimose, Sanae Sakamoto, Shun Sasaki, Tomoko Jogo, Qingjiang Hu, Yasuo Tsuda, Koji Ando, Yuichiro Nakashima, Hiroshi Saeki, Masaki Mori, Comparison of computed tomography imaging analyses for evaluation after chemotherapy in patients with colorectal cancer
a retrospective pooled analysis of six phase II clinical trials, International Journal of Clinical Oncology, 10.1007/s10147-019-01509-8, 24, 11, 1397-1405, 2019.11, Background: There are several methods for analyzing computed tomography (CT) images to evaluate chemotherapy efficacy in clinical studies. However, the optimal analysis method for each drug is still under debate. We conducted a pooled analysis using data from six phase II studies to evaluate four analysis methods in colorectal cancers (CRCs): morphological responses (MRs), early tumor shrinkage (ETS), depth of response (DpR), and response evaluation criteria in solid tumors (RECIST) ver.1.1. Methods: We included 249 patients in this analysis. Pretreatments and findings of subsequent CT imaging were analyzed based on the MR, ETS, DpR, and RECIST ver.1.1. Differences in overall survival (OS) between the responders and non-responders according to each method were evaluated using survival analysis. Results: The responders had significantly better hazard ratios (HRs) for OS, in terms of DpR (≥ median), ETS, objective response rate (ORR) [complete response (CR) + partial response (PR)], and disease control rate [CR + PR + stable disease (SD)]. Patients with right-sided colon cancers showed better HRs for DpR, but not for ETS and ORR. Contrastingly, patients with left-sided CRCs had better HRs for ETS, DpR, and ORR. MR was not associated with outcomes in this study, even in cases where bevacizumab was used. In patients with liver metastasis, ETS, DpR, and ORR showed better HRs, but not in those with lung metastasis. Conclusion: Early tumor shrinkage and DpR might be predictive markers only in left-sided CRCs with liver metastasis. Each imaging analysis has a different value based on the primary and metastatic sites..
356. Shun Sasaki, Tetsuo Ikeda, Shin ichiro Okihara, Shotaro Nishimura, Ryu Nakadate, Hiroshi Saeki, Eiji Oki, Masaki Mori, Makoto Hashizume, Yoshihiko Maehara, Principles and development of collagen-mediated tissue fusion induced by laser irradiation, Scientific reports, 10.1038/s41598-019-45486-4, 9, 1, 2019.12, The mechanism underlying tissue fusion mediated by laser irradiation remains unclear. We clarify the mechanisms underlying laser-mediated tissue fusion using a novel model. Microscopic examinations of morphological changes within the adventitia of a bovine carotid artery and a collagen sheet prepared from bovine dermis showed collagen fibril bundle loosening and collagen fibre swelling following heating at 46 °C. An incised bovine carotid artery covered with a collagen sheet to which pressure and laser heat of 40 °C–52 °C were applied created a structure that was pressure resistant to >300 mmHg. Microscopic analyses of the irradiation site showed collagen fibril interdigitation. Hence, low-temperature laser-mediated tissue fusion causes collagen fibril bundles to loosen and swell, and crimping causes the fibres to intertwine. As the temperature declines, the loosened and swollen fibrils and fibres tighten, and collagen fibre interdigitation is completed. This technology could be applied to fuse tissues during surgery..
357. Yuki Kataoka, Makoto Iimori, Shinichiro Niimi, Hiroshi Tsukihara, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hiroyuki Kitao, Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level, Scientific reports, 10.1038/s41598-019-44399-6, 9, 1, 2019.12, Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because TK1-specific-deficient human cancer cell lines have not been established. Here, we generated TK1-knock-out human colorectal cancer cells using the CRISPR/Cas9 genome editing system and validated the specificity of TK1 knock-out by measuring expression of AFMID, which is encoded on the same locus as TK1. Using TK1-knock-out cells, we confirmed that TK1 is essential for cellular sensitivity to FTD. Furthermore, we demonstrated a correlation between the TK1 expression level and cytotoxicity of FTD using cells with inducible TK1 expression, which were generated from TK1-knock-out cells. Based on our finding that the TK1 expression level correlates with sensitivity to FTD, we suggest that FTD/TPI might efficiently treat cancers with high TK1 expression..
358. Satoshi Yuki, Katsunori Shinozaki, Tomomi Kashiwada, Tetsuya Kusumoto, Masaaki Iwatsuki, Hironaga Satake, Kazuma Kobayashi, Taito Esaki, Yuichiro Nakashima, Hirofumi Kawanaka, Yasunori Emi, Yoshito Komatsu, Mototsugu Shimokawa, Akitaka Makiyama, Hiroshi Saeki, Eiji Oki, Hideo Baba, Masaki Mori, Multicenter phase II study of SOX plus trastuzumab for patients with HER2+ metastatic or recurrent gastric cancer
KSCC/HGCSG/CCOG/PerSeUS 1501B, Cancer chemotherapy and pharmacology, 10.1007/s00280-019-03991-3, 85, 1, 217-223, 2020.01, Background: Trastuzumab (T-mab) combined with cisplatin and fluoropyrimidines is a standard first-line treatment for HER2+ advanced gastric cancer (AGC). We conducted the first phase II trial among four Japanese study groups to assess the efficacy and safety of T-mab + S-1 and oxaliplatin (T-SOX130) for HER2+ AGC or recurrent gastric cancer. Methods: Patients with IHC 3+ or IHC 2+/FISH+ tumors received 80 mg/m2 (80–120 mg/day) oral S-1 on days 1–14, 130 mg/m2 intravenous oxaliplatin on day 1, and intravenous T-mab (8 mg/kg loading dose, 6 mg/kg thereafter) on day 1 of a 21-day cycle. The primary endpoint was centrally assessed response rate (RR). Adverse events were based on the Common Terminology Criteria for Adverse Events (CTCAE) Ver.4.0. Results: We enrolled 42 patients from June 2015 to May 2016. Efficacy and safety analyses were conducted for 39 patients. The data cutoff was May 31, 2018. The confirmed RR was 82.1% (32/39; 90% CI 70.0–90.0); the disease control rate was 87.2% (34/39; 95% CI 73.3–94.4). Nine patients underwent curative surgery after T-SOX130. Median Time to treatment failure (TTF), Progression-free survival (PFS) and Overall survival (OS) was 5.7 (95% CI 4.6–7.0), 7.0 (95% CI 5.5–14.1), and 27.6 (95% CI 15.6–Not reached) months, respectively. Incidences of grade 3–4 adverse events > 10% were thrombocytopenia (17.9%), anorexia (17.9%), anemia (12.8%), neutropenia (10.3%), and hyponatremia (10.3%). Conclusions: T-SOX130 showed promising response and survival with a favorable safety profile and should be considered for patients with HER2+ AGC..
359. Yuichiro Nakashima, Hiroshi Saeki, Qingjiang Hu, Yasuo Tsuda, Yoko Zaitsu, Yuichi Hisamatsu, Koji Ando, Yasue Kimura, Eiji Oki, Masaki Mori, Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer, Annals of Surgical Oncology, 10.1245/s10434-019-07850-6, 27, 2, 492-498, 2020.02, Background: Postoperative changes in skeletal muscle and their influence on outcomes after esophagectomy for patients with esophageal cancer have not been fully investigated. This study aimed to confirm that postoperative skeletal muscle decrease influences long-term patient outcomes. Methods: Data were collected from 218 patients who underwent curative esophagectomy for esophageal cancer whose data were available before and 6 months after surgery. The skeletal muscle index (SMI) was measured at the level of the L3 vertebrae, and the postoperative change in the SMI compared with preoperative values was calculated as the delta SMI. Results: The mean SMI value was − 11.64%, and the median delta SMI value was − 11.88%. The first and third quartiles were defined as cutoffs, and 218 patients were classified as the mild-loss group (54 patients), moderate-loss group (110 patients), and severe-loss group (54 patients). The patients with a more severely reduced SMI had a worse prognosis (5-year overall survival rates: mild loss, 66.6%; moderate loss, 58.8%; and severe loss, 48.5%; p = 0.0314). This correlation between reduced SMI and prognosis also was observed for the patients with preoperative sarcopenia (p < 0.0001), but not for those without preoperative sarcopenia. Conclusions: Postoperative reduced SMI and worse prognosis were significantly associated in esophageal cancer patients..
360. Yuichiro Nakashima, Hiroshi Saeki, Qingjiang Hu, Yasuo Tsuda, Yoko Zaitsu, Yuichi Hisamatsu, Koji Ando, Yasue Kimura, Eiji Oki, Masaki Mori, Changing the Dissectable Layer
Novel Thoracoscopic Esophagectomy Method for Lymphadenectomy along the Left Recurrent Laryngeal Nerve, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2019.10.013, 230, 2, e1-e6, 2020.02.
361. Shinichi Tsuruta, Kenichi Kohashi, Yuichi Yamada, Minako Fujiwara, Yutaka Koga, Eikichi Ihara, Yoshihiro Ogawa, Eiji Oki, Masafumi Nakamura, Yoshinao Oda, Solid-type poorly differentiated adenocarcinoma of the stomach
Deficiency of mismatch repair and SWI/SNF complex, Cancer Science, 10.1111/cas.14301, 111, 3, 1008-1019, 2020.03, ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P =.0268, P =.0181, P =.0224, and P =.0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P =.012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA..
362. Ryosuke Tsutsumi, Tetsuo Ikeda, Hajime Nagahara, Hiroshi Saeki, Yuichiro Nakashima, Eiji Oki, Yoshihiko Maehara, Makoto Hashizume, Efficacy of Novel Multispectral Imaging Device to Determine Anastomosis for Esophagogastrostomy, Journal of Surgical Research, 10.1016/j.jss.2019.04.033, 242, 11-22, 2019.10, Background: Biomedical imaging devices that utilize the optical characteristics of hemoglobin (Hb) have become widespread. In the field of gastroenterology, there is a strong demand for devices that can apply this technique to surgical navigation. We aimed to introduce our novel multispectral device capable of intraoperatively performing quantitative imaging of the oxygen (O 2 ) saturation and Hb amount of tissues noninvasively and in real time, and to examine its application for deciding the appropriate anastomosis point after subtotal or total esophagectomy. Materials and methods: A total of 39 patients with esophageal cancer were studied. Tissue O 2 saturation and Hb amount of the gastric tube just before esophagogastric anastomosis were evaluated using a multispectral tissue quantitative imaging device. The anastomosis point was decided depending on the quantitative values and patterns of both the tissue O 2 saturation and Hb amount. Results: The device can instantaneously and noninvasively quantify and visualize the tissue O 2 saturation and Hb amount using reflected light. The tissue Hb status could be classified into the following four types: good circulation type, congestion type, ischemia type, and mixed type of congestion and ischemia. Postoperative anastomotic failure occurred in 2 cases, and both were mixed cases. Conclusions: The method of quantitatively imaging the tissue O 2 saturation and Hb level in real time and noninvasively using a multispectral device allows instantaneous determination of the anastomosis and related organ conditions, thereby contributing to determining the appropriate treatment direction..
363. Shinichi Tsuruta, Yoshihiro Ohishi, Minako Fujiwara, Eikichi Ihara, Yoshihiro Ogawa, Eiji Oki, Masafumi Nakamura, Yoshinao Oda, Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist, Human Pathology, 10.1016/j.humpath.2019.03.006, 88, 27-38, 2019.06, The Cancer Genome Atlas Research Network classified gastric adenocarcinoma into four molecular subtypes: (1) Epstein-Barr virus–positive (EBV), (2) microsatellite-instable (MSI), (3) chromosomal instable (CIN), and (4) genomically stable (GS). The molecular subtypes of gastric hepatoid adenocarcinomas are still largely unknown. We analyzed 52 hepatoid adenocarcinomas for the expression of surrogate markers of molecular subtypes (MLH1, p53, and EBER in situ hybridization) and some biomarkers (p21, p16, Rb, cyclin D1, cyclin E, β-catenin, Bcl-2, IMP3, ARID1A and HER2), and mutations of TP53, CTNNB1, KRAS, and BRAF. We analyzed 36 solid-type poorly differentiated adenocarcinomas as a control group. Hepatoid adenocarcinomas were categorized as follows: EBV group (EBER-positive), no cases (0%); MSI group (MLH1 loss), three cases (6%); “CIN or GS” (CIN/GS) group (EBER-negative, MLH1 retained), 49 cases (94%). In the CIN/GS group, most of the tumors (59%) had either p53 overexpression or TP53 mutation and a coexisting tubular intestinal-type adenocarcinoma component (90%), suggesting that most hepatoid adenocarcinomas should be categorized as a true CIN group. Hepatoid adenocarcinomas showed relatively frequent expressions of HER2 (score 3+/2+: 21%/19%). Hepatoid adenocarcinomas showed shorter survival, more frequent overexpressions of p16 (67%) and IMP3 (98%) than the control group. None of hepatoid adenocarcinomas had KRAS or CTNNB1 mutations except for one case each, and no hepatoid adenocarcinomas had BRAF mutation. In conclusion, gastric hepatoid adenocarcinomas are a genetically heterogenous group. Most hepatoid adenocarcinomas are “CIN,” but a small number of hepatoid adenocarcinomas with MSI do exist. Hepatoid adenocarcinomas are characterized by overexpressions of p16 and IMP3..
364. Daisuke Hashimoto, Kota Arima, Shigeki Nakagawa, Yuji Negoro, Toshihiko Hirata, Masahiko Hirota, Masafumi Inomata, Kengo Fukuzawa, Takefumi Ohga, Hiroshi Saeki, Eiji Oki, Yo ichi Yamashita, Akira Chikamoto, Hideo Baba, Yoshihiko Maehara, Pancreatic cancer arising from the remnant pancreas after pancreatectomy
a multicenter retrospective study by the Kyushu Study Group of Clinical Cancer, Journal of gastroenterology, 10.1007/s00535-018-01535-9, 54, 5, 437-448, 2019.05, Background: After initial pancreatic resection, local recurrence of pancreatic cancer (PC) or new primary PC can develop in the remnant. There are limited data available regarding this so-called remnant PC. The aim of this retrospective study was to clarify the clinical features and establish a treatment strategy for remnant PC. Methods: A multicenter retrospective study with the Kyushu Study Group of Clinical Cancer was carried out. Clinical data from 50 patients who developed remnant PC were analyzed. RAS mutation analysis of the initial tumor and of remnant PC was performed in 17 cases. Results: The initial pancreatic resections were performed for 37 invasive ductal carcinomas, and for 13 other tumors. Thirty-seven patients underwent a second pancreatectomy for remnant PC (resected group), while thirteen patients were not operated (unresected group). The median overall survival times were 42.2 months in the resected group and 12.3 months in the unresected group (HR 0.374; 95% CI 0.17–0.83). In RAS mutation analysis, 14 cases had at least 1 missense variant of KRAS, HRAS, or NRAS in the initial pancreatic tumor and/or remnant PC. The same missense variants between the initial tumor and remnant PC were discovered only in KRAS of one patient, and in HRAS of one patient. No case had completely consistent missense variants between the initial tumor and remnant PC. Conclusions: This study found that repeated pancreatectomy for remnant PC can prolong patient survival, and RAS mutation analysis indicated that many remnant PCs are developed from metachronous multifocal origins..
365. Kensuke Kudou, Hiroshi Saeki, Yuichiro Nakashima, Koichi Kimura, Kouji Andou, Eiji Oki, Tetsuo Ikeda, Yoshihiko Maehara, Postoperative Skeletal Muscle Loss Predicts Poor Prognosis of Adenocarcinoma of Upper Stomach and Esophagogastric Junction, World journal of surgery, 10.1007/s00268-018-4873-6, 43, 4, 1068-1075, 2019.04, Background: The relationship between postoperative changes in muscle mass and the prognosis of malignancies remains controversial. We aimed to determine whether a decrease in skeletal muscle mass after surgical resection can predict long-term outcomes in patients with adenocarcinoma of upper stomach (AUS) and esophagogastric junction (AEGJ). Methods: We reviewed 146 patients who underwent curative surgery for AUS and AEGJ. We assessed the skeletal muscle index pre- and post-surgery and 6 months postoperatively. The rate of decrease in skeletal muscle index (SMI) was calculated and its relationship with clinicopathological factors and prognosis was analyzed. Results: Among the 146 patients studied, 115 underwent re-assessment of SMI 6 months postoperatively. The mean decrease in SMI was more prominent in patients with recurrence than in those without recurrence (19.0 ± 2.3 vs. 7.4 ± 0.9%, respectively, P < 0.0001). AUS and AEGJ patients with a >19% decrease in SMI showed significantly lower 5-year overall survival and recurrence-free rates than those with a <19% decrease in SMI (recurrence-free survival: 33.4 vs. 89.2%, respectively, P < 0.0001; overall survival: 40.6 vs. 90.0%, respectively, P < 0.0001). Multivariate analyses indicated that a ≥19% decrease in SMI could predict poor overall survival independently in patients with AUS and AEGJ (P = 0.0070). Conclusions: A ≥19% postoperative decrease in SMI was substantially associated with poor survival in patients with AUS and AEGJ..
366. Kensuke Kudou, Hiroshi Saeki, Yuichiro Nakashima, Shun Sasaki, Tomoko Jogo, Kosuke Hirose, Qingjiang Hu, Yasuo Tsuda, Koichi Kimura, Ryota Nakanishi, Nobuhide Kubo, Kouji Andou, Eiji Oki, Tetsuo Ikeda, Yoshihiko Maehara, Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer, American Journal of Surgery, 10.1016/j.amjsurg.2018.07.003, 217, 4, 757-763, 2019.04, Background: There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC). Methods: Patients with AEG and UGC who were judged as non-sarcopenic before surgery were reassessed the presence of postoperative development of sarcopenia 6 months after surgery. Patients were divided into the development group or non-development group, and clinicopathological factors and prognosis between these two groups were analyzed. Results: The 5-year overall survival rates were significantly poorer in the development group than non-development group (68.0% vs. 92.6%, P = 0.0118). Multivariate analyses showed that postoperative development of sarcopenia was an independent prognostic factor for poor overall survival (P = 0.0237). Conclusions: Postoperative development of sarcopenia was associated with a poor prognosis in patients with AEG and UGC..
367. Ken Kato, Taroh Satoh, Kei Muro, Takaki Yoshikawa, Takao Tamura, Yasuo Hamamoto, Keisho Chin, Keiko Minashi, Masahiro Tsuda, Kensei Yamaguchi, Nozomu Machida, Taito Esaki, Masahiro Goto, Yoshito Komatsu, Takako Eguchi Nakajima, Naotoshi Sugimoto, Kazuhiro Yoshida, Eiji Oki, Tomohiro Nishina, Akihito Tsuji, Hirofumi Fujii, Kenji Kunieda, Soh Saitoh, Yasushi Omuro, Mizutomo Azuma, Yasuo Iwamoto, Keisei Taku, Sachio Fushida, Li Tzong Chen, Yoon Koo Kang, Narikazu Boku, A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2), Gastric Cancer, 10.1007/s10120-018-0899-6, 22, 2, 344-354, 2019.03, Background: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. Methods: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6–7.4 versus 3.6 months, 95% CI 2.8–5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42–0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. Conclusions: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials..
368. Eiji Oki, Mototsugu Shimokawa, Kouji Andou, Akihiko Murata, Takao Takahashi, Kiyoshi Maeda, Tetsuya Kusumoto, Yoshinori Munemoto, Ryota Nakanishi, Yuichiro Nakashima, Hiroshi Saeki, Yoshihiko Maehara, Effect of lateral lymph node dissection for mid and low rectal cancer
An ad-hoc analysis of the ACTS-RC (JFMC35-C1) randomized clinical trial, Surgery (United States), 10.1016/j.surg.2018.08.027, 165, 3, 586-592, 2019.03, Background: Lateral lymph node dissection has been 1 of the standard treatments for mid and ow rectal cancer in Japan. The aim of this ad-hoc analysis was to evaluate the impact of lateral lymph node dissection on outcomes in the randomized clinical trial, referred to as the Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial. Methods: The Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial was a randomized, phase III trial of adjuvant chemotherapy of 2 different oral fluoropyrimidines; 445 patients with lower rectal cancer were studied in this ad-hoc analysis out of 959 patients in total, 215 of whom underwent lateral lymph node dissection and 230 did not. Results: There were no significant differences in background characteristics of the patients in the group, except for in age and number of dissected lymph nodes, between the lateral lymph node dissection and without lateral lymph node dissection groups. The age of the younger patients was often used to select candidates for lateral lymph node dissection (lateral lymph node dissection versus non–lateral lymph node dissection; 63.5 ± 8.9 vs 60.7 ± 9.4 [P =.0017]). Lateral lymph node dissection had no impact on relapse-free survival (hazard ratio = 0.941, 95% confidence interval: 0.696–1.271) or overall survival (hazard ratio = 0.858, 95% confidence interval: 0.601–1.224) in all patients with mid and low rectal cancer. In subset analysis, lateral lymph node dissection improved relapse-free survival in female patients and in patients with stage B/C or N3/4 disease. For cumulative recurrence across all patients, the proportion of patients with distant recurrence was slightly greater in the lateral lymph node dissection group but there was no difference in local recurrence. Conclusion: This exploratory analysis did not show that lateral lymph node dissection improves relapse-free survival and overall survival in patients with mid and low rectal cancer. Lateral lymph node dissection may, however, have a prognostic impact on patients with highly invasive rectal cancer..
369. Tadamichi Denda, Daisuke Sakai, Tetsuya Hamaguchi, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Fumio Nagashima, Toshikazu Moriwaki, Taito Esaki, Takeo Sato, Michio Itabashi, Eiji Oki, Toru Sasaki, Yoshinori Sunaga, Samira Ziti-Ljajic, Claire Brillac, Takayuki Yoshino, Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer, Cancer Science, 10.1111/cas.13943, 110, 3, 1032-1043, 2019.03, Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868..
370. Yu Nakaji, Hiroshi Saeki, Kensuke Kudou, Ryota Nakanishi, Masahiko Sugiyama, Yuichiro Nakashima, Kouji Andou, Yoshinao Oda, Eiji Oki, Yoshihiko Maehara, Short- and long-term outcomes of surgical treatment for remnant gastric cancer after distal gastrectomy, Anticancer research, 10.21873/anticanres.13256, 39, 3, 1411-1415, 2019.03, Background/Aim: Remnant gastric cancer (RGC) after distal gastrectomy occurs in 1-2% of patients, while the biological features of RGC are unknown. Patients and Methods: A total of 22 consecutive patients with RGC who underwent total gastrectomy were analyzed. Their disease history included either gastric cancer (n=16) or peptic ulcer (n=6). Overall, 18 underwent open total gastrectomy (OTG) and 4 underwent laparoscopic total gastrectomy (LTG). Results: The mean number of lymph nodes dissected and metastatic lymph nodes was larger in the Ulcer group than in the Carcinoma group (p<0.005). The mean operation time was longer in the LTG than OTG (p<0.005). The median blood loss tended to be smaller in the LTG (p=0.090). Five-year overall and recurrence-free survival rates were 94% and 81%, respectively. Conclusion: The status of lymph node metastasis after surgery for RGC should be cautiously considered in the context of disease history. Both LTG and OTG can be treatment options for RGC..
371. Kensuke Kudou, Hiroshi Saeki, Yuichiro Nakashima, Tomohiro Kamori, Tetsuro Kawazoe, Yasuhiro Haruta, Yoshiaki Fujimoto, Hiroya Matsuoka, Shun Sasaki, Tomoko Jogo, Kosuke Hirose, Qingjiang Hu, Yasuo Tsuda, Koichi Kimura, Kouji Andou, Eiji Oki, Tetsuo Ikeda, Yoshihiko Maehara, C-reactive protein/albumin ratio is a poor prognostic factor of esophagogastric junction and upper gastric cancer, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.14442, 34, 2, 355-363, 2019.02, Background and Aim: The C-reactive protein (CRP)/albumin (Alb) ratio has been reported as a novel prognostic marker in several cancers. The objective of this study was to investigate the prognostic value of the CRP/Alb ratio in patients who underwent surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC). Methods: Data for 144 patients who underwent surgery for AEG and UGC were reviewed. The CRP/Alb ratio, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, Glasgow Prognostic Score, and controlling nutritional status score were calculated, and the relationship between these biomarkers and postoperative prognosis was analyzed. Results: The optimal cutoff value of the CRP/Alb ratio was determined to be 0.1. According to the cutoff value of CRP/Alb ratio, patients were divided into two groups (CRP/Alb < 0.1, n = 124; CRP/Alb ≥ 0.1, n = 20). The 5-year recurrence-free survival and overall survival (OS) rates were significantly lower in the patients with the CRP/Alb ratio ≥ 0.1 than in those with the CRP/Alb ratio < 0.1 (recurrence-free survival: 44.9% vs 77.9%, P = 0.0011; OS: 43.4% vs 82.0%, P < 0.0001). In the multivariate analyses, the N-stage, and CRP/Alb ratio ≥ 0.1 were identified as independent predictive factors for OS in patients with AEG and UGC (P = 0.0061 and P = 0.0439, respectively). Conclusions: The CRP/Alb ratio was strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC..
372. K. Shitara, T. Yamanaka, T. Denda, Y. Tsuji, K. Shinozaki, Y. Komatsu, Y. Kobayashi, J. Furuse, H. Okuda, M. Asayama, K. Akiyoshi, Y. Kagawa, T. Kato, Eiji Oki, T. Ando, Y. Hagiwara, Y. Ohashi, T. Yoshino, Reverce
A randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients, Annals of Oncology, 10.1093/annonc/mdy526, 30, 2, 259-265, 2019.02, Background The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. Patients and methods Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. Results One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. Conclusions The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence..
373. Yoshiaki Nakamura, Takeharu Yamanaka, Keisho Chin, Haruhiko Cho, Hitoshi Katai, Masanori Terashima, Kazunari Misawa, Motohiro Hirao, Kazuhiro Yoshida, Eiji Oki, Mitsuru Sasako, Yasunori Emi, Hideaki Bando, Yoshiyuki Kawashima, Tetsu Fukunaga, Masahiro Gotoh, Takako Ishibashi, Kohei Shitara, Survival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy, Annals of Surgical Oncology, 10.1245/s10434-018-7063-8, 26, 2, 465-472, 2019.02, Background: Two phase 2 trials of oxaliplatin-containing adjuvant therapy for patients with gastric cancer (GC) after D2 gastrectomy were conducted in Japan. The SOXaGC trial evaluated the tolerability and safety of adjuvant therapy with S-1 plus oxaliplatin (SOX), whereas the J-CLASSIC trial evaluated the feasibility of adjuvant therapy with capecitabine plus oxaliplatin (CAPOX). Because both were studies that did not evaluate survival results as study end points, the authors evaluated the survival outcomes for the patients in the two trials. Methods: All 62 and 100 patients in the full analysis set of the SOXaGC and J-CLASSIC trials, respectively, were included in the current study. Their information about survival outcome was collected. The primary end point was relapse-free survival (RFS), and the secondary end point was overall survival (OS). Results: For the pathologic stage (pStage 2) patients treated with CAPOX, the 3-year RFS rate was 87.8% and the 3-year OS rate was 92.7%. For the pStage 3 patients treated with SOX and CAPOX, the 3-year RFS rates were respectively 70.9% and 67.8% (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.50–1.72), whereas the 3-year OS rates were respectively 75.7% and 79.3% (HR, 1.10; 95% CI, 0.54–2.26). Subgroup analysis showed significant interactions between the treatment (SOX vs. CAPOX) and both sex (male vs. female; P = 0.024) and histologic type (diffuse vs. other, P = 0.069). Conclusions: This exploratory analysis demonstrated that SOX and CAPOX are suggested to have similar efficacy for pStage 3 GC patients after D2 gastrectomy. Differences in the treatment effect according to sex and histologic type warrant further evaluation..
374. Hideaki Bando, Yoshinori Kagawa, Takeshi Kato, Kiwamu Akagi, Tadamichi Denda, Tomohiro Nishina, Yoshito Komatsu, Eiji Oki, Toshihiro Kudo, Hiroshi Kumamoto, Takeharu Yamanaka, Takayuki Yoshino, A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer, British journal of cancer, 10.1038/s41416-019-0457-y, 2019.01, Background: OncoBEAM
TM
RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA. Methods: mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma- and tissue-based RAS mutational status were determined by BEAMing, respectively. Results: A total of 280 patients from eight institutions were eligible. The overall agreement between plasma- and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma- and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma- and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions. Conclusion: The clinical validity of OncoBEAM
TM
RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions..
375. Akihiro Nishie, Yoshiki Asayama, Kosei Ishigami, yasuhiro ushijima, Yukihisa Takayama, Daisuke Okamoto, nobuhiro fujita, Daisuke Tsurumaru, Osamu Togao, Koji Sagiyama, Tatsuya Manabe, Eiji Oki, yuichiro kubo, Tomoyuki Hida, Minako Hirahashi-Fujiwara, Jochen Keupp, Hiroshi Honda, Amide proton transfer imaging to predict tumor response to neoadjuvant chemotherapy in locally advanced rectal cancer, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.14315, 34, 1, 140-146, 2019.01, Background and Aim: The amount of proteins and peptides can be estimated with amide proton transfer (APT) imaging. Previous studies demonstrated the usefulness of APT imaging to predict tumor malignancy. We determined whether APT imaging can predict the tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced rectal cancer (LARC). Methods: Seventeen patients with LARC who underwent a pretherapeutic magnetic resonance examination including APT imaging and NAC (at least two courses) were enrolled. The APT-weighted imaging (WI) signal intensity (SI) (%) was defined as magnetization transfer ratio asymmetry (MTR
asym
) at the offset of 3.5 ppm. Each tumor was histologically evaluated for the degree of degeneration and necrosis and then classified as one of five histological Grades (0, none; 1a, less than 1/3; 1b, 1/3 to 2/3; 2, more than 2/3; 3, all). We compared the mean APTWI SIs of the tumors between the Grade 0/1a/1b (low-response group) and Grade 2/3 (high-response group) by Student's t-test. We used receiver operating characteristics curves to determine the diagnostic performance of the APTWI SI for predicting the tumor response. Results: The mean APTWI SI of the low-response group (n = 12; 3.05 ± 1.61%) was significantly higher than that of the high-response group (n = 5; 1.14 ± 1.13%) (P = 0.029). The area under the curve for predicting the tumor response using the APTWI SI was 0.87. When ≥2.75% was used as an indicator of low-response status, 75% sensitivity and 100% specificity of the APTWI SI were obtained. Conclusion: Pretherapeutic APT imaging can predict the tumor response to NAC in patients with LARC..
376. Shun Sasaki, Eiji Oki, Hiroshi Saeki, Takayuki Shimose, Sanae Sakamoto, Qingjiang Hu, Kensuke Kudo, Yasuo Tsuda, Yuichiro Nakashima, Kouji Andou, Yoshito Akagi, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Skeletal muscle loss during systemic chemotherapy for colorectal cancer indicates treatment response
a pooled analysis of a multicenter clinical trial (KSCC 1605-A), International Journal of Clinical Oncology, 10.1007/s10147-019-01460-8, 2019.01, Background: Sarcopenia or degenerative loss of skeletal muscle mass is related to poor prognosis in patients with cancer. This study aimed to clarify the clinical significance of skeletal muscle loss (SML) during chemotherapy for metastatic colorectal cancer (mCRC). Methods: A total of 249 patients who were secondarily registered in a pooled database of mCRC patients with the first-line systemic chemotherapy and prospectively enrolled in six clinical trials of Kyushu Study Group of Clinical Cancer were included in this study. Skeletal muscle area was calculated from computed tomography images before and 3 and 6 months after treatment. Baseline sarcopenia and SML (cut-off value = 9%) were evaluated. Results: Baseline sarcopenia was observed in 135 of 219 patients who were evaluated before treatment. They tended to be male; older; and have lower body mass index, lower visceral and subcutaneous fat contents, and a lower waist circumference (P < 0.01); however, baseline sarcopenia was not associated with prognosis. SML at 3 months was associated with an incidence of adverse events (P = 0.01), poor objective response rate (ORR) (P < 0.01), and poor progression-free survival (PFS) (P = 0.03), and it was an independent predictive factor for poor ORR (P < 0.01) and PFS (P = 0.04). Conclusion: SML at 3 months after systemic chemotherapy for mCRC was associated with poor treatment response. Thus, clarifying the importance of SML prevention guarantees a more effective chemotherapy..
377. Seijiro Sato, Masayuki Nagahashi, Terumoto Koike, Hiroshi Ichikawa, Yoshifumi Shimada, Satoshi Watanabe, Toshiaki Kikuchi, Kazuki Takada, Ryota Nakanishi, Eiji Oki, Tatsuro Okamoto, Kouhei Akazawa, Stephen Lyle, Yiwei Ling, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai, Masanori Tsuchida, Impact of Concurrent Genomic Alterations Detected by Comprehensive Genomic Sequencing on Clinical Outcomes in East-Asian Patients with EGFR-Mutated Lung Adenocarcinoma, Scientific Reports, 10.1038/s41598-017-18560-y, 8, 1, 2018.12, Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease..
378. Daisuke Taniguchi, Hiroshi Saeki, Yuichiro Nakashima, Kensuke Kudou, Ryota Nakanishi, Nobuhide Kubo, Kouji Andou, Eiji Oki, Yoshinao Oda, Yoshihiko Maehara, CD44v9 is associated with epithelial-mesenchymal transition and poor outcomes in esophageal squamous cell carcinoma, Cancer Medicine, 10.1002/cam4.1874, 7, 12, 6258-6268, 2018.12, CD44 serves as a marker of cancer stem cells. Alternative splicing generates the CD44v9 isoform. Cancer stem cells are associated with the epithelial-mesenchymal transition in cancers, although little is known about their role in esophageal squamous cell carcinoma. Here, we aimed to clarify the relationship between CD44v9 expression, the epithelial-mesenchymal transition, and clinicopathological features of patients with esophageal squamous cell carcinoma. CD44v9 levels were higher at the tumor invasive front compared with the center of the tumor and higher in metastatic lymph nodes compared with primary tumors. High levels of CD44v9 at the tumor invasive front were significantly associated with deeper tumor invasion and shorter overall survival and recurrence-free survival. The expression of CD44v9 was increased by treatment with transforming growth factor-β, which induced esophageal squamous cell carcinoma cells to undergo the epithelial-mesenchymal transition. Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells. These results indicate that the expression of CD44v9 at the tumor invasive front induced by stemness was strongly associated with the epithelial-mesenchymal transition and poor prognosis of patients with esophageal squamous cell carcinoma. CD44v9 may therefore serve as a novel prognostic biomarker and a potential therapeutic target for esophageal squamous cell carcinoma..
379. Shinkichi Takamori, Kazuki Takada, Tetsuzo Tagawa, Gouji Toyokawa, Fumihiko Hirai, Nami Yamashita, Tatsuro Okamoto, Eiji Oki, Tomoharu Yoshizumi, Yoshinao Oda, Yoshihiko Maehara, Differences in PD-L1 expression on tumor and immune cells between lung metastases and corresponding primary tumors, Surgical Oncology, 10.1016/j.suronc.2018.08.001, 27, 4, 637-641, 2018.12, Background: It has been reported that the tumor microenvironment, including tumor-associated immune cells (ICs) and programmed cell death-ligand 1 (PD-L1) expression, differs between primary and metastatic tumors. This study aimed to elucidate the differences in PD-L1 expression on tumor cells (TCs) and ICs between lung metastases and corresponding primary tumors. Methods: We analyzed paired lesions from 44 patients diagnosed with lung metastases between 2005 and 2017 at Kyushu University. The percentages of PD-L1-positive TCs and ICs in lung metastases and the primary tumor were classified into five categories (0: <1%; 1: 1%–4%; 2: 5%–9%; 3: 10%–49%; and 4: ≥50%). Lesions in which ≥1% of the TCs and ICs were PD-L1-positive were considered positive. Results: The primary cancers included rectal (n = 19), colon (n = 10), liver (n = 10), bile duct (n = 2), stomach (n = 1), gall bladder (n = 1) and breast (n = 1). Discrepancies in PD-L1 expression on TCs and ICs between lung metastases and primary lesions were observed in 5 (11.4%, κ = 0.23) and 9 (20.5%, κ = 0.11) of the 44 cases, respectively. PD-L1 expression on ICs was higher in lung metastases than paired primary tumors (p = 0.026), although the percentage of PD-L1-positive TCs was not significantly different between lung metastases and primary tumors (p = 0.767). Conclusions: There were significant differences in PD-L1 expression on TCs and ICs between lung metastases and primary tumors. Clinicians should be aware of these differences in the tumor microenvironment when treating patients with immunotherapy..
380. Yuichiro Nakashima, Hiroshi Saeki, Qingjiang Hu, Yasuo Tsuda, Yuichi Hisamatsu, Kouji Andou, Eiji Oki, Yoshihiko Maehara, Neoadjuvant chemotherapy versus chemoradiotherapy for patients with esophageal squamous cell carcinoma, Anticancer research, 10.21873/anticanres.13053, 38, 12, 6809-6814, 2018.12, Aim: To confirm the superiority of neoadjuvant chemoradiotherapy (NACRT) over neoadjuvant chemotherapy (NAC) as preoperative therapy for locally advanced esophageal cancer. Patients and Methods: A total of 298 patients with resectable esophageal cancer were initially enrolled; 62 patients received NAC and 236 patients received NACRT. Propensity score matching was applied to create a study cohort. Results: Postoperative 30-day mortality rate, overall postoperative complication rate, and overall survival time did not differ between those groups. Complete pathological response occurred in one patient treated with NAC and 16 treated with NACRT (p<0.001). In patients with borderline-resectable T4 disease, overall survival was superior in the NACRT group compared to that in the NAC group (p=0.040). Conclusion: No survival advantage was observed between NAC and NACRT groups. Limited to patients with borderline-resectable T4, NACRT achieved a higher rate of primary tumor volume reduction and R0 resection, and a more favorable prognosis compared to NAC..
381. , Hiroshi Saeki, Eiji Oki, Tomomi Kashiwada, Takaaki Arigami, Akitaka Makiyama, Masaaki Iwatsuki, Yukiya Narita, Hironaga Satake, Yoshiko Matsuda, Hideto Sonoda, Mototsugu Shimokawa, Yoshihiko Maehara, Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604), European Journal of Cancer, 10.1016/j.ejca.2018.09.024, 105, 41-49, 2018.12, Background: Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods: Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. Results: Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion: Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing..
382. Yu Imamura, Masayuki Watanabe, Tasuku Toihata, Manabu Takamatsu, Hiroshi Kawachi, Ikumi Haraguchi, Yoko Ogata, Naoya Yoshida, Hiroshi Saeki, Eiji Oki, Kenichi Taguchi, Manabu Yamamoto, Masaru Morita, Shinji Mine, Naoki Hiki, Hideo Baba, Takeshi Sano, Recent incidence trend of surgically resected esophagogastric junction adenocarcinoma and microsatellite instability status in Japanese patients, Digestion, 10.1159/000494406, 99, 1, 6-13, 2018.12, Background: The incidence trend of esophagogastric junction (EGJ) adenocarcinoma in Japan has not been sufficiently investigated. Little is known about the microsatellite instability (MSI) status of this tumor. Summary: Previously published studies analyzing the trend of EGJ adenocarcinoma in Japan were reviewed. And a trend of surgically resected cases (Siewert type I-III) utilizing a retrospective multicenter cohort of 379 patients from 4 academic institutions in Japan investigated. Although an increasing trend in the last 2 reports was considered controversial, our cohort demonstrated a growing number of EGJ adenocarcinoma cases between 2006 and 2013. This trend was evident, especially in Siewert type I cases. In the previous 16 studies that performed MSI testing, MSI-high tumors ranged 0-8.3%, though there were no fixed microsatellite markers on EGJ adenocarcinoma. In a recent comprehensive genetic analysis by The Cancer Genome Atlas, MSI testing using the following 7 markers, BAT25, BAT26, BAT40, D2S123, D5S346, D17S250 and TGFR-II showed a favorable correlation with hypermutated tumors. We performed MSI testing using 6 of those markers, except TGFR-II, on 206 cases from one institution, and detected 15 cases (7.3%) with MSI-high. The prevalence of MSI-high was 0% in Siewert type I, 7.6% in type II, and 16.7% in type III. Key message: The number of surgically resected EGJ adenocarcinoma cases gradually increased, and MSI-high was infrequent in Siewert type I-II tumors in our Japanese cohort. Considering MSI-high as a predictive biomarker for emerging immune checkpoint inhibitors, MSI status is becoming more beneficial in EGJ adenocarcinoma..
383. Kenji Tsuchihashi, Mamoru Ito, Toshikazu Moriwaki, Shota Fukuoka, Hiroya Taniguchi, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Kenji Katsumata, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Hiroyuki Okuyama, Daisuke Sakai, Hideki Ueno, Takao Tamura, Kimihiro Yamashita, Junji Kishimoto, Yasuhiro Shimada, Eishi Baba, Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer, Clinical Colorectal Cancer, 10.1016/j.clcc.2018.07.004, 17, 4, e687-e697, 2018.12, The survival and safety of patients with metastatic colorectal cancer treated with trifluridine/tipiracil or regorafenib as later-line chemotherapy were retrospectively examined according to the modified Glasgow Prognostic Score (mGPS). Overall and progression-free survival were strongly correlated with mGPS in all patients. The frequency of adverse events was generally similar in each mGPS group. Background: Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. Patients and Methods: A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared. Results: The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2-11.6 months), 6.5 months (95% CI, 5.3-7.1 months), and 3.9 months (95% CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1-3.0 months), 2.0 months (95% CI, 1.9-2.3 months), and 1.7 months (95% CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P <.001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95% CI, 0.93-2.25; P =.097; PFS: hazard ratio, 1.57, 95% CI, 1.01-2.44; P =.047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS. Conclusions: The mGPS before later-line chemotherapy is strongly correlated with survival in patients with mCRC..
384. Tomohiro Shibata, Eriko Tokunaga, Satoshi Hattori, Kosuke Watari, Yuichi Murakami, Nami Yamashita, Eiji Oki, Junji Itou, Masakazu Toi, Yoshihiko Maehara, Michihiko Kuwano, Mayumi Ono, Y-box binding protein YBX1 and its correlated genes as biomarkers for poor outcomes in patients with breast cancer, Oncotarget, 9, 98, 37216-37228, 2018.12, The enhanced expression of the Y-box binding protein YBX1 is consistently correlated with poor outcomes or reduced survival of breast cancer patients. However, the mechanism underlying the association between increased YBX1 expression and poor outcomes has yet to be revealed. We searched a database for the top 500 genes that are positively or negatively correlated with YBX1 and with ESR1 in breast cancer patients. We further examined the association between YBX1-correlated genes and breast cancer outcomes in patients at Kyushu University Hospital. More than 60% of genes that are positively correlated with YBX1 are also negatively correlated with ESR1. The enhanced expression levels of the top 20 positively correlated genes mostly predict negative outcomes, while the enhanced expression levels of the top 20 negatively correlated genes mostly predict positive outcomes. Furthermore, in breast cancer patients at Kyushu University Hospital, the expression levels of YBX1 and YBX1-positively correlated genes were significantly higher and the expression levels of genes negatively correlated with YBX1 were significantly lower in patients who relapsed after their primary surgery than in those who did not relapse. The expression of YBX1 together with the expression of its positively or negatively correlated genes may help to predict outcomes as well as resistance to endocrine therapies in breast cancer patients. Determining the expression of YBX1 and its closely correlated genes will contribute to the development of precision therapeutics for breast cancer..
385. Hiroshi Saeki, Yuichiro Nakashima, Kosuke Hirose, Shun Sasaki, Tomoko Jogo, Daisuke Taniguchi, Keitaro Edahiro, Shotaro Korehisa, Kensuke Kudou, Ryota Nakanishi, Nobuhide Kubo, Kouji Andou, Akira Kabashima, Eiji Oki, Yoshihiko Maehara, “Energy-less technique” with mini-clips for recurrent laryngeal nerve lymph node dissection in prone thoracoscopic esophagectomy for esophageal cancer, American Journal of Surgery, 10.1016/j.amjsurg.2017.10.033, 216, 6, 1212-1214, 2018.12, Background: Meticulous recurrent laryngeal nerve (RLN) lymph node dissection in thoracoscopic esophagectomy for esophageal cancer often results in RLN paralysis. Methods: We had attempted to simply cut the vessels around RLN sharply with scissors without using energy device in order to prevent RLN paralysis. However, these procedures often result in minor bleeding. Since we introduced the use of mini-clips for hemostasis before cutting the vessels with scissors, we herein compared the surgical results between before and after the introduction of use of mini-clips. Results: With regard to RLN paralysis, the incidence was 24.0% in the before group; this incidence went down to 5.1% in the after group (P = 0.0259). Moreover, length of hospital stay after surgery was significantly shortened, from 36.1 days to 22.0 days, after the introduction of energy-less techniques with mini-clips (P = 0.0075). Conclusions: Our data demonstrated that this technique contributed to prevent RLN paralysis and to shorten the patient's length of hospital stay..
386. Eisuke Kawakubo, Takuya Matsumoto, Keiji Yoshiya, Sho Yamashita, Tomoko Jogo, Hiroshi Saeki, Eiji Oki, Tadashi Furuyama, Yoshinao Oda, Yoshihiko Maehara, BUBR1 insufficiency is correlated with eNOS reduction experimentally in vitro and in vivo, and in gastric cancer tissue, Anticancer research, 10.21873/anticanres.12960, 38, 11, 6099-6106, 2018.11, Background/Aim: Budding uninhibited by benzimidazole-related 1 (BUBR1) and endothelial nitric oxide synthase (eNOS) are related to aging and angiogenesis. This study examined the effect of low BUBR1 expression on eNOS expression in vivo, in vitro, and human gastric cancer tissues. Materials and Methods: Human umbilical vein endothelial cells (HUVECs) were passaged to investigate the effect of aging on BUBR1 and eNOS expression; expression of eNOS and phospho-eNOS protein was assessed in BUBR1 siRNAtransfected HUVECs. Additionally, guanosine 3′,5′ cyclic monophosphate (cGMP) and eNOS protein levels were measured in BUBR1-insufficient mice (Bubr1L/-). BUBR1 and eNOS expression levels were also evaluated in human gastric cancer tissues. Results: BUBR1 and eNOS, but not p-eNOS, levels were reduced significantly in aged and BUBR1 siRNAtransfected HUVECs. Additionally, cGMP production and the eNOS protein level were reduced in Bubr1L/- mice. Human gastric cancer tissues with low BUBR1 expression showed no eNOS expression. Conclusion: A decrease in BUBR1 reduced eNOS bioavailability through a pathway other than eNOS phosphorylation..
387. Sei Shu, Makoto Iimori, Ryota Nakanishi, Tomoko Jogo, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Changes in HER2 expression and amplification status following preoperative chemotherapy for gastric cancer, In Vivo, 10.21873/invivo.11405, 32, 6, 1491-1498, 2018.11, Background: It is essential to establish a strategy for second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer; however, HER2 expression status after chemotherapy treatment is not routinely determined. Materials and Methods: We analyzed 25 cases of gastric cancer that received preoperative chemotherapy and selected the six pre-treatment samples that were HER2- positive. Pre- and post-treatment tumor samples were examined for HER2 expression, and for HER2, epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (MET) gene amplification. Results: Three patients had been treated with trastuzumab plus chemotherapy, and three patients with cytotoxic chemotherapy alone. Only one case that had an initial HER2 score of 3+ and had received trastuzumab plus chemotherapy remained HER2-positive after treatment. Decrease or loss of HER2 expression and amplification was observed in the other five patients. Amplification of EGFR or MET was not observed in any preor post-treatment specimens. Conclusion: Our data suggest that trastuzumab plus chemotherapy or chemotherapy alone may induce loss of HER2 positivity..
388. Yumiko Kinoshita, Rieko Izukura, Mami Miyazono, Shuntaro Nagai, Eiji Oki, Maki Kanaoka, Hisako Nakao, Akiko Chishaki, Ryuichi Mibu, Effect of age factors on health-related quality of life in patients with lower rectal cancer after sphincter-saving surgery
A 1-year longitudinal study, Archives of Gerontology and Geriatrics, 10.1016/j.archger.2018.09.004, 79, 185-191, 2018.11, Purpose: To examine age-related factors influencing health-related quality of life (HR-QOL) among patients with lower rectal cancer during the 12-month period after sphincter-saving surgery (SSS). Material and methods: In this 1-year longitudinal study, 137 patients (120 patients completed, and 82 aged ≥60 years) answered the European Organization for Research and Treatment of Cancer questionnaire (EORTC-C30/CR38) assessing their HR-QOL and related factors during the 12 months after SSS. Results: No significant differences in HR-QOL were found before surgery. Only among those aged ≥60 years, global health status/QOL and cognitive functioning showed a significant decrease one month after surgery. At one month after SSS, the role functioning of groups <60 years old (which is negatively related to defecation problems, insomnia, and financial difficulties) was lower compared to those aged ≥60 years; and role functioning was significantly related to global health status/QOL. Six months after SSS, the global health status/QOL had recovered. In both groups, global health status/QOL was related to role and social functioning. Among participants aged <60 years, global health status/QOL was significantly related to emotional functioning, which is related to future perspective. Among participants aged ≥60 years only, global health status/QOL was significantly related to cognitive functioning; pain, financial difficulties, and defecation problems negatively influenced HR-QOL. Symptoms specific after SSS: defecation problems (in both group), micturition problems (only ≥60 years), and sexual problems (only<60 years) influenced HR-QOL. Conclusion: Health care providers should assess the influence of age-related factors during the early post-operative period after SSS to improve HR-QOL..
389. Daisuke Tsurumaru, Yusuke Nishimuta, Toshio Muraki, Yoshiki Asayama, Akihiro Nishie, Eiji Oki, Hiroshi Honda, Gastric cancer with synchronous and metachronous hepatic metastasis predicted by enhancement pattern on multiphasic contrast-enhanced CT, European Journal of Radiology, 10.1016/j.ejrad.2018.09.030, 108, 165-171, 2018.11, Objective: The purpose of this study was to examine the relationship between the CT features of the primary-site gastric cancer and the concurrent existence or postoperative recurrence of hepatic metastasis. Materials and methods: From January 2013 to July 2016, 125 patients with advanced gastric cancer who were evaluated by gastroscopy and contrast-enhanced CT at our institution were included. Eleven patients had hepatic metastasis at the time of diagnosis (synchronous hepatic metastasis). Five patients had hepatic recurrence after surgery (metachronous hepatic metastasis, median follow-up period of 313 days), and another 56 patients had no hepatic recurrence during follow-up period (negative hepatic metastasis, median follow-up period of 1102 days). Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. We compared the parameters of synchronous, metachronous and negative hepatic-metastasis. We calculated diagnostic performance of CT for diagnosing synchronous and metachronous hepatic metastasis. Results: The peak enhancement was significantly diff; erent between the three groups for both readers (reader 1, p = 0.0001; reader 2, p = 0.0002). Most of the synchronous and metachronous hepatic metastasis had peak enhancement in the arterial or portal phase. The CT attenuation values of synchronous and metachronous hepatic metastasis were significantly higher than those of negative hepatic metastasis in the delayed phase according to both readers (reader 1, p = 0.0003; reader 2, p = 0.0002). In predicting synchronous hepatic metastasis using peak enhancement, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 72.7%, 89.3%, 57.1%, 94.3%, and 86.6% for reader 1, and 54.5%, 94.6%, 66.7%, 91.4%, and 88.1% for reader 2. In predicting metachronous hepatic metastasis, the sensitivity, specificity, PPV, NPV, and accuracy were 60.0%, 89.3%, 33.0%, 94.3%, and 86.9% for reader 1, and 40.0%, 94.6%, 40.0%, 94.6%, and 90.2% for reader 2. Conclusion: Our study showed that gastric cancer with synchronous and metachronous hepatic metastasis tends to show early enhancement with a washout pattern on contrast-enhanced CT. This feature would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of gastric cancer..
390. Nami Yamashita, Eriko Tokunaga, Makoto Iimori, Yuka Inoue, Kimihiro Tanaka, Hiroyuki Kitao, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Epithelial Paradox
Clinical Significance of Coexpression of E-cadherin and Vimentin With Regard to Invasion and Metastasis of Breast Cancer, Clinical Breast Cancer, 10.1016/j.clbc.2018.02.002, 18, 5, e1003-e1009, 2018.10, E-cadherin and vimentin are regarded as major conventional canonical markers of epithelial–mesenchymal transition. Both E-cadherin– and vimentin-positive tumors had the worst prognosis among all cases. Further, E-cadherin and vimentin protein is colocalized within the same tumor cells, suggesting the existence of an aggressive subpopulation in the primary tumor nest of breast cancer. Background: E-cadherin and vimentin are regarded as major conventional canonical markers of the epithelial–mesenchymal transition. It is commonly assumed that E-cadherin is uniformly lost during the process of epithelial–mesenchymal transition. Breast tumor cells typically invade as a cohesive multicellular unit in a process called collective invasion. The aim of this study was to reveal the clinical importance of the expression pattern of E-cadherin and vimentin in breast cancer. Methods: E-cadherin and vimentin protein expression was evaluated by immunohistochemistry in 176 invasive breast cancer samples. Among these, E-cadherin and vimentin expression were evaluated in the set of primary site and metastatic lymph nodes in 65 cases. In addition, E-cadherin and vimentin expression were analyzed by confocal laser scanning microscopy to see E-cadherin and vimentin localization in the breast cancer cells. Results: Both at the primary site and metastatic lymph nodes, both E-cadherin– and vimentin-positive tumors had the worst disease-free and overall survival among all cases. In addition, E-cadherin and vimentin protein is colocalized within the same tumor cells in a human breast cancer specimen. Conclusion: Our present data suggest the existence of an aggressive subpopulation in the primary tumor nest of breast cancer..
391. Gabrielle S. Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E. Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O’Day, Rachel Rendak, Wei li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K. Rustgi, Kwok Kin Wong, J. Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A. Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J. Bass, Erratum to
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition (Nature Medicine, (2018), 24, 7, (968-977), 10.1038/s41591-018-0022-x), Nature medicine, 10.1038/s41591-018-0168-6, 24, 10, 2018.10, In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article..
392. Keitaro Edahiro, Makoto Iimori, Takashi Kobunai, Tomomi Morikawa-Ichinose, Daisuke Miura, Yuki Kataoka, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara, Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity, Molecular Cancer Research, 10.1158/1541-7786.MCR-17-0686, 16, 10, 1483-1490, 2018.10, Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Experimentally, drug resistance is established in cell lines in vitro by repeated, continuous exposure to escalating concentrations of the drug; however, the precise mechanism underlying the acquired resistance is not always known. Here, it is demonstrated that the human colorectal cancer cell line DLD1 with acquired resistance to trifluridine (FTD), a key component of the novel, orally administered nucleoside analoguetype chemotherapeutic drug trifluridine/tipiracil, lacks functional thymidine kinase 1 (TK1) expression because of one nonsense mutation in the coding exon. Targeted disruption of the TK1 gene also conferred severe FTD resistance, indicating that the loss of TK1 protein expression is the primary cause of FTD resistance. Both FTD-resistant DLD1 cells and DLD1- TK1 cells exhibited similar 5-fluorouracil (5-FU) sensitivity to that of the parental DLD1 line. The quantity of cellular pyrimidine nucleotides in these cells and the kinetics of thymidylate synthase ternary complex formation in 5-FU- treated cells is similar to DLD1 cells, indicating that 5-FU metabolism and cytotoxicity were unaffected. The current data provide molecular-based evidence that acquired resistance to FTD does not confer 5-FU resistance, implying that 5-FU- based chemotherapy would be effective even in tumors that become refractory to FTD during trifluridine/tipiracil treatment..
393. Akihiro Nishie, Yukihisa Takayama, Yoshiki Asayama, Kosei Ishigami, yasuhiro ushijima, Daisuke Okamoto, nobuhiro fujita, Daisuke Tsurumaru, Osamu Togao, Tatsuya Manabe, Eiji Oki, Yuichiro Kubo, Tomoyuki Hida, Minako Hirahashi-Fujiwara, Jochen Keupp, Hiroshi Honda, Amide proton transfer imaging can predict tumor grade in rectal cancer, Magnetic Resonance Imaging, 10.1016/j.mri.2018.04.017, 51, 96-103, 2018.09, Purpose: To prospectively investigate the ability of amide proton transfer (APT) imaging, in comparison with that of diffusion-weighted imaging (DWI), to predict pathological factors in rectal cancer. Materials and methods: Twenty-two patients who underwent MR examination including APT imaging and DWI for evaluation of rectal cancer were enrolled. APT signal intensity (SI) was defined as the magnetization transfer asymmetry at 3.5 ppm and was mapped. An apparent diffusion coefficient (ADC) map was generated using b-values of 0, 500 and 1000 s/mm2. APT SI and ADC were calculated by placing regions-of-interest in the tumors on these maps. Pathological factors including tumor size and tumor grade were also evaluated. Average APT SIs or ADCs were compared between the two groups classified based on each pathological factor using Student's t-test. Results: The average APT SI of tumors with diameters of 5 cm or more (3.09 ± 1.41%) was significantly higher than that of tumors with diameters < 5 cm (1.83 ± 1.38%). In addition, the average APT SI of moderately differentiated adenocarcinoma (2.82 ± 1.51%) was significantly higher than that of well-differentiated adenocarcinoma (1.24 ± 0.57%). There was no difference in ADC between groups classified based on any pathological factor. Conclusion: Amide proton transfer imaging can predict tumor grade in rectal cancer..
394. Eiji Oki, Takeshi Kato, Hideaki Bando, Takayuki Yoshino, Kei Muro, Hiroya Taniguchi, Yoshinori Kagawa, Kentaro Yamazaki, Tatsuro Yamaguchi, Akihito Tsuji, Shigeyoshi Iwamoto, Goro Nakayama, Yasunori Emi, Tetsuo Touyama, Masato Nakamura, Masahito Kotaka, Hideki Sakisaka, Takeharu Yamanaka, Akiyoshi Kanazawa, A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer
QUATTRO Study, Clinical Colorectal Cancer, 10.1016/j.clcc.2018.01.011, 17, 2, 147-155, 2018.06, FOLFOXIRI plus bevacizumab is an effective for Asian metastatic colorectal cancer patients and the safety profile is manageable by adopting appropriate measures, even if severe neutropenia and febrile neutropenia develop at a higher frequency in ethnic Asian patients with UGT1A1*6 and *28 polymorphism. Background: FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. Patients and Methods: This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. Results: A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P =.004). Conclusions: FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered..
395. Oki E, Kato T, Bando H, Yoshino T, Muro K, Taniguchi H, Kagawa Y, Ymazaki K, Yamaguchi T, Tsuji A, Iwamoto S, Nkayama G, Emi Y, Touyama T, Nakamura M, Kotaka M, Sakisaka H, Yamanaka T, Kanazawa A, A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study, Clin Coloreclal Cancer, 9, 17, 30313, 2018.05.
396. Toshiki Iwai, Yui Harada, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Yoshikazu Yonemitsu, Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells, Oncotarget, 10.18632/oncotarget.24811, 9, 25, 17620-17630, 2018.04, The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr- 1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a prodrug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte-colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy..
397. Yuji Miyamoto, Akihito Tsuji, Hiroaki Tanioka, Soichiro Maekawa, Hirofumi Kawanaka, Masaki Kitazono, Eiji Oki, Yasunori Emi, Hidetsugu Murakami, Yutaka Ogata, Hiroshi Saeki, Mototsugu Shimokawa, Shoji Natsugoe, Yoshito Akagi, Hideo Baba, Yoshihiko Maehara, Correction to
S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102) (International Journal of Clinical Oncology, (2016), 21, 4, (705-712), 10.1007/s10147-015-0943-z), International Journal of Clinical Oncology, 10.1007/s10147-017-1212-0, 23, 2, 2018.04, In the original publication, in Abstract, the sentence that reads as, “Oral S-1 at a dose of 80 mg/m2 was. drug-free interval” should read as, “Oral S-1 at a dose of 40 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval..
398. Yasuhiro Haruta, Ryota Nakanishi, Tomoko Jogo, Yuichiro Nakashima, Hiroshi Saeki, Eiji Oki, Minako Fujiwara, Yoshinao Oda, Yoshihiko Maehara, Gastric cancer of "Crawling type" detected by additional gastrectomy after endoscopic submucosal resection, Anticancer Research, 10.21873/anticanres.12479, 38, 4, 2335-2338, 2018.04, “Crawling type” gastric cancer (GC) is known as a rare variant of early GCs, which is difficult to diagnose at an early stage because of low-grade nuclear atypia and a morphology mimicking intestinal metaplasia. This is a case report of a 69-year-old woman who was diagnosed with early-stage gastric cancer. She had endoscopic submucosal resection (ESD) and histologically, both horizontal and vertical margins were negative. Seven months after ESD, a new lesion of the stomach was detected by follow-up gastroscopy. Laparoscopic distal gastrectomy was performed and “crawling type” glands were observed throughout the whole area of the tumor. We should keep this variant in mind, especially when a tumor is superficial depressed or superficial flat type in the middle of the stomach. Careful observation with multiple biopsies of all mucosal layer and a re-biopsy is the key procedure for obtaining the right diagnosis. Endoscopic and histological characteristics should also be reviewed..
399. Masahiko Sugiyama, Eiji Oki, Kouji Andou, Yuichiro Nakashima, Hiroshi Saeki, Yoshihiko Maehara, Laparoscopic Proximal Gastrectomy Maintains Body Weight and Skeletal Muscle Better Than Total Gastrectomy, World Journal of Surgery, 10.1007/s00268-018-4625-7, 1-7, 2018.04, Background: Laparoscopic proximal gastrectomy (LPG) is performed as a function-preserving surgery for patients with early proximal gastric malignant tumors; however, whether LPG has advantages postoperatively compared with laparoscopic total gastrectomy (LTG) is debatable, especially with regard to nutritional outcomes. Methods: We evaluated 20 patients who underwent LTG and 10 patients who underwent LPG with double tract reconstruction (LPG-DT) who were diagnosed preoperatively with T1a or T1b N0 Stage IA gastric cancer in our department in the same time period. The statistical relevance of complications, surgical maneuvers, clinical factors and changes in weight, skeletal muscle index (SMI) and serum albumin levels after surgery was compared between the LPG-DT group and the LTG group. Results: No differences between groups were observed in patient demographics, operation time, blood loss, complications, number of dissected lymph nodes and pathological stage. The body weight reduction rate was significantly lower in the LPG-DT group compared with the LTG group at 6 months (5.7 vs. 14.9%, respectively; p = 0.0045) and 1 year after surgery (9.6 vs. 17.9%, respectively; p = 0.0042). The SMI reduction rate of the LPG-DT group in the first postoperative year was significantly lower than that of the LTG group (9.3 vs. 18.3%, respectively; p = 0.0057). Conclusions: Patients with early gastric cancer who underwent LPG-DT had acceptable morbidity and mortality, similar to those who underwent LTG. Body weight and SMI reduction rates were lower in the LPG-DT group than in the LTG group. Thus, LPG-DT is an appropriate procedure for patients with clinical Stage IA proximal gastric cancer..
400. Hiroaki Tanioka, Yuji Miyamoto, Akihito Tsuji, Masako Asayama, Takeshi Shiraishi, Satoshi Yuki, Masahito Kotaka, Akitaka Makiyama, Mototsugu Shimokawa, Takayuki Shimose, Satohiro Masuda, Takuhiro Yamaguchi, Yoshito Komatsu, Hiroshi Saeki, Yasunori Emi, Hideo Baba, Eiji Oki, Yoshihiko Maehara, Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise
A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402), Oncology, 10.1159/000486624, 94, 5, 289-296, 2018.04, Background: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib-related fatigue and/or malaise. Patients and Methods: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1-28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute's CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in-cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). Results: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade ≥2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). Conclusion: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise..
401. Yuka Inoue, Nami Yamashita, U. E.O. Hiroki, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Eriko Tokunaga, Yoshihiko Maehara, The clinical usefulness of the LigaSure™ small jaw in axillary lymph node dissection in patients with breast cancer, Anticancer Research, 10.21873/anticanres.12483, 38, 4, 2359-2362, 2018.04, Background: The LigaSure™ small jaw (LS-SJ) multifunctional tissue sealing system is mainly used in cervical operations. We aimed to evaluate the clinical efficacy of the LS-SJ in axillary lymph node dissection (ALND) in comparison to the conventional method. Patients and Methods: Ninety-two patients with breast cancer who underwent total mastectomy and ALND were included in this study. The patients were divided into the LS-SJ group (n=43) and the conventional-ALND (c-ALND) group (n=49). Results: Patients with high body mass index values had a greater drainage volume and longer time to drain removal. The drainage volume was in the LS-SJ group was significantly lower than that in the c-ALND group. The time to drain removal and the hospitalization period were also significantly shorter in the LS-SJ group. The LS-SJ was more effective for ALND in obese patients. Conclusion: The results suggest the clinical usefulness of LS-SJ in ALND in patients with breast cancer, especially in obese patients..
402. Shotaro Korehisa, Tetsuo Ikeda, Shinji Okano, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Makoto Hashizume, Yoshihiko Maehara, A novel histological examination with dynamic three-dimensional reconstruction from multiple immunohistochemically stained sections of a PD-L1-positive colon cancer, Histopathology, 10.1111/his.13400, 72, 4, 697-703, 2018.03, Aims: Programmed cell death-ligand 1 (PD-L1) expression is observed in patients with microsatellite instability-high (MSI-H) colon cancer, which is susceptible to immune checkpoint blockade. The aim of this study was to investigate the interrelationship between PD-L1-positive cells and cytotoxic T cells, lymphatic vessels and vascular endothelium by using histological examination with the three-dimensional (3D) reconstruction of a PD-L1-positive colon cancer. Methods and results: Serial sections of MSI-H colon cancer tissue were stained with haematoxylin and eosin (H&E) and Masson trichrome stains; immunohistochemical analysis of PD-L1, CD8, D2-40 and CD31 was performed. Several 3D models of MSI-H colon cancer were reconstructed with a 3D data visualisation system. Moreover, 18 serial sections were stained with PD-L1, cytokeratin AE1/AE3, CD45, CD31, CD68 and H&E in the same case to confirm that PD-L1 was expressed on tumour cells, CD31-positive cells and macrophages in the invasive frontal region. Notably, there was a peak in the expression of PD-L1 and CD31 in the invasive frontal region. D2-40-positive cells were abundant in the overall tumour stroma, and CD8-positive cells infiltrated the tumour parenchyma. PD-L1 was expressed on tumour cells in the parenchyma and other cells in the stroma. Additional staining of 18 consecutive sections revealed that the other cells were CD68-positive and CD45-positive macrophages and CD31-positive proliferating vascular endothelial cells. Conclusions: We confirmed that PD-L1 was highly expressed in the invasive frontal region in 3D models of MSI-H colon cancer tissue. This method can be useful for accurately evaluating the localisation of immune checkpoint molecules..
403. Eiji Oki, A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC). , Ann Oncol 2016; 27(7):1266-72., 2017.05.
404. Oki E, Okano S, Saeki H, Umemoto Y, Teraishi K, Nakaji Y, Ando K, Zaitsu Y, Yamashita N, Sugiyama M, Nakashima Y, Ohgaki K, Oda Y, Maehara Y, Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma., Oncology, 93, 6, 387-394, 2017.05.
405. Eiji Oki, Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302), GASTRIC CANCER, 10.1007/s10120-015-0530-z, 19, 3, 968-976, 2016.07.
406. Eiji Oki, Clinical aspect and molecular mechanism of DNA aneuploidy in gastric cancers, J Gastroenterol , 47, 4, 351-358, 2012.08.
407. Oki E, Sakaguchi Y, Ohgaki K, Saeki H, Chinen Y, Minami K, Sakamoto Y, Toh Y, Kusumoto T, Maehara Y., Feasibility of delta-shaped anastomoses in totally laparoscopic distal gastrectomy, Eur Surg Res, 47, 5, 205-210, 2011.10, BACKGROUND: Delta-shaped (DS) anastomosis is a new reconstruction method for totally laparoscopic distal gastrectomy (TLDG) using a linear stapler. We evaluated the feasibility of using this method for TLDG.
METHODS: A retrospective analysis was performed in 114 patients who underwent TLDG with DS anastomosis. Twenty-four patients reconstructed with a Roux-en-Y (RY) anastomosis during the same period were analyzed as control subjects.
RESULTS: The patient characteristics of DS and RY anastomoses were slightly different in terms of tumor location and extent of lymph node dissection, since this was not a prospective comparative study. Blood loss, postoperative complication rate and postoperative hospital stay were not different between the two groups. There was only 1 case of anastomotic leakage, and no case of anastomotic stricture after DS anastomosis. The length of the operation using DS anastomosis was significantly shorter than for RY anastomosis. The rates of body weight loss were not significantly different at 1 year after the operation.
CONCLUSIONS: Although this was a small retrospective analysis, DS anastomosis was feasible, required a shorter operation time, and had no associated complications. This method can therefore be recommended as a standard procedure for TLDG.

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408. Oki E, Sakaguchi Y, Ohgaki K, Minami K, Yasuo S, Akimoto T, Toh Y, Kusumoto T, Okamura T, Maehara Y., Surgical complications and the risk factors of totally laparoscopic distal gastrectomy, Surg Laparosc Endosc Percutan Tech. , 21, 3, 146-150, 2011.06.
409. Oki E, Sakaguchi Y, Hiroshige S, Kusumoto T, Kakeji Y, Maehara Y, Preservation of an aberrant hepatic artery arising from the left gastric artery during laparoscopic gastrectomy for gastric cancer., J Am Coll Surg, 212, 5, 25-27, 2011.05.
410. Oki E, Kakeji Y, Zhao Y, Yoshida R, Ando K, Masuda T, Ohgaki K, Morita M, Maehara Y, Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability, Ann Surg Oncol, 16, 9, 2510-2515, 2009.09.
411. Oki E, Zhao Y, Yoshida R, Masuda T, Ando K, Sugiyama M, Tokunaga E, Morita M, Kakeji Y, Maehara Y., Checkpoint with forkhead-associated and ring finger promoter hypermethylation correlates with microsatellite instability in gastric cancer., World J Gastroenterol, 15(20):2520-2525, 2009, 2009.07.
412. Oki E, Kakeji Y, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Yamamoto M, Ikebe M, Maehara Y., Impact of Loss of Heterozygosity of PTEN on the Prognosis of Gastric Cancer, J Gastroentel Hepatol, 2006.08.
413. Oki E, Maehara Y, Tokunaga E, Shibahara K, Hasuda S, Kakeji Y, Sugimachi K., Detection of disseminated cancer cells in bone marrow of gastric cancer using real time quantitative reverse transcriptase polymerase chain reaction, Cancer letters, 10.1016/S0304-3835(02)00057-5, 188, 1-2, 191-198, 188(1-2):191-8, 2002.12.
414. J. Ren, R. Datta, H. Shioya, Y. Li, E. Oki, V. Biedermann, A. Bharti, D. Kufe., p73beta is regulated by protein kinase Cdelta catalytic fragment generated in the apoptotic response to DNA damage., Journal of Biological Chemistry, 13;277(37):33758-65, 2002.09.
415. R. Datta, E. Oki, K Endo , V. Biedermann, J. Ren, D. Kufe., XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage., Journal of Biological Chemistry, 275(24):18476-81, 2000.10.
416. Endo K, Oki E (equal corresponding), Biedermann V, Kojima H, Yoshida K, Johannes FJ, Kufe D, Datta R, Proteolytic cleavage and activation of protein kinase C [micro] by caspase-3 in the apoptotic response of cells to 1-beta -D-arabinofuranosylcytosine and other genotoxic agents, Jounal of Biological Chemistry, 16;275(24):18476-81, 2000.06.
417. Oki E, Oda S, Maehara Y, Sugimachi K., Mutated gene-specific phenotypes of dinucletide repeat instability in human colorectal carcinoma cell lines defiecient in DNA mismatch repair, Oncogene, 10.1038/sj.onc.1202583, 18, 12, 2143-2147, 18: 2143-2147, 1999.01.
418. Oki E, Sakaguchi Y, Toh Y, Oda S, Maehara Y, Yamamoto N, Sugimachi K., Induction of apoptosis in human tumor xenografts after oral administration of uracil and tegafur to nude mice bearing tumors, British Journal of Cancer, 10.1038/bjc.1998.552, 78, 5, 625-630, 78: 625-630, 1998.01.
419. Yasushi Toh, Eiji Oki, Shinya Oda, Eriko Tokunaga, Shinji Ohno, Yoshihiko Maehara, Garth L. Nicolson, Keizo Sugimachi, Overexpression of the MTA1 gene in gastrointestinal carcinomas
Correlation with invasion and metastasis, International Journal of Cancer, 10.1002/(SICI)1097-0215(19970822)74:4<459::AID-IJC18>3.0.CO;2-4, 74, 4, 459-463, 1997.10, The total gene is a recently identified novel candidate metastasis- associated gene. The deduced amino acid sequence contains an src homology-3 domain binding motif, a zinc finger motif and possible phosphorylation sites, suggesting that this gene is involved in signal transduction or regulation of gene expression. The purpose of our study was to examine the mRNA expression levels of the MTAI, the human homologue of the rat mta1 gene in colorectal and gastric carcinomas and thus to evaluate the relevance of the expression of this gene to human carcinoma progression. The expression of MTAI mRNA in 36 colorectal and 34 gastric carcinoma samples was compared with that in corresponding normal mucosa tissues by semi-quantitative reverse- transcription polymerase chain reaction (RT-PCR) and the results were compared with clinicopathologic data. A relative overexpression of MTAI mRNA (tumor/normal ratio ≤2) was observed in 14 of 36 (38.9%) colorectal carcinomas and 13 of 34 (38.2%) gastric carcinomas. Clinicopathologic correlations demonstrated that in colorectal carcinomas, tumors overexpressing MTAI mRNA exhibited a significantly deeper wall invasion and a higher rate of metastasis to lymph nodes, and tended to be at an advanced Dukes' stage with frequent lymphatic involvement. In gastric carcinomas, the tumors overexpressing MTAI mRNA showed significantly higher rates of serosal invasion and lymph node metastasis and tended to have a higher rate of vascular involvement. Our data suggest that overexpression of the MTAI gene correlates with tumor invasion and the presence of metastases and that a high expression of MTAI mRNA may be a potential indicator for assessing the malignant potential of colorectal and gastric carcinomas..
420. Oki E, Oda S(equal corresponding), Maehara Y, Sugimachi K., Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis, Nucleic Acids Research, 10.1093/nar/25.17.3415, 25, 17, 3415-3420, 25: 3415-3420, 1997.01.
421. Y. Maehara, S. Oda, E. Oki, E. Tokunaga, K. Sugimachi, Laboratory investigation for cancer diagnosis and treatment, Japanese Journal of Clinical Chemistry, 26, 3, 125-133, 1997.01, A number of laboratory tests have been used to diagnose cancer and for post-treatment follow-up of patients with cancer. The aims of these tests are; 1, evaluation of the biological characteristics of each cancer; 2, identification of micrometastases of cancer, for example to the lymph node, bone marrow and peripheral blood; 3, detection of patients at high risk for developing cancer. Cancer diagnosis and treatment should be improved by further developments in molecular biology and clinical chemistry, in the next century..
422. Yasushi Toh, Eiji Oki, Shinya Oda, Masaaki Tomoda, Shinichi Tomisaki, Yuji Ichiyoshi, Shinji Ohno, Keizo Sugimachi, An integrated microsatellite length analysis using an automated fluorescent DNA sequencer, Cancer Research, 56, 12, 2688-2691, 1996.06, Analyzing microsatellite instability (MI) in malignant tumors is thought in be useful for screening cancer patients to identify those patients with a higher risk of developing second malignant tumors. In this paper, we report a new, accurate, and efficient method of detecting MI using an automated fluorescent DNA sequencer and a computer that automatically calculates the size, height, and area of each fluorescent product, making it possible to assess MI more accurately and more rapidly. The primers for amplification of each microsatellite locus are labeled by two different fluorescent dyes, rox (red) and fam (blue). The rox-labeled primer was used for the tumor, whereas the fam-labeled primer was used for the corresponding normal tissue. Two amplified products from both the tumor and the normal tissue were co-loaded into a single lane of the sequencing gel and were analyzed. MI could be detected based on the presence of different waving patterns. Furthermore, several loci could also be analyzed simultaneously for MI in a single lane. Using this method, we examined the frequency of MI in gastric cancer. The results showed that 5 of 22 (22.7%) gastric cancers were MI-positive, which corresponds to the findings of previous reports that used the radioisotopic method. The improved method may open up the possibility of performing routine examination of MI in many cancer patients and offers hope for the potential clinical application of MI analysis as a follow-up evaluation of cancer patients..
423. Toh Y, Oki E, Oda S, Tomoda M, Tomisaki S, Ichiyoshi Y, Ohno S, Sugimachi K., An integrated microsatellite length analysis using an automated fluoresent DNA sequencer, Cancer Research, 56, 12, 2688-2691, 56: 2688-2692, 1996.01.
424. Y. Toh, Eiji Oki, S. Oda, Yoshihiko Maehara, K. Sugimachi, Induction of apoptosis by UFT and evaluation of antitumor effectiveness, Therapeutic Research, 17, 6, 466-473, 1996.01, Apoptosis is known to be induced in cancer cells by carcinostatic agents, radiation, hyperthermia or anticancer therapies. Gene products, for example p53, bcl-2 have been shown to be involved with the induction of apoptosis. Therefore we studied the relation between p53 genotype and induction of apoptosis by various carcinostatic agents using a number of human cancer cell strains. Second, hyperthermia was applied to patients with rectal cancer, and the change in the number of apoptotic cells was analyzed in vivo to evaluate the relation between induction of apoptosis and the effectiveness of chemotherapy and thermotherapy. In addition, UFT was given orally to nude mice transplanted with human cancer cell strains to analyze the apoptosis inducing power of UFT and the effectiveness of its antitumor activity. The following conclusions were drawn following these experiments: 1) there is a strong tendency for induction of apoptosis to occur with normal p53 developed tumor, 2) induction of apoptosis correlates with the effectiveness of antitumor activity, 3) UFT induces apoptosis, and 4) at least a part of its antitumor effectiveness is due to apoptosis..
425. Oki E, Zhao Y, Yoshida R, Masuda T, Ando K, Sugiyama M, Tokunaga E, Morita M, Kakeji Y, Maehara Y., Checkpoint with forkhead-associated and ring finger promoter hypermethylation correlates with microsatellite World J Gastroenterolin gastric cancer., World J Gastroenterol, 15(20):2520-2525, 2009.
426. Oki E, Kakeji Y, Zhao Y, Yoshida R, Ando K, Masuda T, Ohgaki K, Morita M, Maehara Y, Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability, Ann Surg Oncol., 16(9):2510-2515, 2009.
427. Oki E, Zhao Y, Yoshida R, Egashira A, Ohgaki K, Morita M, Kakeji Y, Maehara Y., The difference in p53 mutations between cancers of the upper and lower gastrointestinal tract., Digestion, 79 Suppl 1:33-39, 2009.
428. Oki E, Kakeji Y, Taketomi A, Yamashita Y, Ohgaki K, Harada N, Iguchi T, Shibahara K, Sadanaga N, Morita M, Maehara Y, Transient Elastography for the Prediction of Oxaliplatin-Associated Liver Injury in Colon Cancer Patients, J Gastrointest Cancer., 39(1-4):82-85, 2008.
429. Oki E, Kakeji Y, Baba H, Nishida K, Koga T, Tokunaga E, Egashira A, Ikeda K, Yoshida R, Yamamoto M, Morita M, Maehara Y, Clinical significance of cytokeratin positive cells in bone marrow of gastric cancer patients, J Cancer Res Clin Oncol, 113:995-1000, 2007.
430. Oki E, Morita M, Kakeji Y, Ikebe M, Sadanaga N, Egasira A, Nishida K, Koga T, Ohata M, Honboh T, Yamamoto M, Baba H, Maehara Y. , Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer., Dis Esophagus., 20(4):301-304, 2007.
431. Sakurai M, Zhao Y, Oki E, Kakeji Y, Oda S, Maehara Y, High-resolution fluorescent analysis of microsatellite instability in gastric cancer, Eur J Gastroenterol Hepatol, 19(8):701-709, 2007.
432. Tokunaga E, Oki E, Nishida K, Koga T, Yoshida R, Ikeda K, Kojima A, Egashira A, Morita M, Kakeji Y, Maehara YE, Kakeji Y, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Yamamoto M, Ikebe M, Maehara Y., Aberrant hypermethylation of the promoter region of the CHFR gene is rare in primary breast cancer., Breast Cancer Res Treat, 97(2):199-203,2006.
433. Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Baba H, Maehara Y., Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients., Int J Cancer, 15;118(2):284-9, 2006.
434. Oki E, Watanabe M, Ikebe M, Morita M, Futatsugi M,, Yoshihiro Kakeji Y, Baba H and Maehara Y., Histological and biological characteristics of esophageal dysplasia, Esophagus, 2:129-132, 2005.
435. Oda S, Maehara Y, Ikeda Y, Oki E, Egashira A, Okamura Y, Takahashi I, Kakeji Y, Sumiyoshi Y, Miyashita K, Yamada Y, Zhao Y, Hattori H, Taguchi K, Ikeuchi T, Tsuzuki T, Sekiguchi M, Karran P, Yoshida MA, Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability., Nucleic Acids Res, 33(5):1628-1636, 2005.
436. Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y, Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer., Int J Cancer., 117(3):376-380, 2005.
437. Tanaka Y, Miyamoto S, Suzuki SO, Oki E, Yagi H, Sonoda K, Yamazaki A, Mizushima H, Maehara Y, Mekada E, Nakano H., Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer, Clin Cancer Res., 11(13):4783-4792, 2005.
438. Oki E, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Watanabe M, Ikebe M, Kakeji Y, Baba H, Maehara Y, Genetic Mutual Relationship between PTEN and p53 in Gastric Cancer., Cancer Lett, 227(1):33-88, 2005.
439. Oki E, OkuyamaT, Higashi H, Yoshida M, Baba H and Maehara Y, Preoperative Insertion of Transanal Ileus Tube for Treatment of Acute Obstruction in Cancer of the Colon and Rectum, A-P J Clin Oncol, 1: 88-91, 2005.