Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Eiji Oki Last modified date:2019.06.28

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


Papers
1. 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..
2. 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..
3. 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..
4. 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..
5. 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..
6. 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..
7. 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..
8. 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..
9. 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..
10. 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..
11. 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..
12. , 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..
13. 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..
14. 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..
15. 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..
16. 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..
17. 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..
18. 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..
19. 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..
20. 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..
21. 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..
22. 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..
23. 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..
24. 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..
25. 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..
26. 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..
27. 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..
28. 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..
29. 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..
30. 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..
31. 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..
32. 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..
33. 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..
34. 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..
35. 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..
36. 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..
37. 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..
38. 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..
39. 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..
40. 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..
41. 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.
42. 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.
43. 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.
44. 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.
45. Eiji Oki, Clinical aspect and molecular mechanism of DNA aneuploidy in gastric cancers, J Gastroenterol , 47, 4, 351-358, 2012.08.
46. 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.

.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. 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.
70. 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.
71. 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.
72. 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.
73. 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.
74. 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.