| 1. |
Katano M, Morisaki T, Matsuo T, Nakamura M, Kubota E, Hisatsugu T, Interleuikin-2 (IL-2) production by human B-cell line , Cellular Immuno, 159, 2, 262-270, 1994.04, A human B-cell line (Hairy-BM) constitutively secreting interleukin-2 (IL-2) was established from tumor tissue resected surgically from a patient with breast cancer. Hairy-BM was found to be 100% CD20+, 98% surface immunoglobulin (sIg) G+, 98% sIg kappa chain+, 100% HLA-DR+, 94% IL-2 receptor (IL-2R alpha), 98% IL-2R beta, and devoid of T-cell, monocyte, and natural killer cell surface antigens. The B-cell origin of Hairy-BM was also confirmed by clonally rearranged Ig heavy- and Ig light-chain genes. The growth of Hairy-BM expressing IL-2R was promoted by recombinant IL-2 (rIL-2) and anti-CD25 antibody significantly blocked the growth enhancement. IL-2 secretion from Hairy-BM was confirmed by radioimmunoassay. By using a sensitive polymerase chain reaction technique, we demonstrated that Hairy-BM expressed IL-2 mRNA, IL-2R alpha mRNA, and IL-2R beta mRNA. These findings indicate that certain B-cells not only produce, but also respond to IL-2 in an autocrine fashion with increased proliferation.". |
| 2. |
Katano M, Matsuo T, Morisaki T, Naito K, Nagumo F, Kubota E, Nakamura M, Hisatsugu T, Tadano J, Increased proliferation of a human breast carcinoma cell line by recombinant interleukin-2, Cancer Immunol Immunother, 39, 3, 161-166, 1994.04, Two adenocarcinoma cell lines, Breast M25-SF and Breast M, were established from tumor tissue resected surgically from a patient with breast cancer. One, Breast M25-SF, expresses interleukin-2 receptor (IL-2R) on the cell surface and the other, Breast M does not. The effects of recombinant interleukin-2 (rIL-2) on the proliferation of these cell lines were investigated. The growth of Breast M25-SF was significantly promoted by rIL-2 ranging from 1.25 U/ml to 640 U/ml. Anti-CD25 (Tac) antibody significantly blocked the growth enhancement of Breast M25-SF by rIL-2. Breast M, however, did not respond to rIL-2. To confirm more directly the promotion of Breast M25-SF growth by rIL-2, cloning of IL-2 responders from parent Breast M25-SF cells was carried out by limiting dilution without feeder cells in 96-well microplates. No colony formation was found in 24 wells without rIL-2. Eleven, 13 and 6 clones were established from groups of 24 wells containing rIL-2 at 200, 20 and 2 U/ml respectively. All of the clones expressed IL-2R and respond to rIL-2. By using a sensitive polymerase chain reaction technique, we demonstrated that Breast M25-SF but not Breast M expressed IL-2 mRNA, and IL-2 secretion from Breast M25-SF but not Breast M was also confirmed by radioimmunoassay. These findings suggest a role for IL-2 in autocrine support of Breast M25-SF growth. IL-2 may play an important role in the growth control of breast carcinoma cells. ". |
| 3. |
Morisaki T, Katano M, Ikubo A, Anan K, Nakamura M, Nakamura Kenjiro, Sato H, Tanaka M, Torisu M, Immunosuppressive cytokines (IL-10, TGF-beta) genes expression in human gastric carcinoma tissues., J Surg Oncol, 63, 4, 234-239, 1996.04, BACKGROUND: Contribution of immunosuppressive cytokines to tumor progression in many types of cancers has been suggested. To characterize the in vivo expression of immunosuppressive cytokines in gastric cancer, we analyzed the messenger RNA (mRNA) expression of transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) in human gastric carcinoma tissues. METHODS: Both tumor tissues and nontumor tissues from each resected specimen of 29 primary gastric carcinomas were tested for IL-10 and TGF-beta mRNA expression by the reverse transcriptase-polymerase chain reaction (RT-PCR), and the mRNA expression was correlated with various pathological parameters of the tumors. RESULTS: Among the 29 tumors, mRNAs of TGF-beta and IL-10 were detected in 79% and 62% of tumor samples, respectively. These cytokines were detected only in 31% for TGF-beta and 17% for IL-10 in nontumor samples. Both mRNAs were frequently expressed in the poorly differentiated adenocarcinomas and the tumor tissues with high degree of stage or lymph node metastasis. CONCLUSIONS: Local expression of immunosuppressive cytokines may contribute to the progression of primary gastric carcinomas possibly through immunosuppression.". |
| 4. |
Noguchi E, Hayashi N, Azuma Y, Seki T, Nakamura M, Nakashima N, Yanagida M, He X, Mueller U, Sazer S, Nishimoto T, Dis3, implicated in mitotic control, binds directory to Ran and enhances the GEF activity of RCC1., EMBO J, 15, 20, 5595-5605, 1996.04, Using the two-hybrid method, we isolated a Saccharomyces cerevisiae cDNA encoding a protein homologous to Schizosaccharomyces pombe protein Dis3sp, using as bait, human GTPase Ran. The DIS3 gene is essential for viability and complements S.pombe mutant dis3-54 which is defective in mitosis. Although Dis3sc has no homology to RanBP1, it bound directly to Ran and the S.cerevisiae Ran homologue Cnr1, but not to the S.cerevisiae RCC1 homologue Srm1. Upon binding to Ran with a 1:1 molar ratio, Dis3sc enhanced a nucleotide-releasing activity of RCC1 on Ran. In the presence of Dis3sc, the K(m) of RCC1 on Ran decreased by half, while the kcat was unchanged. In vivo, Dis3sp was present as oligomers of M(r) 670-200 kDa as previously reported, and the 200 kDa oligomer of Dis3sp was found to include Spi1 and Pim1, the S.pombe homologues of Ran and RCC1, respectively. Although the biological function of the heterotrimeric oligomer consisting of Dis3, Spi1 and Pim1 is unknown, our results indicate that Dis3 is a component of the RCC1-Ran pathway. ". |
| 5. |
Nakamura M, Katano M, Fujimoto K, Morisaki T, A new prognostic strategy for gastric carcinoma mRNA expression of tumor growth-related factors in endoscopic biopsy specimens., Ann Surg, 226, 1, 35-42, 1997.04, OBJECTIVE: The study analyzed the prognostic value of the transcription of several tumor growth-related genes in gastric carcinoma biopsy specimens. SUMMARY BACKGROUND DATA: The nodal status is one of the most significant prognostic factors in gastric carcinoma. There are, however, no satisfactory parameters for the preoperative assessment of nodal status. METHODS: A reverse transcriptase-polymerase chain reaction analysis was used to analyze the transcription of several tumor growth-related genes in endoscopic biopsy specimens from 78 gastric carcinomas. The factors examined were cyclin D1, cyclin E, urokinase-type plasminogen activator, 72-kd type IV collagenase, vascular endothelial growth factor, platelet-derived growth factor-A (PDGF-A), transforming growth factor-beta, and interleukin-10. The relation between the mRNA expression and the clinical pathologic parameters was analyzed statistically. RESULTS: The incidence of PDGF-A (p = 0.010) and transforming growth factor-beta (p = 0.009) mRNA expression increased as the pathologic stage advanced. Nodal metastasis correlated with cyclin D1 (p = 0.045), cyclin E (p = 0.037), urokinase-type plasminogen activator (p = 0.047), and PDGF-A (p = 0.003) mRNA. Interestingly, the expression of PDGF-A mRNA showed a positive correlation (p = 0.004) with the early presence of lymph node metastases. CONCLUSIONS: Tumor growth-related factor mRNA in biopsy specimens may be a new prognostic tool. ". |
| 6. |
Nakamura M, Masuda H, Horii J, Kuma K, Yokoyama N, Ohba T, Nishitani H, Miyata T, Tanaka M, Nishimoto T, When overexpressed, a novel centrosomal protein, ranBPM, causes ectopic microtubule nucleation similar to γ-tubulin., J Cell Biol , 143, 4, 1041-1052, 1998.04, A novel human protein with a molecular mass of 55 kD, designated RanBPM, was isolated with the two-hybrid method using Ran as a bait. Mouse and hamster RanBPM possessed a polypeptide identical to the human one. Furthermore, Saccharomyces cerevisiae was found to have a gene, YGL227w, the COOH-terminal half of which is 30% identical to RanBPM. Anti-RanBPM antibodies revealed that RanBPM was localized within the centrosome throughout the cell cycle. Overexpression of RanBPM produced multiple spots which were colocalized with gamma-tubulin and acted as ectopic microtubule nucleation sites, resulting in a reorganization of microtubule network. RanBPM cosedimented with the centrosomal fractions by sucrose- density gradient centrifugation. The formation of microtubule asters was inhibited not only by anti- RanBPM antibodies, but also by nonhydrolyzable GTP-Ran. Indeed, RanBPM specifically interacted with GTP-Ran in two-hybrid assay. The central part of asters stained by anti-RanBPM antibodies or by the mAb to gamma-tubulin was faded by the addition of GTPgammaS-Ran, but not by the addition of anti-RanBPM anti- bodies. These results provide evidence that the Ran-binding protein, RanBPM, is involved in microtubule nucleation, thereby suggesting that Ran regulates the centrosome through RanBPM. ". |
| 7. |
Nakamura M, Katano M, Fujimoto K, Miyazaki K, Morisaki T, Mori M, Transforming growth factor β1（TGF-β1）is a preoperative prognostic indicator in advanced gastric carcinoma., Br J Cancer, 78, 10, 1373-1378, 1998.04, It has been generally accepted that transforming growth factor beta1 (TGF-beta1) has both negative and positive effects on tumour growth and progression. This study analysed the prognostic value of TGF-beta1 mRNA in advanced gastric carcinoma. A reverse transcriptase-polymerase chain reaction analysis (RT-PCR) was used for TGF-beta1 in endoscopic biopsy specimens from 42 advanced gastric carcinomas. Thirty specimens expressed TGF-beta1 mRNA while 12 specimens did not. The follow-up duration ranged from 4 to 37 months (mean 22.8 months). TGF-beta1-positive group demonstrated a shorter overall survival compared with the TGF-beta1 -negative group (P=0.0014). A significant correlation was also found in the 32 patients who underwent curative resection (P=0.0048). Significant correlations were found between TGF-beta1 mRNA expression and both stage (P=0.0015) and nodal involvement (P=0.0060). Multivariate analysis demonstrated that only TGF-beta1 mRNA expression (P=0.0306) was an independent prognostic factor. All of ten patients who underwent non-curative resection expressed TGF-beta1 mRNA. Expression of TGF-beta1 mRNA in gastric biopsy specimens may be an important preoperative prognostic variable for advanced gastric carcinoma. . |
| 8. |
Katano M, Nakamura M, Fujimoto K, Miyazaki K, Morisaki T, Prognostic value of platelet-derived growth factor-A（PDGF-A） in gastric carcinoma., Ann Surg, 227, 3, 365-371, 1998.04, OBJECTIVE: Because our previous study indicated that PDGF-A mRNA expression in biopsy specimens might identify a subgroup of high-risk patients with gastric carcinoma, in this study we analyzed the prognostic value of platelet-derived growth factor-A (PDGF-A) gene expression in gastric carcinoma biopsy specimens. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to analyze the PDGF-A gene expression in 65 gastric carcinoma endoscopic biopsy specimens. The 65 patients were divided into a PDGF-A-positive group (29 patients) and a PDGF-A-negative group (36 patients). RESULTS: On the basis of 2-year follow-up data, the PDGF-A-positive group demonstrated a shorter overall survival rate compared with the PDGF-A-negative group (p |
| 9. |
Katano M, Nakamura M, Kuwahara A, Fujimoto K, Matsunaga H, Miyazaki K, Morisaki T, Expression of interleukin(IL)-12 mRNA in gastric carcinoma specimens : cellular antitumor immune responses, J Surg Oncol, 67, 1, 11-17, 1998.04, BACKGROUND AND OBJECTIVES: Several tumor-related antigen peptides that are recognized by autologous cytolytic T cells (CTL) have been reported. However, most human solid tumors, including gastric carcinoma, are only weakly immunogenic. In this study, we focused on interleukin (IL)-12 and interferon-gamma (IFN-gamma) as key cytokines for estimating positive cellular immune responses. METHODS: To estimate the immunogenicity of gastric carcinomas, we examined IL-12 and IFN-gamma at mRNA levels by reverse transcription-polymerase chain reaction assay (RT-PCR) in tumor specimens and adjacent nontumor specimens from 36 gastric carcinoma patients. RESULTS: IL-12 expression was detected in 12 tumor specimens and in only two adjacent nontumor specimens (P = .003). The frequency of IFN-gamma gene expression was higher in the IL-12 mRNA-positive tumor specimens than in the IL-12 mRNA-negative tumor specimens (P = .015). In the IL-12 mRNA-positive tumors, IFN-gamma expression was higher in the tumor specimens than in the adjacent nontumor specimens (P = .007). Conversely, in the IL-12 mRNA-negative tumors, IFN-gamma expression was lower in the tumor specimens than in the nontumor specimens (P = .03). Many tumor-infiltrating mononuclear cells, predominantly T cells, were found in four of the 12 IL-12-mRNA-positive tumor specimens and in none of the 24 IL-12-mRNA-negative tumor specimens (P = .008). CONCLUSIONS: These data suggest that possible immune responses against a tumor may occur at the mRNA level in approximately one-third of gastric carcinomas. ". |
| 10. |
Ohba T, Nakamura M, Nishitani H, Nishimoto T, Self-organization of microtubule asters induced in Xenopus egg extracts by GTP-bound Ran, Science, 284, 5418, 1356- 1358, 1999.04. |
| 11. |
Kuwahara A, Katano M, Nakamura M, Fujimoto K, Miyazaki K, Mori M, Morisaki T, New therapeutic strategy for gastric carcinoma:a two-step evaluation of malignant potential from its molecular biologic and pathologic chartacteristics., J Surg Oncol, 72, 3, 142-149, 1999.04, BACKGROUND AND OBJECTIVES: A previous study of ours indicated that platelet-derived growth factor-A (PDGF-A) mRNA expression in biopsy specimens can identify a subgroup of high-risk gastric carcinoma patients, while clinicopathologic studies have shown that lymph node involvement is an important risk factor for predicting overall survival. To identify gastric carcinoma patients at high risk for recurrence, we assessed a two-step evaluation consisting of mRNA expression of tumor growth-related factors and the histopathologic findings. METHODS: The reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assay the gene expression of PDGF-A and transforming growth factor-beta1 (TGF-beta1) in 69 gastric carcinoma endoscopic biopsy specimens (prospective cohort). The corresponding gastric carcinoma surgical specimens were classified histologically. Finally, the patients' survival curves were calculated. The relationships among the mRNA expression, histopathologic findings, and survival period were analyzed statistically. RESULTS: Nodal involvement correlated with PDGF-A and TGF-beta1 mRNA expression in early and advanced carcinomas, respectively. Both PDGF-A mRNA and TGF-beta1 mRNA expression were independent preoperative prognostic indicators in advanced cases. The ratio of involved nodes (n1) to total perigastric lymph nodes dissected (percentage of involved nodes) was the most independent postoperative prognostic indicator in advanced cases. Early carcinomas were divided preoperatively into two types. Advanced carcinomas were divided preoperatively into three. These were divided again postoperatively according to the percentage of involved nodes into high- and low-malignacy groups. CONCLUSIONS: A two-step evaluation of the malignant potential of gastric carcinoma by a combination of preoperative evaluation for PDGF-A and TGF-beta1 expression and postoperative pathologic examination would yield a more accurate prognosis for patients with gastric carcinoma. Copyright 1999 Wiley-Liss, Inc. ". |
| 12. |
Sato N, Mizumoto K, Nakamura M, Nakamura Kenjiro, Kusumoto M, Niiyama H, Ogawa T, Tanaka M, Centrosome abnormalities in pancreatic ductal carcinoma, Clin Cancer Res, 5, 5, 963-970, 1999.04, The centrosome plays an important role in microtubule nucleation and organization, ensuring the establishment of cell polarity and balanced chromosome segregation. Recent studies have suggested that the loss of cell polarity and/or chromosome missegregation (aneuploidy) in human malignant tumors could result from defects in centrosome function. Using immunofluorescence analysis with an antibody to gamma-tubulin (a well-characterized centrosomal component), we examined surgically resected human pancreatic tissues for centrosome abnormalities. The tissues included ductal carcinomas (n = 13), adenomas (n = 3), endocrine tumors (n = 3), chronic pancreatitis (n = 5), and normal pancreatic tissues (n = 12). We found that most (85%) carcinomas and some adenomas displayed abnormal centrosome profiles, characterized by an increase in size and number of centrosomes, and by their irregular distribution. In contrast, none of normal ductal and stromal tissues showed these abnormalities. These findings suggest that centrosome abnormalities may develop at a relatively early stage of pancreatic ductal carcinogenesis.". |
| 13. |
Kusumoto M, Ogawa T, Mizumoto K, Ueno H, Niiyama H, Sato N, Nakamura M, Tanaka M, Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells., Clin Cancer Res, 5, 8, 2140-2147, 1999.04, Evidence for a relationship between overexpression of wild-type p53 and telomerase activity remains controversial. We investigated whether p53 gene transduction could cause telomerase inhibition in pancreatic cancer cell lines, focusing on the relation of transduction to growth arrest, cell cycle arrest, and apoptotic cell death. The cells were infected with recombinant adenovirus expressing wild-type p53 or p21WAF1 at a multiplicity of infection of 100 or were continuously exposed to 10 microM VP-16, which is well known to induce apoptosis. Adenovirus-mediated p53 gene transduction caused G1 cell cycle arrest, apoptosis, and resultant growth inhibition in MIA PaCa-2 cells; the cell number 2 days after infection was 50% of preinfection value, and 13% of the cells were dead. Moreover, the transduction resulted in complete depression of telomerase activity through down-regulation of hTERT mRNA expression. In contrast, p21WAF1 gene transduction only arrested cell growth and cell cycle at G1 phase, and VP-16 treatment inhibited cell growth with G2-M arrest and apoptosis; after treatment, the cell number was 73% of pretreatment, and 12% of the cells were dead. Neither p21WAF1 gene transduction nor VP-16 treatment caused telomerase inhibition. Similar results were obtained in two other pancreatic cancer cell lines, SUIT-2 and AsPC-1. Thus, our results demonstrate that the p53 gene transduction directly inhibits telomerase activity, independent of its effects on cell growth arrest, cell cycle arrest, and apoptosis.". |
| 14. |
Sato N, Mizumoto K, Nakamura M, Tanaka M, Radiation-induced centrosome overduplication and multiple mitotic spindles in human tumor cells, Exp Cell Res, 255, 2, 321-326, 2000.04, The centrosome is a highly regulated organelle and its proper duplication is indispensable for the formation of bipolar mitotic spindles and balanced chromosome segregation. To elucidate a possible linkage between centrosome duplication and radiation-induced nuclear damage, we examined centrosome dynamics in U2-OS osteosarcoma cells following gamma-irradiation. Nearly all control cells contained one or two centrosomes, and at mitosis more than 97% of the cells displayed typical bipolar spindles. In contrast, over 20% of cells at 48 h after 10 Gy gamma-irradiation contained more than two centrosomes, and 60% of the mitotic cells showed aberrant spindles organized by multiple poles. Remarkably, the cells with multiple centrosomes frequently exhibited changes in size and/or morphology of the nucleus, including micronuclei formation. We conclude that abnormal centrosome duplication could be one of the key events involved in nuclear fragmentation and perhaps even cell death following irradiation. Copyright 2000 Academic Press. . |
| 15. |
Sato N, Mizumoto K, Nakamura M, Ueno H, Minamishima YA, Farber JL, Tanaka M, A possible role for centrosome overduplication in radiation-induced cell death, Oncogene, 19, 46, 5281-5290, 2000.04, Radiotherapy plays a key role in the treatment of many tumors; however, the precise mechanisms responsible for radiation-induced cell death remain uncertain. We have reported previously that ionizing radiation induces centrosome overduplication in human tumor cells. The present study was designed to elucidate a possible link between centrosome dysregulation and radiation-induced cell death. Exposure to 10 Gy gamma-radiation resulted in a substantial increase in cells containing an abnormally high number of centrosomes in a variety of cell lines derived from different types of human solid tumors. These aberrant centrosomes contribute to the assembly of multipolar spindles, thereby causing an unbalanced division of chromosomes and mitotic cell death characterized by the appearance of multi- or micronucleated cells. An extensive analysis of a panel of 10 tumor cell lines revealed a positive correlation between the fraction of cells with multiple centrosomes and the fraction with these nuclear abnormalities after irradiation. When the centrosome overduplication was blocked by enforced expression of p21Waf1/Cip1, the radiation-induced lethality was drastically rescued. Taken together, these results indicate that centrosome overduplication may be a critical event leading to mitotic failure and subsequent cell death following exposure to ionizing radiation. . |
| 16. |
Kishi S, Wulf G, Nakamura M, Lu KP, Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors., Oncogene, 20, 12, 1497-1508, 2001.04, Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential. ". |
| 17. |
Shono M, Sato N, MizumotoK, Maehara N, Nakamura M, Nagai E, Tanaka M, Stepwise progression of centrosome defects associated with local tumor growth and metastatic process of human pancreatic carcinoma cells transplanted orthotopically into nude mice, Lab Invest, 81, 7, 945-952, 2001.04, Recent evidence indicates that loss of centrosome integrity may be a major cause of genetic instability underlying various human cancers. The aim of this study was to define the role of centrosome defects during the in vivo tumor progression of pancreatic carcinoma using an orthotopic implantation model. Injection of Suit-2 human pancreatic cancer cells into the pancreata of nude mice reproduced the pattern of local tumor growth and distant metastasis observed in humans. Pancreatic xenografts, peritoneal disseminations, and hepatic metastases were harvested, and tumor cells were examined for centrosomes by immunofluorescence microscopy. Centrosome abnormalities, characterized by increased numbers of centrosomes, were detected in only a small fraction of parental Suit-2 cells in culture, whereas the frequency was markedly increased in cells isolated from the pancreatic xenografts. Abnormal centrosome numbers were found at higher frequencies in metastatic foci than in pancreatic xenografts. A significant positive correlation existed between the fraction of cells with multiple centrosomes and that with multipolar mitotic spindles, suggesting a functional involvement of aberrant centrosomes in spindle disorganization and chromosome missegregation. In addition, the increased frequency of abnormal centrosomes was associated with an enhanced degree of chromosomal instability. These findings suggest a novel model of pancreatic tumor progression whereby a stepwise increase in the magnitude of centrosomal abnormalities confers an increased chance for aberrant mitotic events, thus accelerating genetic instability and causing the tumor to progress to a more advanced stage. ". |
| 18. |
Ryo A, Nakamura M, Wulf G, Liou YC, Lu KP, Pin1 regulates turnover and subcellular localization of betacatenin by inhibiting its interaction with APC., Nat Cell Biol, 3, 9, 793-801, 2001.04, Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta-catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of beta-catenin in vitro. Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta-catenin signalling and its overexpression might contribute to the upregulation of beta-catenin in tumours such as breast cancer, in which APC or beta-catenin mutations are not common. ". |
| 19. |
Nishitani H, Hirose E, Uchimura Y, Nakamura M, Umeda M, Nishii K, Mori N, Nishimoto T, Full-sized RanBMP cDNA encodes a protein possessing a long stretch of proline and glutamine within the N-terminal region, comprising a large protein complex, Gene, 272, 1-2, 25-33, 2001.04, Previously isolated RanBPM, a Ran-binding protein in the microtubule-organizing center, which had been thought to play a role in Ran-stimulated microtubule assembly, turned out to be a truncated protein. To clarify the function of RanBPM, we cloned the full-sized RanBPM cDNA that encodes a 90 kDa protein, compared to the previously isolated cDNA that encoded a 55 kDa protein. The newly cloned 5' coding region contains a great number of cytidine and guanidine nucleotides, like the CpG island. Thus, full-sized RanBPM cDNA encodes a long stretch of proline and glutamine residues in the N-terminal region. It comprises a protein complex of more than 670 kDa. Ran was detected in this complex when RanBPM and Ran were both ectopically expressed. New antibodies to RanBPM were prepared against three different regions of RanBPM. All of them detected a 90 kDa protein that is predominantly localized both in the nucleus and in the cytoplasmic region surrounding the centrosome, but none of them stained the centrosome. In this context, our previous notion that RanBPM is a centrosomal protein should be discarded. RanBPM is well conserved in the animal kingdom. It may play an important role in uncovering Ran-dependent nuclear events. ". |
| 20. |
Shono M, Sato N, Mizumoto K, Minamishima Y, Nakamura M, Maehara N, Urashima T, Saimura M, Qian L, Nishio S, Nagai E, Tanaka M, Effect of serum depletion on centrosome overduplication and death of human pancreatic cancer cells after exposure to radiation., Cancer Lett, 170, 1, 81-89, 2001.04, The tumor microenvironment is one of the key factors affecting the cellular response to radiation; however, the influence of serum concentration on tumor radiosensitivity remains poorly understood. We recently discovered that gamma-irradiation of tumor cells causes centrosome overduplication, which may lead to lethal nuclear fragmentation through the establishment of multipolar mitotic spindles. In the present study, we investigated the effect of serum depletion on radiation-induced cell death in relation to the centrosome dynamics in human pancreatic cancer cells. Exposure of Capan-1 cells to gamma-irradiation resulted in a time-dependent increase in cells containing multiple centrosomes in association with the appearance of mitotic cell death. Treatment of irradiated cells with serum depletion drastically accelerated centrosome overduplication and the formation of multipolar spindles, resulting in increased nuclear fragmentation and cell death. Cell cycle analysis of irradiated cultures revealed that the reduced serum level increased the population of cells arrested in the G2/M phase, which might be responsible for the abnormal centrosome accumulation. These findings suggest that serum concentration can influence radiation-induced cell killing through modulating cell cycle progression and possibly centrosome overduplication. ". |
| 21. |
Nakamura M, Zhou XZ, Lu KP, Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization., Curr Biol, 11, 13, 1062-1067, 2001.04, Human EB1 was originally cloned as a protein that interacts with the COOH terminus of adenomatous polyposis coli (APC). Interestingly, this interaction is often disrupted in colon cancer, due to mutations in APC. EB1 also interacts with the plus-ends of microtubules and targets APC to microtubule tips. Since APC is detected on the kinetochores of chromosomes, it has been hypothesized that the EB1-APC interaction connects microtubule spindles to the kinetochores and regulates microtubule stability. In yeast, EB1 regulates microtubule dynamics, and its binding domain in APC may be conserved in Kar9, an EB1 binding protein involved in the microtubule-capturing mechanism. These results suggest that the interaction of EB1 and APC is important and may be conserved. However, it is largely unknown whether the EB1-APC interaction affects microtubule dynamics. Here, we show that EB1 potently promotes microtubule polymerization in vitro and in permeabilized cells, but, surprisingly, only in the presence of the COOH-terminal EB1 binding domain of APC (C-APC). Significantly, this C-APC activity is abolished by phosphorylation, which also disrupts its ability to bind to EB1. Furthermore, yeast EB1 protein effectively substitutes for the human protein but also requires C-APC in promoting microtubule polymerization. Finally, C-APC is able to promote microtubule polymerization when stably expressed in APC mutant cells, demonstrating the ability of C-APC to promote microtubule assembly in vivo. Thus, the interaction between EB1 and APC plays an essential role in the regulation of microtubule polymerization, and a similar mechanism may be conserved in yeast. ". |
| 22. |
Sato N, Mizumoto K, Nakamura M, Maehara N, Minamishima Y, Nishio S, Nagai E, Tanaka M, Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells, Cancer Genet Cytogenet, 126, 1, 13-19, 2001.04, Chromosomal instability, characterized by abnormal numbers or structures of chromosomes, is a common feature of human cancers, but the mechanisms behind these changes are still unclear. Since centrosomes play a pivotal role in balanced chromosomal segregation during mitosis, we attempted to investigate the association between centrosome abnormalities and chromosomal instability in a large number of human pancreatic cancer cell lines. Immunofluorescence microscopy revealed centrosomes that were highly atypical with respect to their size, shape, and number in most cell lines. These abnormal centrosomes contributed to the assembly of multipolar spindles, resulting in defective mitosis and chromosome mis-segregation. Interestingly, a high frequency of centrosome defects inversely correlated with the growth rate of cells in culture. Fluorescence in situ hybridization revealed a dramatic variation of chromosome numbers in cell lines with the defective centrosome phenotype. Furthermore, a significant positive correlation existed between the level of centrosome defects and the level of chromosomal imbalances. These results indicate that centrosome abnormalities can lead to spindle disorganization and chromosome segregation errors, which may drive the accumulation of chromosomal alterations. Thus, defects in centrosome function may be an underlying cause of genetic instability in human pancreatic cancers. ". |
| 23. |
Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP, A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle., Curr Biol, 11, 19, 1512-1516, 2001.04, Pin2/TRF1 was independently identified as a telomeric DNA binding protein (TRF1) [1] and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its ability to induce mitotic catastrophe [2, 3]. Pin2/TRF1 has been shown to bind telomeric DNA as a dimer [3-7] and to negatively regulate telomere length [8-11]. Interestingly, Pin2/TRF1 levels are regulated during the cell cycle, being increased in late G2 and mitosis and degraded as cells exit from mitosis [3]. Furthermore, overexpression of Pin2/TRF1 induces mitotic entry and then apoptosis [12]. This Pin2/TRF1 activity can be significantly potentiated by the microtubule-disrupting agent nocodazole [12] but is suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is important for preventing apoptosis upon DNA damage [13]. These results suggest a role for Pin2/TRF1 in mitosis. However, nothing is known about how Pin2/TRF1 is involved in mitotic progression. Here, we describe a surprising physical interaction between Pin2/TRF1 and microtubules in a cell cycle-specific manner. Both expressed and endogenous Pin2/TRF1 proteins were localized to the mitotic spindle during mitosis. Furthermore, Pin2/TRF1 directly bound microtubules via its C-terminal domain. Moreover, Pin2/TRF1 also promoted microtubule polymerization in vitro. These results demonstrate for the first time a specific interaction between Pin2/TRF1 and microtubules in a mitosis-specific manner, and they suggest a new role for Pin2/TRF1 in modulating the function of microtubules during mitosis.. |
| 24. |
Ryo A, Liou Y. C, Wulf G, Nakamura M, Lee S. W, Lu K. P, PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells, Mol Cell Biol, 22, 15, 5281-5295, 2002.04. |
| 25. |
Nakamura M, Zhou XZ, Kishi K, Lu KP
, Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle
, FEBS Lett, 514, 2-3, 193-198, 2002.04, Pin2/TRF1 was independently identified as a telomeric DNA-binding protein (TRF1) that regulates telomere length, and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its lethal phenotype. We have previously demonstrated that Pin2/TRF1 levels are cell cycle-regulated and its overexpression induces mitotic arrest and then apoptosis. This Pin2/TRF1 activity can be potentiated by microtubule-disrupting agents, but suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is critical in mediating for many, but not all, ATM-dependent phenotypes. Interestingly, Pin2/TRF1 specifically localizes to mitotic spindles in mitotic cells and affects the microtubule polymerization in vitro. These results suggest a role of Pin2/TRF1 in mitosis. However, nothing is known about whether Pin2/TRF1 affects the spindle function in mitotic progression. Here we characterized a new Pin2/TRF1-interacting protein, EB1, that was originally identified in our yeast two-hybrid screen. Pin2/TRF1 bound EB1 both in vitro and in vivo and they also co-localize at the mitotic spindle in cells. Furthermore, EB1 inhibits the ability of Pin2/TRF1 to promote microtubule polymerization in vitro. Given that EB1 is a microtubule plus end-binding protein, these results further confirm a specific interaction between Pin2/TRF1 and the mitotic spindle. More importantly, we have shown that inhibition of Pin2/TRF1 in ataxia-telangiectasia cells is able to fully restore their mitotic spindle defect in response to microtubule disruption, demonstrating for the first time a functional involvement of Pin2/TRF1 in mitotic spindle regulation.
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| 26. |
Morisaki T, Matsumoto K, Onishi H, Kuroki H, Baba E, Tasaki A, Kubo M, Nakamura M, Inaba S, Yamaguchi K, Tanaka M, Katano M, Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T cells for cancer patients: rationale, current progress, and perspectives, Hum Cell, 16, 4, 175-182, 2003.04, Effective adoptive cancer immunotherapy depends on an ability to generate tumor-antigen-presenting cells and tumor-reactive effector lymphocytes and to deliver these effector cells to the tumor. Dendritic cells (DCs) are the most potent antigen-presenting cells, capable of sensitizing T cells to new and recall antigens. Many studies have shown that tumors express unique proteins that can be loaded on DCs to trigger an immune response. The current experimental and clinical statuses of adoptive transfer of tumor antigen-pulsed DCs and vaccine-primed activated T cells are summarized herein. Clinical trials of antigen-pulsed DCs have been conducted in patients with various types of cancer, including non-Hodgkin lymphoma, multiple myeloma, prostate cancer, renal cell carcinoma, malignant melanoma, colorectal cancer, and non-small cell lung cancer. These studies have shown that antigen-loaded DC vaccination is safe and promising for the treatment of cancer. In addition, tumor vaccine-primed T cells have been shown to induce antitumor activity in vivo. Several clinical studies are being conducted on the use of vaccine-primed T cells such as tumor-drainage lymph node. It is reasonable to consider using both tumor antigen-pulsed DCs and vaccine-primed lymphocytes as adjuvants. We are now investigating the use of autologous whole tumor antigen-pulsed DCs and the DC vaccine-primed activated lymphocytes in patients with multiple metastasis of solid tumors.
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| 27. |
Morisaki T, Matsumoto K, Kuroki H, Kubo M, Baba E, Onishi H, Tasaki A, Nakamura M, Inaba S, Katano M, Combined immunotherapy with intracavital injection of activated lymphocytes, monocyte-derived dendritic cells and low-dose OK-432 in patients with malignant effusion.
, Anticancer Res, 23, 6a, 4459-4465, 2003.04, We have conducted a pilot study with combined immunotherapy using autologous lymphocytes activated ex vivo and monocyte-derived dendritic cells in combination with low-dose OK-432, a streptococcal preparation, in five patients with peritoneal or pleural carcinomatosis who were resistant to standard chemotherapy. All patients were given 3 to 10 courses of the combined immunotherapy. No severe adverse reactions occurred. Effusion production was decreased in all of the patients. Significant decreases in tumor markers of both effusions and sera as well as effusion volume occurred in all of the patients. Cytological examinations revealed a marked decrease or disappearance of cancer cells in those effusions. Three patients showed increase in IFN-gamma levels in the effusions. The overall prognosis of the patients was acceptable and the mean survival time was more than 9 months. The locoregional immunotherapy seems to be encouraging in view of therapeutic modality in patients who are resistant to standard chemotherapy. Our study provides a new protocol for immunotherapy and warrants further phase I/II clinical study for chemo-resistant patients with malignant effusion.
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| 28. |
Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M, Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer
, Cancer Res, 64, 17, 6071-6074, 2004.04, The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Genetic analysis has demonstrated a critical role for the Hh pathway in mammary gland morphogenesis. Disruption of Patched1, a component of the Hh pathway, results in abnormal growth of mammary duct. Recent studies have shown constitutive activation of the Hh pathway in various types of malignancies. However, it remains unclear whether this pathway is activated in human breast cancer. Here, we determined the expression of the components, including Sonic Hh, Patched1, and Gli1, of the Hh pathway by immunohistochemical staining in a series of 52 human breast carcinomas. All of 52 tumors display staining of high intensity for Gli1 when compared with adjacent normal tissue. The nuclear staining ratio of Gli1 correlates with expression of estrogen receptor and histologic type. Exposure to cyclopamine, a steroidal alkaloid that blocks the Hh pathway, suppresses expression of Gli1 and the growth of the Hh pathway-activated breast carcinoma cells. These data indicate that the Hh pathway is a new candidate for therapeutic target of breast cancer.
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| 29. |
Kim K. T, Ongusaha P. P, Hong Y. K, Kurdistani S. K, Nakamura M, Lu K. P, Lee S. W, Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint, J Biol Chem, 279, 37, 38597-38602, 2004.04. |
| 30. |
Matsumoto K, Morisaki T, Kuroki H, Kubo M, Onishi H, Nakamura K, Nakahara C, Kuga H, Baba E, Nakamura M, Hirata K, Tanaka M, Katano M, Exosomes secreted from monocyte-derived dendritic cells support in vitro naive CD4+ T cell survival through NF-(kappa)B activation, Cell Immunol, 231, 1-2, 20-29, 2004.04, Abstract
We investigated the effect of exosomes secreted from human monocyte-derived dendritic cells (Mo-DCs), which are generated from PBMCs in response to treatment with GM-CSF and IL-4, on naive CD4+ T cell survival in vitro. Exosomes isolated from culture supernatants of Mo-DCs (>90% purity) were purified with anti-HLA-DP, -DQ, -DR-coated paramagnetic beads. Purified exosomes prolonged the survival of naive CD4+ T cells (>98% purity) in vitro. Treatment with neutralizing mAb against HLA-DR significantly decreased the supportive effect of purified exosomes on CD4+ T cell survival. Exosomes increased nuclear translocation of NF-(kappa)B in naive CD4+ T cells, and NF-(kappa)B activation was significantly suppressed by anti-HLA-DR mAb or NF-(kappa)B inhibitor pyrrolidine dithiocarbamate (PDTC). In addition, PDTC inhibited the effect of exosomes on naive CD4+ T cell survival. Thus, exosomes secreted by Mo-DCs appear to support naive CD4+ T cell survival via NF-(kappa)B activation induced by interaction of HLA-DR and TCRs.
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| 31. |
Yamaguchi K, Nakamura M, Shirahane K, Konomi H, Torata N, Hamasaki N, Kawakita M, Tanaka M, Urine diacetylspermine as a novel tumour maker for pancreatobiliary carcinomas, Digestive and Liver disease , 37, 3, 190-194, 2005.04. |
| 32. |
Koga K, Matsumoto K, Akiyoshi T, Kubo M, Yamanaka N, Tasaki A, Nakashima H, Nakamura M, Kuroki S, Tanaka M, Katano M, Purification, characterization and biological significance of tumor-derived exosomes., Anticancer Res, 25, 6A, 3703-3707, 2005.04, Abstract
Exosomes are nanovesicles that are released into the extracellular environment during the fusion of multivesicular bodies with the plasma membrane. Exosomes released from dendritic cells, dexosomes, have several biological functions, for example as immunostimulants. Some tumor cells also secrete exosomes (Tu-exosomes). Although experimental data obtained with the use of dexosomes suggest a biological function of Tu-exosomes, this still remains poorly understood. To examine the function of Tu-exosomes, we established a method for collecting highly purified Tu-exosomes, using paramagnetic beads coated with antibodies against tumor-specific proteins such as HER2/neu. With these antibody-coated beads (Ab-beads), it was possible to collect HER2-expressing Tu-exosomes of high purity. Tu-exosomes were also collected from malignant ascites, which contain exosomes secreted from various types of cells such as tumor cells, lymphoid cells and mesothelial cells. The isolation of Tu-exosomes was confirmed by FACS analysis. With regard to their biological functions, Tu-exosomes cultured with a human breast cancer cell line bound to the cell surface and increased tumor cell proliferation. These data indicate that Tu-exosomes may have physiological functions.
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| 33. |
Yamaguchi K, Nakamura M, Shirahane K, Kawamoto M, Konomi H, Ohta M, Tanaka M, Pancreatic juice cytology in IPMN of the pancreas.
, Pancreatology, 5, 4-5, 416-421, 2005.04, Background: Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is a disease ranging from adenoma to borderline (with moderate dysplasia) and further to carcinoma (noninvasive and invasive) and surgical strategy is different by the grades of dysplasia. Methods: Preoperativepancreatic juice cytology in IPMN was reviewed in 71 patients with IPMN who underwent surgical resection. Results: The IPMN was adenoma in 48 patients, borderline in 13 and carcinoma (invasive) in 10. The sensitivity of pancreatic juice cytology in malignant IPMN was 40% (4/10). In 4 patients with the 48 IPM adenomas, diagnosis of pancreatic juice cytology was class IV or V. One of the 4 cases was considered to be an overdiagnosis of cytology, but the other 3 cases were considered to be a consequence of accompanying carcinoma in situ (or PanIN-3) (2 patients) or invasive ductal adenocarcinoma (1 patient) apart from IPMN. Sensitivity of pancreatic juice cytology was higher in IPMN of the main duct type with mucin hypersecretion and with mural nodules. Conclusions: These findings suggest that pancreatic juice cytology in IPMN is useful especially in the main duct type with mucin hypersecretion and mural nodules. When the diagnosis of pancreatic juice cytology is malignant in otherwise benign-looking IPMNs, coexistence of pancreatic carcinoma should be suspected. Copyright (c) 2005 S. Karger AG, Basel and IAP.
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| 34. |
Kubo M, Morisaki T, Matsumoto K, Tasaki A, Yamanaka N, Nakashima H, Kuroki H, Nakamura K, Nakamura M, Katano M, Paclitaxel probably enhances cytotoxicity of natural killer cells against breast carcinoma cells by increasing perforin production, Cancer Immunol Immunother, 54, 5, 468-476, 2005.04. |
| 35. |
Tasaki A, Akiyoshi T, Koga K, Nakashima h, Yamanaka N, Kubo M, Matsumoto K, Kojima M, Tanaka M, Nakamura M, Katano M, Immunohistochemical staining of hedgehog pathway-related proteins in human thymomas, Anticancer Res, 25, 6A, 3697-3701, 2005.04, The thymus plays an essential role in the maturing of progenitor cells to functional T cells. Recent studies suggest that the Hedgehog (Hh) signaling pathway contributes to this differentiation process. However, there is limited information concerning the expression of Hh pathway-related proteins (Hh proteins) in the human thymus. The staining of Hh proteins in the thymic epithelium of 26 surgically resected thymoma tissues was examined by immunohistochemistry. The staining of sonic Hh (Shh) correlated relatively well with the World Health Organization histological classification of thymoma. The higher the grade, the fainter the staining. However, no significant difference in Shh staining was found between normal and neoplastic epithelia. Interestingly, Gli1 staining in thymomas was significantly greater than that in normal thymus (p < 0.0001). Thus, some members of the Hh signaling pathway may contribute to the development of thymoma.. |
| 36. |
Yamaguchi K, Shirahane K, Nakamura M, Su D, Konomi H, Motoyama K Sugitani A, Mizumoto K, Tanaka M, Frozen section and permanent diagnoses of the bile duct margin in gallbladder and bile duct cancer., HPB (Oxford), 7, 2, 135-138, 2005.04. |
| 37. |
Nakashima H, Tasaki A, Kubo M, Kuroki H, Matsumoto K, Tanaka M, Nakamura M, Morisaki T, Katano M, Effects of docetaxel on antigen presentation-related functions of human monocyte-derived dendritic cells.
, Cancer Chemother Pharmacol, 55, 5, 479-487, 2005.04, PURPOSE: Docetaxel (TXT) is a unique chemotherapeutic agent that has been approved for treating various types of malignancies. TXT stabilizes microtubule assembly in cells and causes various dysfunctions of microtubule-dependent cellular events. Patients with advanced malignancies are beginning to receive TXT in combination with immunotherapy; however, the influence of TXT at clinically achievable serum concentrations (less than 10(-6) M) on antigen presentation-related functions of human monocyte-derived dendritic cells (Mo-DCs) remains unclear. METHODS: Immature Mo-DCs (imMo-DCs) were generated from peripheral blood monocytes with interleukin-4 and granulocyte-macrophage colony-stimulating factor in vitro. Mature Mo-DCs (mMo-DCs) were induced from imMo-DCs with tumor necrosis factor-alpha and prostaglandin E(2). RESULTS: TXT at concentrations lower than 10(-7) M did not significantly affect cellular viability, phagocytosis, or expression of antigen presentation-related molecules of Mo-DCs. In contrast, TXT at concentrations lower than 10(-9) M significantly suppressed directional motility of imMo-DCs toward MIP-1alpha and of mMo-DCs toward MIP-3beta. However, TXT had no effect on either CCR1 expression by imMo-DCs or CCR7 expression by mMo-DCs. No gross changes in the microtubule skeleton were evident by immunofluorescence microscopy after treatment with TXT at less than 10(-8) M. However, reduced numbers of imMo-DCs with podosomes localized primarily in one cell region were observed. CONCLUSIONS: The present results indicate that different concentrations of TXT influence antigen presentation-related functions differently. In particular, TXT at relatively low therapeutic doses disrupts chemotactic motility of Mo-DCs.
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| 38. |
Katano M, Morisaki T, Koga K, Nakamura M, Onishi H, Matsumoto K, Tasaki A, Nakashima H, Akiyoshi T, Nakamura M, Combination therapy with tumor cell-pulsed dendritic cells and activated lymphocytes for patients with disseminated carcinomas., Anticancer Res, 25, 6A, 3771-3776, 2005.04. |
| 39. |
Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M, Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer., Cancer Res, 66, 14, 7041-7049, 2006.04, Abstract
The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-kappaB (NF-kappaB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-kappaB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-kappaB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-kappaB by inflammatory stimuli, including interleukin-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-kappaB. NF-kappaB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-kappaB suppressed the enhanced cell proliferation. Our data suggest that NF-kappaB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-kappaB activation in part through Shh overexpression.
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| 40. |
Akiyoshi T, Nakamura M, Nakashima H, Yao T, Tsuneyoshi M, Tanaka M, Katano M, Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation., Gut, 55, 7, 991-999, 2006.04, BACKGROUND: Early events in the progression of 90% of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pathways in colonic epithelial cell differentiation. AIMS: To investigate whether expression of Gli1, a transactivator of Hh signalling, can suppress Wnt signalling and inhibit proliferation of human colorectal cancer cells. METHODS: Gli1 and nuclear beta-catenin expression were examined in a series of 40 human colorectal cancers by immunohistochemistry. We quantified Gli1 and nuclear beta-catenin staining as markers of Hh and Wnt pathway activation, respectively. Two human colon cancer cell lines, SW480 and HCT116, with mutations in APC and beta-catenin, respectively, were used. The effects of Gli1 overexpression on Wnt transcriptional activity, beta-catenin subcellular distribution, and proliferation in these cells were analysed. RESULTS: Nuclear accumulation of beta-catenin and the Gli1 staining level were inversely associated in the 40 human colorectal cancers. Wnt transcriptional activity was reduced in Gli1 transfected cells. These effects were observed even in Gli1 transfected cells cotransfected with mutated beta-catenin. Furthermore, nuclear accumulation of beta-catenin was diminished compared with that in empty vector transfected cells, and downregulated transcription of c-Myc was observed in Gli1 transfected cells. Proliferation of Gli1 transfected cells was also significantly suppressed compared with that in empty vector transfected cells. CONCLUSIONS: Our data suggest that Gli1 plays an inhibitory role in the development of colorectal cancer involving Wnt signalling, even in cases with the stabilising mutation of beta-catenin.
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| 41. |
Yanai K, Nagai S, Wada J, Yamanaka N, Nakamura M, Torata N, Noshiro H, Tsuneyoshi M, Tanaka M, Katano M, Hedgehog signaling pathway is a possible therapeutic target for gastric cancer., J Surg Oncol, 95, 1, 55-62, 2007.04, BACKGROUND AND OBJECTIVES: It has been shown that the hedgehog (Hh) signaling pathway is activated in gastric cancer. To investigate the viability of the Hh pathway as a therapeutic target, we analyzed activation of the Hh pathway in gastric cancer. METHODS: Surgically resected gastric carcinoma specimens and lymph nodes were analyzed immunohistochemically. We used the percentage of cancer cells with nuclear translocation of Gli1 as a marker of Hh pathway activation. RESULTS: Nuclear localization of Gli1 was higher in 28 undifferentiated-type tumors than in 30 differentiated-type tumors. Eighteen of the fifty-eight cancer specimens consisted of a mixture of a histologically predominant part and a small area with different histology. In these 18 tumors, the percentage of cells showing nuclear staining of Gli1 was higher in the undifferentiated-type part than in the differentiated-type part. Nuclear staining of Gli1 in primary tumors was positively correlated with lymph node metastasis. The Gli1 nuclear staining percentage of metastatic lymph nodes correlated closely with that of each primary carcinoma. Cyclopamine, a Hh pathway inhibitor, suppressed the growth of gastric cancer cells in vitro. CONCLUSIONS: The Hh pathway may be a useful therapeutic target for such as undifferentiated-type gastric cancer with lymph node metastasis.
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| 42. |
Nakamura M, Kubo M, Yanai K, Mikami Y, Ikebe M, Nagai S, Yamaguchi K, Tanaka M, Katano M
, Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation., Anticancer Res, 27, 6A, 3743-3748, 2007.04, BACKGROUND: The hedgehog (Hh) signaling pathway is aberrantly activated in many human carcinomas including pancreatic cancer and regulates tumor cell growth. Overproduction of sonic hedgehog (Shh), a ligand of the Hh signaling pathway, increases the Hh signaling activity through transmitting the signal to patched-1 (Ptch1), the receptor of the Hh signaling pathway. MATERIALS AND METHODS: a-Ptch1 antibodies were raised against an oligo-peptide, designed according to the Ptch1 aminoacid sequence. The specificity of a-Ptch1 was examined by immunoblotting and immuno-fluorescence, and biological effects were detected by RT-PCR and cell proliferation assay using two pancreatic cancer cell lines, Panc1 and SUIT-2. RESULTS: a-Ptch1 recognized a 160 kDa protein as shown by immunoblotting and cell surface staining of pancreatic cancer cells. Incubation with a-Ptch1 suppressed Hh signaling activity and proliferation of pancreatic cancer cells. CONCLUSION: These results provide a new strategy for controling Hh dependent development of pancreatic cancer and other Hh related carcinomas.
PMID: 17970037 [PubMed - in process]
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| 43. |
Wada J, Yamasaki A, Nagai S, Yanai K, Fuchino K, Kameda C, Tanaka Haruo, Koga K, Nakashima H, Nakamura M, Tanaka M, Katano M, Morisaki T, Regulatory T-cells are possible effect prediction markers of immunotherapy for cancer patients., Anticancer Res, 28, 4C, 2401-2408, 2008.04, We previously showed that a combination therapy with tumor cell-pulsed monocyte-derived dendritic cells (DCs) and activated lymphocytes was well tolerated in patients with disseminated carcinomas. Recently, accumulating evidence has indicated that regulatory T-cells (Tregs), a unique population of CD4+ T-cells, are increased in patients with several advanced malignancies and prevent cell-mediated immune responses against tumors. However, reports analyzing the relationship between the Tregs population and the effects of immunotherapy are extremely rare. In the present study, 22 patients received an intravenous injection of DC-activated lymphocytes (DAK) and/or a subcutaneous injection of tumor-pulsed DCs (DC vaccine) every 2 to 4 weeks. The Tregs were defined based on their expression of CD4, CD25 and FOXP3, a transcription factor. Most CD4+CD25high T-cells expressed FOXP3. Therefore, CD4+CD25high T-cells were evaluated as Tregs in the present study. As reported previously, the percentage of Tregs (% Tregs) among total CD4+ T-cells in peripheral blood mononuclear cells (PBMCs) was significantly higher for advanced cancer patients than for healthy volunteers. When the patients were divided into three groups according to their survival time, i.e. 12 short-survival patients, 4 medium-survival patients and 6 long-survival patients, the % Tregs of the long-survival patients before the therapy was significantly lower than that of the short-survival patients (p=0.026). The % Tregs decreased after the therapy, although the difference did not reach statistical significance. When the patients were divided into a high group (>4.99%: 7 patients) and a low group (
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| 44. |
Koga K, Nakamura M, Nakashima H, Akiyoshi T, Kubo M, Sato N, Kuroki S, Nomura M, Tanaka M, Katano M, Novel link between estrogen receptor alpha and hedgehog pathway in breast cancer., Anticancer Res, 28, 2A, 731-740, 2008.04, Ligand-dependent constitutive activation of the hedgehog (Hh) pathway is important in the development of various carcinomas including breast cancer. A link between estrogen receptor alpha (ERalpha) and the Hh pathway in human breast cancer is shown here for the first time. In ERalpha-positive cells, estrogen depletion decreased the expression of sonic hedgehog (Shh), a ligand of the Hh pathway, while estrogen supplementation triggered Shh up-regulation. This estrogen-induced Shh expression activated the Hh pathway in a ligand-dependent manner, and increased cell proliferation. These effects were suppressed by ERalpha inhibitors, including ICI 182,780 (ICI), the dominant negative form of ERalpha and small interfering RNA (siRNA) against ERalpha. Consistent with the in vitro data, a positive correlation between ERalpha and Shh expression was found in breast cancer tissues. These data suggest that ERalpha regulates the Hh pathway through Shh induction, and promotes breast cancer development.
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| 45. |
Nagai S, Nakamura M, Yanai K, Wada J, Akiyoshi T, Nakashima H, Ohuchida K, Sato N, Tanaka M, Katano M, Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation., Cancer Sci, 99
, 7, 1377-1384, 2008.04, The hedgehog (Hh) signaling pathway has been reported to be associated with the growth of pancreatic cancer, but its role in the invasive phenotype is poorly understood. Therefore, we investigated the role of the Hh pathway in pancreatic cancer cell invasiveness using a Matrigel invasion assay. Blockade of the Hh pathway by cyclopamine inhibited pancreatic cancer cell invasion in association with a decreased expression of matrix metalloproteinase (MMP)-9. By contrast, activation of the Hh pathway by the addition of exogenous Sonic hedgehog increased cell invasion and MMP-9 expression. Stable transfection of pancreatic cancer cells with Gli1 increased their invasiveness, which was associated with activation of MMP-9. We also showed that inhibition of MMP-9 by small interfering RNA blocked the increased invasiveness of Gli1-transfected cells. Furthermore, inhibition of Gli1 by small interfering RNA suppressed the invasiveness and MMP-9 expression of pancreatic cancer cells. Taken together, these findings suggest that members of the Hh pathway, especially Gli1, play an important role in the invasiveness of pancreatic cancer cells through the regulation of MMP-9 expression.
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| 46. |
Akiyoshi T, Nakamura M, Yanai K, Nagai S, Wada J, Koga K, Nakashima H, Sato N, Tanaka M, Katano M, Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells., Gastroenterology, 134, 1, 131-144, 2008.04, BACKGROUND & AIMS: Colorectal cancers are resistant to conventional chemotherapeutic treatments, including taxanes. gamma-Secretase is a multimeric membrane protein complex responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid beta-precursor protein and Notch. gamma-Secretase inhibitors have attracted increasing interest as anticancer drugs because of their ability to inhibit Notch signaling. However, the therapeutic usefulness of gamma-secretase inhibitors against colorectal cancers remains unclear. METHODS: The effects of gamma-secretase inhibitors on growth and apoptosis induced by various chemotherapeutic agents in colon cancer cells were evaluated using Hoechst 33342 staining, colony formation assay, and cell cycle analysis. The effect of gamma-secretase inhibitors on taxane-induced mitotic arrest was evaluated using the cyclin B1-associated histone H1 kinase assay and MPM-2 reactivity. The involvement of Notch signaling was evaluated by the silencing of Notch/CBF1 signaling by RNA interference. RESULTS: gamma-Secretase inhibitors enhanced taxane-induced mitotic arrest and apoptosis of colon cancer cells both in vitro and in vivo, although gamma-secretase inhibitors alone did not affect growth and apoptosis of colon cancer cells. We also showed that this effect by gamma-secretase inhibitors was restricted to taxanes and colon cancer cells. Silencing of Notch/CBF1 signaling failed to affect paclitaxel-induced mitotic arrest and apoptosis. CONCLUSIONS: These data suggest that gamma-secretase inhibitors could be a new therapeutic modality for overcoming resistance to taxanes in colorectal cancers.. |
| 47. |
Yanai K, Nakamura M, Akiyoshi T, Nagai S, Wada J, Koga K, Noshiro H, Nagai E, Tsuneyoshi M, Tanaka M, Katano M.
, Crosstalk of hedgehog and Wnt pathways in gastric cancer., Cancer Lett, 263, 1, 145-156, 2008.04, Morphogenic signals like Hedgehog (Hh) and Wnt are reported to play critical roles in the progression of gastric cancer. We aimed to assess the relationship between Hh and Wnt signaling pathways. In 58 gastric cancer specimens, Wnt pathway activation was inversely correlated with Hh pathway activation. When AGS gastric cancer cells, in which Wnt signaling was constitutively active, were used as a target cell line, Gli1 overexpression suppressed Wnt transcriptional activity, nuclear beta-catenin accumulation and proliferation of AGS cells. Knock-down of beta-catenin by siRNA suppressed Wnt pathway activity and proliferation of AGS cells. Our data may provide some clues for the treatment of gastric cancer associated with Wnt signaling activation.
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| 48. |
Tanaka Haruo, Nakamura M, Kameda C, Kubo M, Sato N, Kuroki S, Tanaka M, Katano M, The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells.
, Anticancer Res, 29, 6, 2147-2157, 2009.04, The side population (SP) and the CD44(+)/CD24(-/low) population have been reported in separate studies to include more tumorigenic cells than other populations, and to have the ability to form new tumors and undergo heterogeneous differentiation in breast cancer tissue. However, the relationship between these two populations has not yet been explored in breast cancer cells. Here it is shown that the SP and the CD44(+)/CD24(-/low) populations are overlapping. Both populations were resistant to paclitaxel. Components of the Hedgehog (Hh) signaling pathway were more highly expressed in these cell populations at both the mRNA and protein levels compared with other populations. Furthermore, inhibition of Hh signaling activity suppressed the proliferation of both populations. The significance of Hh signaling activity in the proliferation of both populations was confirmed by the effect of an si-RNA against Gli1, a trans-activator of the Hh signaling pathway, on the proliferation of both populations. These data suggest that the Hh signaling pathway is essential for the proliferation of the tumorigenic population of breast cancer cells, and that this pathway might represent a new candidate for breast cancer therapy targeting cancer stem cells.
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| 49. |
Kameda C, Tanaka Haruo, Yamasaki A, Nakamura M, Koga K, Sato N, Kubo M, Kuroki S, Tanaka M, Katano M
, The Hedgehog pathway is a possible therapeutic target for patients with estrogen receptor-negative breast cancer, Anticancer Res, 29, 3, 871-879, 2009.04, Understanding the expression patterns of estrogen receptor-alpha (ERalpha) is essential for determining therapeutic strategies for patients with breast cancer. The prognosis of patients with ERalpha-negative breast cancer is still poor. We have previously shown that Hedgehog (Hh) signaling is constitutively activated in breast cancer and that Hh signaling could be a new therapeutic target. Therefore, in this study, whether or not Hh signaling could be utilized as a therapeutic target for patients with ERalpha-negative breast cancer was examined. For this purpose, three ERalpha-negative breast cancer cell lines were used in which Hh pathway-related molecules such as the ligand Patched1 and the transcriptional factor Gli1 as target cells are expressed. Cyclopamine, an inhibitor of the Hh pathway, significantly suppressed both the cell proliferation and invasion ability of these cancer cells. In addition, the knockdown of Gli1 by RNA interference in these cells also significantly reduced both cell proliferation and invasion ability. Since our previous data have shown a constitutive activation of the Hh pathway in surgically-resected ERalpha-negative breast cancer specimens, the Hh pathway, especially Gli1, may be a useful therapeutic target for patients with ERalpha-negative breast cancer.
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| 50. |
Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, Koga K, Nakamura M, Tanaka M, Morisaki T, Katano M, The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions, Anticancer Res, 29, 3, 881-888, 2009.04, AbstractIt has been suggested that immunosuppressive cytokines such as transforming growth factor beta (TGF-beta) and interleukin 10 play an important role in the induction and/or maintenance of regulatory T-cells (Tregs) in patients with cancer. In the present study, whether or not vascular endothelial growth factor (VEGF) contributes to the induction and/or maintenance of Tregs was examined, because of experience with a patient in whom a positive correlation between VEGF concentration and the percentage of Tregs (% Tregs) among the total CD4(+) T-cells in the pleural effusion was found during dendritic cell activated lymphocyte therapy. CD4(+)CD25(high) T-cells were estimated as Tregs in the present study. In an in vitro experimental system, VEGF-containing malignant effusions increased the % Tregs in autologous peripheral blood mononuclear cells (PBMCs), which could be suppressed by the addition of a humanized monoclonal anti-VEGF antibody (bevaciz
umab [Avastin]). When VEGF-producing hepatic carcinoma cells were mix-cultured with PBMCs, the % Tregs increased and this increase was also suppressed by the addition of bevacizumab. Whether or not bevacizumab can affect the % Tregs of PBMCs in patients with colon cancer was also examined. Three out of four patients showed a significant decrease of the % Tregs after intravenous injection of bevacizumab. Interestingly, the expression of VEGF receptor-2 (VEGFR-2) was higher in Tregs than in other CD4(+) T-cells. Taken together, the data presented here indicate a contribution of VEGF to induction and/or maintenance of Tregs in patients with cancer.. |
| 51. |
Nakamura M, Wada J, Suzuki H, Tanaka M, Katano M, Morisaki T, Long-term Outcome of Immunotherapy for Patients with Refractory Pancreatic Cancer, Anticancer Res, 29, 3, 831-836, 2009.04, BACKGROUND: Pancreatic cancer is one of the most fatal human cancers, with a 5-year survival rate of
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| 52. |
Ikebe M, Kitaura Y, Nakamura M, Tanaka Haruo, Yamasaki A, Nagai S, Wada J, Yanai K, Koga K, Sato N, Kubo M, Tanaka M, Onishi H, Katano M, Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway
, J Surg Oncol, 100, 8, 725-731, 2009.04, BACKGROUND: Inflammation plays a multifaceted role in cancer progression, and NF-kappaB is one of the key factors connecting inflammation with cancer progression. We have shown that lipopolysaccharide (LPS) promotes NF-kappaB activation in colon cancer cells and pancreatic cancer cells. However, it is unclear why inflammatory stimuli can induce NF-kappaB activation in cancer cells. METHODS: We used two human pancreatic cancer cells, Panc-1 and AsPC-1, as target cells. LPS was used as an inflammatory stimulus. To confirm the participation of TLR4/NF-kappaB signaling pathway, we used three different NF-kappaB inhibitors (PDTC, IkappaBalpha mutant, and NF-kappaB decoy ODN) and siRNAs (against TLR4, MyD88, and MMP-9). Effect of LPS on pancreatic cancer cell invasive ability was determined by Matrigel invasion assay. RESULTS: LPS increased the invasive ability of pancreatic cancer cells, while blockade of NF-kappaB pathway decreased the LPS-dependent increased invasive ability. Blockade of TLR4 or MyD88 by siRNA also decreased the LPS-dependent increased invasive ability. CONCLUSION: These results suggest that TLR/MyD88/NF-kappaB signaling pathway plays a significant role in connecting inflammation and cancer invasion and progression. Copyright 2009 Wiley-Liss, Inc.
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| 53. |
Xu R, Sato N, Yanai K, Akiyoshi T, Nagai S, Wada J, Koga K, Mibu R, Nakamura M, Katano M, Enhancement of paclitaxel-induced apoptosis by inhibition of mitogen-activated protein kinase pathway in colon cancer cells, Anticancer Res, 29, 1, 261-270, 2009.04, Resistance to chemotherapy represents a major obstacle to improving the survival of patients with colorectal cancer. In this study, the inhibition of the mitogen-activated protein kinase (MAPK) pathway was demonstrated to markedly enhance the apoptosis of colon cancer cells induced by paclitaxel, one of the key chemotherapeutic drugs widely used to treat various types of cancer. The treatment of the colon cancer cell lines SW480 and DLD-1 with paclitaxel resulted in increased activation of the MAPK pathway, which was blocked by PD98059, a MEK inhibitor. In both cell lines, MAPK inhibition by PD98059 led to a dramatic enhancement of the paclitaxel-induced apoptosis, as determined by cell cycle analysis and Hoechst 33342 staining, although the inhibitor alone did not affect apoptosis. This effect was restricted to paclitaxel since PD98059 did not alter the sensitivity to other drugs, including 5-fluorouracil (5-FU) and camptothecin (CPT). Importantly, selective blockage of the MAPK pathway by small interfering RNA (siRNA) also increased the apoptotic cell death induced by paclitaxel. These findings highlight the importance of the MAPK pathway in paclitaxel-induced apoptosis and suggest that a combined treatment with paclitaxel and MEK inhibitors could be an attractive therapeutic strategy against colon cancer. |
| 54. |
Yamasaki A, Shoda M, Iijima H, Nagai S, Wada J, Suzuki H, Chikazawa N, Tasaka T, Kameda C, Tanaka Haruo, Ikebe M, Jo E, Sato N, Nakamura M, Sekine F, Morisaki T, Katano M, A protein-bound polysaccharide, PSK, enhances tumor suppression induced by docetaxel in a gastric cancer xenograft model
, Anticancer Res, 29, 3, 843-850, 2009.04, BACKGROUND: We have reported previously that docetaxel (TXT) induces apoptosis and nuclear factor-kappaB (NF-kappaB) activation, and that blockade of NF-kappaB activation augments TXT-induced apoptosis in human gastric cancer cells. In addition, we have also shown that a protein-bound polysaccharide PSK enhances TXT-induced apoptosis through NF-kappaB inhibition in human pancreatic cancer cells. Based on these observations, in the present study the possibility that PSK could enhance TXT-mediated tumor suppression was examined in vivo and in vitro. MATERIALS AND METHODS: A gastric cancer xenograft model was used to examine the enhanced TXT-mediated tumor suppression by PSK in vivo. The effects of PSK on proliferation and apoptosis induced by TXT in gastric cancer cells were evaluated in vitro using a human gastric cancer cell line, MK-1. The effect of PSK on increased TXT-induced invasion was also measured. RESULTS: PSK enhanced TXT-mediated tumor suppression in vivo. Immunohistochemical analyses of the tumors revealed that TXT increased NF-kappaB activation in the tumors and this was suppressed by PSK. In the ex vivo experimental system, PSK enhanced the growth inhibition and apoptosis induced by TXT in the MK-1 cells and reduced the increased invasive ability induced by TXT. CONCLUSION: PSK enhanced TXT-induced tumor suppression in a gastric cancer xenograft model.
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| 55. |
Kameda C, Nakamura M, Tanaka Haruo, Yamasaki A, Kubo M, Tanaka M, Onishi H, Katano M, Oestrogen receptor-alpha contributes to the regulation of the hedgehog signalling pathway in ERalpha-positive gastric cancer
, Br J Cancer, 102, 4, 738-747, 2010.04, BACKGROUND: Oestrogen receptor-alpha (ERalpha) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERalpha-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. METHODS: We used 17-beta-oestradiol (E2) as a stimulator against the ERalpha pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERalpha (ERalpha siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERalpha-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. RESULTS: In ERalpha-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-beta-Oestradiol-induced cell proliferation was suppressed by ICI, ERalpha siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERalpha siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERalpha and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERalpha and Hh pathways. CONCLUSION: Our data indicate that activation of the ERalpha pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERalpha-positive gastric cancer.
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| 56. |
Sadakari Y, Otsuka T, Ohuchida K, Tsutsumi K, Takahata S, Nakamura M, Mizumoto K, Tanaka M, MicroRNA expression analyses in preoperative pancreatic juice samples of pancreatic ductal adenocarcinoma.
, JOP, 11, 6, 587-592, 2010.04, Abstract
CONTEXT: Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma.
OBJECTIVE: The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine whether specific microRNAs in pancreatic juice could be used for detecting pancreatic ductal adenocarcinoma.
METHODS: Relative expression levels of microRNA-21 and microRNA-155 in formalin-fixed paraffin-embedded tissues of resected specimens (no. 13) and pancreatic juice samples collected using preoperative endoscopic retrograde cholangiopancreatography (no. 21) were quantified and their expression levels were then compared to pancreatic ductal adenocarcinoma and chronic pancreatitis.
RESULTS: Relative expression levels of microRNA-21 in tissue and pancreatic juice samples were significantly higher in pancreatic ductal adenocarcinoma than those in chronic pancreatitis (P=0.009 and P=0.021, respectively). The same results were obtained in the expression levels of microRNA-155 in tissue and pancreatic juice between pancreatic ductal adenocarcinoma and chronic pancreatitis (P=0.014 and P=0.021, respectively). Expression levels of microRNA-21 and microRNA-155 did not correlate with the preoperative cytological results of pancreatic juice.
CONCLUSION: MicroRNA-21 and microRNA-155 in pancreatic juice have the potential of becoming biomarkers for diagnosing pancreatic ductal adenocarcinoma.
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| 57. |
Sadakari Y, Ohuchida K, Nakata K, Ohtsuka T, Aishima S, Takahata S, Nakamura M, Mizumoto K, Tanaka M, Invasive carcinoma derived from the nonintestinal type intraductal papillary mucinous neoplasm of the pancreas has a poorer prognosis than that derived from the intestinal type, Surgery, 147, 6, 812-817, 2010.04, BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is divided into 4 subtypes: an intestinal type, a gastric type, a pancreatobiliary type, and an oncocytic type. The purposes of this study were to clarify the outcomes and the characteristics of invasive carcinoma derived from IPMN (invasive IPMC) by focusing on these subtypes with a comparison to conventional invasive ductal carcinoma (IDC) of the pancreas. METHODS: A total of 30 patients with invasive IPMC were reviewed, and the tumors were divided into 2 pathologic subtypes, intestinal and nonintestinal type. The prognosis and characteristics of the 2 subtypes were evaluated. Furthermore, the prognosis of 119 patients with conventional IDC was compared with that of patients with invasive carcinoma derived from the intestinal or nonintestinal type IPMN. RESULTS: The 5-year survival rate of patients with the nonintestinal type (0.0%) was as poor as that of patients with conventional IDC (19.9%; P = .67). The patients with the intestinal type (66.7%) had a more favorable prognosis than patients with conventional IDC (P
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| 58. |
Chikazawa N, Tanaka Haruo, Tasaka T, Nakamura M, Tanaka M, Onishi H, Katano M, Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells
, Anticancer Res, 30, 6, 2041-2048, 2010.04, BACKGROUND: The prognosis of advanced or recurrent colorectal cancer is still poor. Dye-effluxing side population (SP) colon cancer cells are reportedly resistant to chemotherapeutic agents. Most sporadic colorectal cancers involve constitutive activation of the Wnt signaling pathway. In this study, we examined the effect of the Wnt signaling on SP cells and the possibility that inhibition of Wnt signaling may decrease the resistance to chemotherapeutic drugs in the human colon cancer cells.
MATERIALS AND METHODS: Drug resistance of SP cells to 5-fluorouracil (5-FU) and irinotecan, decrease of SP cells by the Wnt signaling inhibition and activation of the Wnt signaling of the sorted SP cells were examined using the SW480 colon cancer cell line. mRNA expressions of ATP-binding cassette (ABC) transporters when Wnt signaling was inhibited were evaluated with real-time PCR using colon cancer cell lines (SW480, DLD-1, HCT116, HT29 and LOVO). The sensitivity to irinotecan and paclitaxel when the Wnt signaling was inhibited was investigated using SW480. Inhibition of Wnt signaling was performed by siRNA of beta-catenin.
RESULTS: SP cells showed more resistance to 5-FU and irinotecan, and higher activation of the Wnt signaling pathway, than non-SP cells. Silencing of beta-catenin decreased significantly more SP cells than non-SP cells. Expression of ABC transporter genes, such as ABCB1 and ABCG2, was significantly higher in SP cells than non-SP cells. Silencing of beta-catenin decreased transcription of these ABC transporter genes; beta-catenin-silenced cells became relatively sensitive to paclitaxel and irinotecan.
CONCLUSION: These results indicate that inhibiting the Wnt signaling pathway may be a fruitful strategy for targeting chemotherapy-resistant colon cancer cells, including SP cells.
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| 59. |
Kobayashi K, Sadakari Y, Ohtsuka T, Takahata S, Nakamura M, Mizumoto K, Tanaka M
, Factors in Intraductal Papillary Mucinous Neoplasms of the Pancreas Predictive of Lymph Node Metastasis
, Pancreatology, 10, 6, 720-725, 2010.04, Background: Little is known about the frequency of lymph node metastasis (LNM) in intraductal papillary mucinous neoplasms (IPMNs), and we have not been able to determine how much lymph node dissection is necessary in individual cases. The aim of this study was to investigate the predictive factors for the LNM in IPMNs. Methods: Medical records of 120 patients pathologically diagnosed as having IPMN were reviewed, and 16 possible predictive factors regarding the LNM were analyzed. Results: LNM was observed in 7 patients (6%), all of whom were diagnosed as having mural nodules preoperatively. Sensitivity, specificity, and accuracy of preoperative imaging for detecting mural nodules of IPMNs in this study were 84, 97, and 90%, respectively. Univariate analysis using 61 patients having mural nodules preoperatively revealed that the size of mural nodules ≥10 mm and positive imaging findings for invasive tumor and possible LNM were significant predictive factors for the LNM. Multivariate analysis demonstrated that only an imaging finding for invasive tumor was an independent significant predictive factor. Positive and negative predictive values of the imaging finding of invasive IPMNs for LNM were 50 and 98%, respectively. Conclusions: Standard lymph node dissection would be recommended in patients with IPMNs with mural nodules demonstrating preoperative imaging findings for invasive carcinomas. and IAP.
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| 60. |
Sadakari Y, Ienaga J, Kobayashi K, Miyasaka Y, Takahata S, Nakamura M, Mizumoto K, Tanaka M, Cyst Size Indicates Malignant Transformation in Branch Duct Intraductal Papillary Mucinous Neoplasm of the Pancreas Without Mural Nodules, Pancreas, 39, 2, 232-236, 2010.04, In branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas, the importance of the cyst size to predict malignancy is still controversial. Our aim was to elucidate the malignant potential of branch duct IPMN without mural nodules (flat branch duct IPMN). METHODS:: Seventy-three patients with flat branch duct IPMNs were studied in our institution. RESULTS:: There were 6 malignant IPMNs in this series, all of which were 30 mm or more in size, whereas there was no malignancy in IPMNs of less than 30 mm. Statistically significant predictors of malignancy were atypical cytological condition and main pancreatic duct (MPD) diameter of 5 mm or more. The cyst size of 30 mm or more tended to be associated with malignancy. The frequency of malignancy in flat branch duct IPMNs with the size of 30 mm or more and MPD diameter of less than 5 mm was 3.6%, whereas there were 5 malignant cases (26.3%) in flat branch duct IPMNs with the size of 30 mm or more and MPD diameter of 5 mm or more. CONCLUSIONS:: We conclude that the size criteria (>/=30 mm) to predict malignancy proposed in the international consensus guidelines is appropriate and resection or meticulous follow-up using cytological examination and MPD dilatation is needed in patients with flat branch duct IPMNs.
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| 61. |
Aly MY, Tsutsumi K, Nakamura M, Sato N, Takahata S, Ueda J, Shimizu S, Redwan AA, Tanaka M, Comparative study of laparoscopic and open distal pancreatectomy
, J Laparoendosc Adv Surg Tech A, 20, 5, 435-440, 2010.04, BACKGROUND: Laparoscopic distal pancreatectomy (LDP) has been shown to be an effective surgical option for benign lesions in the body and tail of the pancreas. However, its advantages and disadvantages have not been well characterized. In this study, we compared the outcomes of LDP and open pancreatectomy performed in our clinic.
MATERIALS AND METHODS: Peri- and postoperative outcomes were retrospectively compared between patients with benign pancreatic disorders who underwent open distal pancreatectomy (ODP) (n = 35) and those who underwent LDP (n = 40). The peri- and postoperative factors analyzed included operative time, blood loss, hospital stay, postoperative recovery, biochemical findings, and complications.
RESULTS: LDP was associated with significantly less operative blood loss (363 versus 606 mL; P = 0.001) and shorter hospital stay (22 versus 27 day; P = 0.009), but longer operative time (342 versus 250 min; P = 0.000), compared with ODP. There were no significant differences between the two groups in complication rates or postoperative recovery, except for the significantly shorter duration of postoperative pain-killer intake and earlier improvement of the biochemical analysis in LDP than in ODP.
CONCLUSIONS: LDP appears to be a safe, desirable procedure for the management of benign pancreatic diseases, with outcomes similar to ODP
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| 62. |
Tsutsumi K, Ohtsuka T, Oda Y, Sadakari Y, Mori Y, Aishima S, Takahata S, Nakamura M, Mizumoto K, Tanaka M, A History of Acute Pancreatitis in Intraductal Papillary Mucinous Neoplasms of the Pancreas Is a Potential Predictive Factor for Malignant Papillary Subtype
, Pancreatology, 10, 6, 707-712, 2010.04, Background/Aims: There are several reports regarding intraductal papillary mucinous neoplasms (IPMNs) detected after the occurrence of acute pancreatitis. Although the presence of symptoms is regarded as a factor for predicting malignant IPMNs, there have been few reports demonstrating whether a history of acute pancreatitis is a predictor of malignancy. The aim of this study was to evaluate the relationship between a history of acute pancreatitis and clinicopathological features of IPMNs including the papillary subtype. Methods: The data of 150 IPMNs resected between 1990 and 2009 were retrospectively reviewed. They were classified into IPMNs with or without history of acute pancreatitis, and then the clinicopathological features were compared between the 2 groups. Results: Nineteen (13%) of the 150 patients had a history of acute pancreatitis. Nine of them had repeated episodes of pancreatitis; however, severe pancreatitis was uncommon. The diameter of the main pancreatic duct of the pancreatitis group was significantly larger than that of the nonpancreatitis group (p = 0.04). The pancreatitis group had a significantly higher frequency of carcinoma derived from IPMNs than the nonpancreatitis group (p = 0.03). The incidence of intestinal-type IPMNs in the pancreatitis group was significantly higher than that in the nonpancreatitis group (p
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| 63. |
Nakamura M, Ueda J, Kono H, Aly MY, Takahata S, Shimizu S, Tanaka M, Prolonged peri-firing compression with a linear stapler prevents pancreatic fistula in laparoscopic distal pancreatectomy.
, Surg Endosc, 25, 3, 867-871, 2011.04, BACKGROUND: Laparoscopic distal pancreatectomy (Lap-DP) is one of the most accepted laparoscopic procedures in the field of pancreatic surgery. However, pancreatic fistula remains a major and frequent complication in Lap-DP, as in open surgery. The aim of this retrospective study is to clarify the advantages of prolonged peri-firing compression (PFC) with a linear stapler for prevention of pancreatic fistula after laparoscopic distal pancreatectomy.
PATIENTS AND METHODS: Incidence of pancreatic fistula in clinical levels (equivalent to grades B and C defined by the International Study Group of Pancreatic Fistula (ISGPF)) was retrospectively compared between patients who underwent Lap-DP with PFC (PFC group, n = 17) and those who underwent Lap-DP without PFC (no-PFC group, n = 25).
RESULTS: Incidence of clinical pancreatic fistula was significantly lower in the PFC group than in the no-PFC group. Consistent with the results for pancreatic fistula, peritoneal drainage period and postoperative hospital stay were shorter in the PFC group than in the no-PFC group.
CONCLUSIONS: Our data show that PFC effectively prevents pancreatic fistula and shortens postoperative hospital stay after Lap-DP.
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| 64. |
Nakamura M, Nagayoshi Y, Kono H, Mori Y, Otsuka T, Takahata S, Shimizu S, Tanaka M, Lateral approach for laparoscopic splenic vessel-preserving distal pancreatectomy.
, Surgery, 150, 2, 326-331, 2011.04, AIM: We sought to evaluate the feasibility of the lateral approach for laparoscopic splenic vessel-preserving distal pancreatectomy (LA-SVPDP).
BACKGROUND: Complete preservation of the splenic vessels is an ideal outcome in spleen-preserving distal pancreatectomy (SPDP). However, the preservation of the vessels is challenging in laparoscopic surgery because the splenic vein is often embedded in the pancreatic parenchyma. Herein we have described LA-SVPDP, the most feasible method for laparoscopic SPDP, and the outcome of our initial experience.
PATIENTS: Twenty-three patients underwent laparoscopic SPDP. Before we adopted LA-SVPDP, 8 patients underwent the Warshaw method and 6 underwent SVPDP. After the adoption of LA-SVPDP, 8 patients underwent LA-SVPDP and 1 donor underwent the Warshaw method.
RESULTS: None of patients undergoing LA-SVPDP required conversion to an open operation, whereas 2 patients undergoing the other procedures were converted to open operations. Five out of 8 patients who underwent the Warshaw method showed engorgement of the gastric veins, revealed by computed tomography. However, only 1 of the 5 patients showed mild gastric varices on endoscopy.
CONCLUSION: Although the Warshaw method is acceptable with a low incidence of gastric varices in our analysis, SVPDP is a feasible approach for SPDP. Our LA-SVPDP technique may contribute to safer and easier SVPDP in laparoscopic surgery.
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| 65. |
Chen G, Goto Y, Sakamoto R, Tanaka K, Matsubara E, Nakamura M, Zheng H. Lu J, Takayanagi R, . Nomura M
, GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor.
, Biochem Biophys Res Commun, 404, 3, 809-815, 2011.04, Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from anandrogen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.
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| 66. |
Tsutsumi K, Sato N, Tanabe R, Mizumoto K, Morimatsu K, Kayashima T, Fujita H, Ohuchida K, Ohtsuka T, Takahata S, Nakamura M, Tanaka M, Claudin-4 Expression Predicts Survival in Pancreatic Ductal Adenocarcinoma
, Ann Surg Oncol, 19, Suppl3, S491-499, 2011.04, Abstract
BACKGROUND: Identification of prognostic markers would be useful in the clinical management of patients with pancreatic ductal adenocarcinoma (PDAC). The clinical relevance of claudin-4 (CLDN4), recently identified as overexpressed in PDAC, is unknown.
METHODS: Using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), we analyzed CLDN4 mRNA expression in a panel of 9 pancreatic cancer cell lines and formalin-fixed paraffin-embedded (FFPE) tissues from 100 patients with PDAC. The CLDN4 expression levels were then correlated with clinicopathological variables and patient outcome. We also performed immunohistochemical analysis in 20 FFPE samples of PDAC to investigate the expression of CLDN4 protein.
RESULTS: Increased expression of CLDN4 was confirmed in all the pancreatic cancer cell lines tested compared with normal ductal epithelial cells and fibroblasts. We found that low expression of CLDN4 was significantly associated with shorter survival in patients with PDAC (hazard ratio; 1.362, 95% confidence interval; 1.011-1.873, P = 0.0419). Patients with high CLDN4 expression survived longer for a median of 63.0 months, compared with 14.7 months in patients with low CLDN4 expression (P = 0.0067). In immunohistochemical analysis, the level of CLDN4 mRNA expression was significantly correlated with the expression of CLDN4 protein (P = 0.0168).
CONCLUSION: Increased expression of CLDN4 mRNA predicts better prognosis in PDAC.
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| 67. |
Nakamura M, Tanaka Haruo, Nagayoshi Y, Nakashima H, Tsutsumi K, Otsuka T, Takahata S, Tanaka M, Okada H, Targeting the hedgehog signaling pathway with interacting peptides to Patched-1, J Gastroenterol, 47, 4, 452-460, 2012.04, BACKGROUND:
The hedgehog (Hh) signaling pathway is aberrantly activated in many cancers. Overproduction of sonic hedgehog (Shh), a ligand in the Hh pathway, increases Hh signaling activity by inhibiting Patched-1 (Ptch1), a suppressive receptor in the Hh pathway. The purpose of this study was to establish a novel strategy for treating pancreatic cancer and other Hh-dependent cancers through control of the tumor-suppressive function of Ptch1.
METHODS:
We synthesized seven interacting peptides to the amino-acid sequence of the Ptch1 docking site for Shh. Human pancreatic cancer cell lines (AsPC-1, SUIT2) were cultured in the presence or absence of the peptides. Cell proliferation was assessed by cell counting and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activity of the Hh pathway was estimated by real-time polymerase chain reaction of the target gene product Gli1. To confirm their anti-tumor activity in vivo, the effect of the peptides in a mouse model of pancreatic cancer was determined. Finally, the Hh signaling activity of the xenograft was examined.
RESULTS:
Three of the interacting peptides to Ptch1 suppressed the proliferation of the two pancreatic cancer cell lines and decreased the expression of Gli1, both in vitro and in vivo.
CONCLUSIONS:
This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.
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| 68. |
Ohuchida K, Mizumoto K, Lin C, Yamaguchi H, Ohtsuka T, Sato N, Toma H, Nakamura M, Nagai E, Hashizume M, Tanaka M, MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene, Ann Surg Oncol, 19, 7, 2394-2402, 2012.04, Abstract
BACKGROUND:
There is increasing evidence that microRNAs are differentially expressed in many types of cancers. Despite progress in analyses of microRNAs in several types of cancers, the functional contributions of microRNAs to pancreatic cancer remain unclear.
METHODS:
In the present study, the expression levels of specific microRNAs identified by microarray analyses were examined in a panel of 15 pancreatic cancer cell lines. We then investigated the functional roles of these microRNAs in the proliferation and invasion of pancreatic cancer cells.
RESULTS:
Based on the microarray data, we found frequent and marked overexpression of miR-10a, miR-92, and miR-17-5p in pancreatic cancer cell lines. Microdissection analyses revealed that miR-10a was overexpressed in pancreatic cancer cells isolated from a subset of primary tumors (12 of 20, 60%) compared with precursor lesions and normal ducts (P<.01 in vitro experiments revealed that mir-10a inhibitors decreased the invasiveness of pancreatic cancer cells but had no effect on their proliferation. inhibition hoxa1 a target promoted>CONCLUSIONS:
The present data suggest that miR-10a is overexpressed in a subset of pancreatic cancers and is involved in the invasive potential of pancreatic cancer cells partially via suppression of HOXA1.. |
| 69. |
Tanabe R, Otsuka T, Miyatake E, Kawamoto M, Nakamura M, Takahata S, Tanaka M, Manometric Evidence of Earlier Recovery of Fasting Gastric Motility after Antecolic Duodenojejunostomy than after Retrocolic Duodenojejunostomy following PPPD., Hepatogastroenterology, 59, 118, 1981-1985, 2012.04, Backgrounds/Aims: Gastric stasis is a unique complication of pylorus-preserving pancreatoduodenectomy (PPPD). Although some studies reported less prevalence of gastric stasis after antecolic duodenojejunostomy, there have been no reports on detailed comparison of gastric motility after antecolic vs. retrocolic duodenojejunostomy after PPPD. Methodology: Thirty-six patients underwent PPPD with the modified Child reconstruction. Retrocolic duodenojejunostomy was utilized in initial 13 patients (retrocolic group). For comparison, antecolic duodenojejunostomy was employed in subsequent 23 patients (antecolic group). A manometric tube assembly was inserted into the gastric antrum and jejunum during PPPD. Gastrointestinal motility was recorded for 3 hours a day, starting on 6 to 14 days after surgery and repeated at a weekly interval until the first appearance of phase 3 gastric motility. Various clinical parameters were also assessed. Results: Recovery of gastric phase 3 was identified in 19 of 36 patients. Recovery of phase 3 was faster in antecolic group than in retrocolic group (p |
| 70. |
Mori Y, Otsuka T, Kono H, Ideno N, Aso T, Nagayoshi Y, Takahata S, Nakamura M, Ishigami K, Aishima S, Oda Y, Tanaka M, Management strategy for multifocal branch duct intraductal papillary mucinous neoplasms of the pancreas., Pancreas, 41, 7, 1008-1012, 2012.04, OBJECTIVES:
Branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs) often are composed of multifocal lesions. We aimed to clarify the clinicopathologic features of multifocal BD-IPMNs.
METHODS:
Medical records of 211 patients with BD-IPMNs (169 solitary and 42 multifocal) were retrospectively analyzed. We compared the pathological grade of resected IPMNs and the resulting clinical course between solitary and multifocal BD-IPMNs.
RESULTS:
Sixty-nine patients (54 with solitary and 15 with multifocal BD-IPMNs) underwent pancreatectomy, and of these patients, 62 exhibited at least 1 malignant predictor. There was no significant difference in the prevalence of malignancy in the resected BD-IPMNs between the 2 groups. In the remaining 142 patients who exhibited no malignant predictors, both groups demonstrated no differences in morphologic changes of BD-IPMNs. Seventeen distinct ductal carcinomas were identified in both groups, and there was no difference in the prevalence of ductal carcinoma between the 2 groups. Moreover, there was no significant difference in the disease-specific survival rate between the 2 groups.
CONCLUSIONS:
In patients with multifocal BD-IPMNs, resection is only warranted for lesions that exhibit malignancy predictors; moreover, closer attention to the potential presence or development of distinct ductal carcinoma in patients with multifocal and solitary BD-IPMNs is warranted.
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| 71. |
Yasui T, Takahata S, Kono H, Nagayoshi Y, Mori Y, Tsutsumi K, Sadakari Y, Otsuka T, Nakamura M, Tanaka M, Is cholecystectomy necessary after endoscopic treatment of bile duct stones in patients older than 80 years of age?
, J Gastroenterol, 47, 1, 65-70, 2012.04, Abstract
BACKGROUND AND AIMS: Although patients with cholecystocholedocholithiasis are generally referred to cholecystectomy after endoscopic sphincterotomy (ES) and common bile duct clearance, we often have a conflict whether cholecystectomy is necessary in very elderly patients with comorbid diseases. The aim of this study is to assess whether cholecystectomy in very elderly patients is justified after ES.
PATIENTS AND METHODS: Patients with cholecystocholedocholithiasis who underwent ES and stone extraction and were followed-up for more than 10 years were retrospectively reviewed. We divided these patients into two groups: the elderly group (equal to or more than 80 years old) and young group (less than 80 years old) and compared late biliary complications and mortality.
RESULTS: The 10-year cumulative incidence of overall biliary complications was significantly lower in cholecystectomized patients than in patients with gallbladder in situ in the young group (7.5 vs. 21.7%, p = 0.0037), but not different in the elderly group (8.3 vs. 7.4%, p = 0.92). When each complication was evaluated separately, the rate of recurrent common bile duct stones (CBDS) was not different, but that of acute cholecystitis was significantly lower in the elderly group than in the young group (4.1 vs. 22.6%, p = 0.011).
CONCLUSIONS: In very elderly patients the incidence of acute cholecystitis is low even when the gallbladder is preserved after endoscopic treatment of CBDS, with a similar risk of CBDS recurrence. Thus, it may not be necessary to recommend cholecystectomy after ES for CBDS in very elderly patients.
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| 72. |
Otsuka T, Kono H, Tanabe R, Nagayoshi Y, Mori Y, Sadakari Y, Takahata S, Oda Y, Aishima S, Igarashi H, Ito T, Ishigami K, Nakamura M, MizumotoK, Tanaka M, Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas.
, Am J Surg, 204, 1, 44-48, 2012.04, Abstract
BACKGROUND: Frequency and characteristics of metachronous occurrence of multifocal intraductal papillary mucinous neoplasms (IPMNs) or distinct pancreatic ductal adenocarcinomas (PDACs) in the remnant pancreas during follow-up evaluation after pancreatectomy for IPMNs have not been well known. The aim of this study was to investigate the outcomes after resection of IPMNs, especially focusing on the metachronous occurrence of multifocal IPMNs and distinct PDACs.
METHODS: Medical records of 172 patients who underwent resection of IPMNs were reviewed retrospectively, and the data regarding the occurrence of metachronous IPMNs or PDACs in the remnant pancreas during a mean postoperative follow-up period of 64 months were collected.
RESULTS: The incidence including synchronous and metachronous multifocal occurrence of IPMNs was 20% (34 of 172), and that of distinct PDACs was 9.9% (17 of 172). Ten metachronous IPMNs developed in the remnant pancreas after a mean time of 23 postoperative months (range, 12-84 mo), and 2 with main duct IPMNs (both were carcinoma in situ) required remnant pancreatectomy. Six distinct PDACs developed in the remnant pancreas after a mean time of 84 postoperative months (range, 12-150 mo). Four of them were found to have a tumor with a size of less than 2 cm, whereas the remaining 2 PDACs were found to be unresectable more than 10 years after resection of IPMNs.
CONCLUSIONS: Intense long-term follow-up evaluation is necessary for the early detection of metachronous occurrence of distinct PDACs as well as malignant IPMNs after resection of IPMNs.
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| 73. |
Higashida M, Matsumoto H, Kubota H, Murakami H, Kawabe Y, Nakashima H, Oka Y, Okumura H, Nakamura M, Hirai T, Evaluation of 5-FU plasma concentration by 13C breath test in patients treated with oral 5-FU analogs, Anticancer Res, 32, 12, 5407-5414, 2012.04. |
| 74. |
Mori Y, Otsuka T, Tsutsumi K, Yasui T, Ueda J, Takahata S, Nakamura M, Tanaka M, Different incretin responses after pancreatoduodenectomy and distal pancreatectomy, Pancreas, 41, 3, 455-460, 2012.04,
OBJECTIVES:
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins to stimulate insulin secretion. The aims of this study were to investigate the postoperative β-cell function and hormonal responses of GLP-1 and GIP after pancreatoduodenectomy (PD) and distal pancreatectomy (DP).
METHODS:
Oral glucose tolerance tests were performed in 34 patients (20 PD and 14 DP) before and 1 month after operation. The changes in the serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance, and pancreatic β-cell function (BCF) were analyzed. GLP-1 and GIP were also measured.
RESULTS:
There was no patient with postoperative deterioration of glucose tolerance after PD, whereas impairment of glucose metabolism was observed after DP. Homeostasis model assessment of insulin resistance decreased after PD, whereas those after DP showed no change. The postoperative BCF were lower than preoperative values in both groups. GLP-1 increased after DP but not after PD, whereas GIP decreased after PD but not after DP.
CONCLUSIONS:
The changes in glucose metabolism and incretin responses were different between PD and DP. The increased level of GLP-1 after DP might reflect the relatively insufficient BCF; and thus, perioperative administration of GLP-1 might improve the diabetic condition after DP.
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| 75. |
Tsutsumi K, Otsuka T, Mori Y, Fujino M, Yasui T, Aishima S, Takahata S, Nakamura M, Ito T, Tanaka M, Analysis of lymph node metastasis in pancreatic neuroendocrine tumors (PNETs) based on the tumor size and hormonal production, J Gastroenterol, 47, 6, 678-685, 2012.04, BACKGROUND:Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production.METHODS:Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated.RESULTS:There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was signific
antly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm.CONCLUSIONS:Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.. |
| 76. |
Otsuka T, Kono H, Nagayoshi Y, Mori Y, Tsutsumi K, Sadakari Y, Takahata S, Morimatsu K, Aishima S, Igarashi H, Ito T, Ishigami K, Nakamura M, Mizumoto K, Tanaka M, An increase in the number of predictive factors augments the likelihood of malignancy in branch duct intraductal papillary mucinous neoplasm of the pancreas.
, Surgery, 151, 1, 76-83, 2012.04, Abstract
BACKGROUND: International consensus guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas provide several factors that can be used to predict which IPMNs will become malignant.The sensitivity of each factor's predictive accuracy, however, is relatively low, making it difficult to determine the appropriate treatment in individual cases. The aim of this study was to investigate whether increasing the number of predictive factors might augment the sensitivity of the established guidelines to detect malignant IPMNs.
METHODS: The medical records of 138 patients with IPMNs resected at our institution were reviewed. Possible malignant predictors were analyzed by univariate and multivariate analysis, and the effects of the number of factors and the predictive score of the pathologic results were examined. The cutoff points for the number of predictors to discriminate between malignant and nonmalignant IPMNs were established by constructing receiver operating characteristic curves.
RESULTS: A predictive analysis could not be carried out for the main duct IPMNs because of the high prevalence of malignancy and the small number of significant predictors associated with them. For malignant branch duct IPMNs, however, we identified 4 predictive factors that helped determine the correct diagnosis as follows: (1) the presence of a cyst ≥30 mm in diameter; (2) the presence of mural nodules; (3) a history of acute pancreatitis; and (4) atypical results of pancreatic juice cytology. An increase in the number of these factors significantly affected the sensitivity to predict malignancy. The area under the curve for the number of predictors for malignant branch duct IPMNs was 0.856, and the sensitivity and specificity were 96% and 71%, respectively, when the cutoff point was set at 2. The predictive scoring system also showed the same values of sensitivity and specificity for the number of factors.
CONCLUSION: Patients with branch duct IPMNs who have 2 or more of the 4 predictive factors described above should undergo standard pancreatectomy with lymph node dissection, whereas patients who present with 0 or 1 predictive factor can be treated by minimal pancreatectomy without nodal dissection or by careful observation without resection. All patients with main duct IPMNs, therefore, should be treated with resection as suspected malignancies.
Copyright © 2011 Mosby, Inc. All rights reserved.
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| 77. |
Matsumoto H, Higashida M, Kubota H, Murakami H, Tsutsumi K, Nakashima H, Oka Y, Okumura H, Nakamura M, Hirai T, An immunoassay method for the pharmacokinetics of 5-fluorouracil in patients with gastric cancer administered adjuvant chemotherapy, Anticancer Res, 32, 11, 5111-5114, 2012.04. |
| 78. |
Matsumoto H, Hirabayashi Y, Kubota H, Murakami H, Higashida M, Haruma K, Hiratsuka J, Nakamura M, Hirai T, A combined therapy with docetaxel and nedaplatin for relapsed and metastatic esophageal carcinoma, Anticancer Res, 32, 5, 1827-1831, 2012.04. |
| 79. |
Otsuka T, Ideno N, Aso T, Nagayoshi Y, Kono H, Mori Y, Takahata S, Oda Y, Aishima S, Igarashi H, Ito T, Ishigami K, Nakamura M, Mizumoto K, Tanaka M, Role of endoscopic retrograde pancreatography for early detection of pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm of the pancreas., J Hepatobiliary Pancreat Sci, 20, 3, 356-361, 2013.04, BACKGROUND:
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found with distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. The aim of this study was to clarify whether endoscopic retrograde pancreatography (ERP) would be useful for the early detection of concomitant PDACs in patients with IPMNs.
METHODS:
Medical records of 179 patients who were histologically confirmed to have IPMNs after resection between 1987 and 2011 were reviewed. The patients having concomitant PDACs were selected, and the diagnostic abilities to detect concomitant PDACs of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and ERP were compared between early (stages 0-I according to Japanese General Rules for Pancreatic Cancer) and advanced (stages II-IV) PDACs.
RESULTS:
A total of 23 PDACs developed synchronously or metachronously in 20 patients, and the prevalence of PDACs concomitant with IPMNs was 11.2 % (20/179). Sensitivities of CT (16 vs. 87 %), MRI (29 vs. 93 %), and EUS (29 vs. 92 %) in the early group were significantly lower than those in the advanced group (p 0.99). Among 7 early PDACs, 3 were diagnosed only by ERP.
CONCLUSIONS:
ERP has an important role in the early diagnosis of distinct PDACs in patients with IPMNs. Further investigation is necessary to clarify the indication and the timing of ERP during management of IPMNs in term of early detection of concomitant PDACs.
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| 80. |
Murakami H, Matsumoto H, Nakamura M, Hirai T, Yamaguchi Y, Octreotide acetate-steroid combination therapy for malignant gastrointestinal obstruction, Anticancer Res, 33, 12, 5557-5560, 2013.04. |
| 81. |
Nakamura M, Nakashima H, Laparoscopic distal pancreatectomy and pancreatoduodenectomy is it worthwhile? A meta-analysis of laparoscopic pancreatectomy, J Hepatobiliary Pancreat Sci, 20, 4, 421-428, 2013.04. |
| 82. |
Ideno N, Ohtsuka T, Kono H, Fujiwara K, Oda Y, Aishima S, Ito T, Tokunaga S, Ohuchida K, Takahata S, Nakamura M, Mizumoto K, Tanaka M, Intraductal Papillary Mucinous Neoplasms of the Pancreas with Distinct Pancreatic Ductal Adenocarcinoma Are Frequently of Gastric Subtype, Ann Surg, 258, 1, 141-151, 2013.04, OBJECTIVE:: To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes. BACKGROUND:: Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types. METHODS:: Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with an
d without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs. RESULTS:: Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC. CONCLUSIONS:: Mucin expression pa
tterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.. |
| 83. |
Kono H, Nakamura M, Ohtsuka T, Nagayoshi Y, Mori Y, Takahata S, Aishima S, Tanaka M, High expression of microRNA-155 is associated with the aggressive malignant behavior of gallbladder carcinoma., Oncol Rep, 30, 1, 17-24, 2013.04, The prognosis of gallbladder cancer (GBC) remains poor despite recent advances in diagnostics and therapeutic strategies. Although the role of microRNAs (miRs) in GBC have not been well documented, miR-155 is known to be associated with inflammation-associated carcinogenesis in various types of cancers. The aim of this study was to investigate the clinical significance of miR-155 expression and the biological functions of miR-155 in GBC. The expression levels of miR-155 in surgically resected GBCs and gallbladders with pancreaticobiliary maljunction (PBM) were assessed by quantitative reverse transcription-polymerase chain reaction. The relationship between the expression levels of miR-155 and clinicopathological features of GBCs was analyzed. Human GBC cell lines were transfected with miR-155 inhibitors or mimics, and the effects on proliferation and invasion were assessed. miR-155 was significantly overexpressed in GBCs when compared with that in gallbladders with PBM (p=0.007) and normal gallbladders (p=0.04). The high expression level of miR-155 in GBCs was significantly associated with the presence of lymph node metastasis (p=0.01) and a poor prognosis (p=0.02). In vitro assays showed that aberrant expression of miR-155 significantly enhanced GBC cell proliferation and invasion. In conclusion, high miR-155 expression correlates with the aggressive behavior of GBCs, and miR-155 may become a prognostic marker and therapeutic target for GBC.. |
| 84. |
Nakamura M, Nakashima H, Tsutsumi K, Matsumoto H, Muta Y, Ueno D, Yoshida K, Hino K, Urakami A, Tanaka M, First jejunal vein oriented mesenteric excision for pancreatoduodenectomy, J Gastroenterol, 48, 8, 989-985, 2013.04, BACKGROUND:
Dissection of the pancreatic head from the superior mesenteric vein (SMV) and artery (SMA) are major points of bleeding in pancreaticoduodenectomy (PD) because of congestion of the pancreatic head. The "SMA-first" approach, which involves ligating the artery from the SMA first, can be used to solve this problem. However, the SMA-first approach has problematic anatomical issues. We applied a new surgical approach, first jejunal vein oriented mesenteric excision (FME), for PD. This study aimed to clarify the effect of FME on reduction of bleeding during PD.
METHODS:
The jejunal vein, the most frequent source of bleeding during dissection of the mesoduodenum, was identified at the beginning of dissection of the pancreatic head from SMV and SMA. The mesoduodenum, including plural IPDAs, was completely divided before dissection of the pancreatic head from the SMV. The perioperative outcomes of two groups, patients who underwent FME-based PD and patients who underwent standard PD, were compared. Additionally, the spatial characteristics of the first jejunal vein (FJV) were analyzed using computed tomography.
RESULTS:
FME-based PD significantly reduced intraoperative blood loss compared with conventional PD (569 vs. 1094 ml, P = 0.0315). The median distance of the FJV was 0 mm from the middle colic artery and 0 mm from the third portion of the duodenum. The FJV was posterior to the SMA in the majority of the patients but was anterior to the SMA in 16.7 % of patients.
CONCLUSIONS:
FME is useful for reducing intraoperative bleeding.
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| 85. |
Nakamura M, Ohtsuka T, Nakashima H, Nagayoshi Y, Kono H, Tsutsumi K, Takahata S, Tanaka M, Extensive distal pancreatectomy for pancreatic tumor., Anticancer Res, 33, 1, 267-270, 2013.04, Aim: The purpose of this study was to evaluate the feasibility and advantages of extensive distal pancreatectomy (ExDP).
PATIENTS AND METHODS:
We retrospectively analyzed our experience in 24 patients, who underwent ExDP or total pancreatectomy (TP) for the treatment of pancreatic cancer (22 patients) or benign tumor (two patients).
RESULTS:
ExDP was associated with less blood loss (p=0.0189), shorter operative times (p=0.024), lower rates of worsening of diabetes mellitus (p
CONCLUSION:
ExDP is a feasible and function-preserving operation for the treatment of pancreatic tumors in the body of the pancreas near the portal vein.
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| 86. |
Murakami H, Matsumoto H, Kubota H, Higashida M, Nakamura M, Hirai T, Evaluation of electrical activity after vagus nerve-preserving distal gastrectomy using multichannel electrogastrography, J Smooth Muscle Res, 49, 1-14, 2013.04. |
| 87. |
Kubota H, Matsumoto H, Higashida M, Murakami H, Nakashima H, Oka Y, Okumura H, Yamamura M, Nakamura M, Hirai T, Eicosapentaenoic acid modifies cytokine activity and inhibits cell proliferation in an oesophageal cancer cell line, Anticancer Res, 33, 10, 4319-4324, 2013.04. |
| 88. |
Nakamura M, Kayashima T, Fujiwara K, Nagayoshi Y, Kono H, Ohtsuka T, Takahata S, Mizumoto K, Tanaka M, Combination therapy of portal vein resection and adjuvant gemcitabine improved prognosis of advanced pancreatic cancer, Hepatogastroenterology, 60, 122, 354-357, 2013.04, Abstract
Background/Aims: Although adjuvant chemotherapy (AC) using gemcitabine improves the prognosis of patients with resectable pancreatic cancer, the effect of gemcitabine AC on the prognosis of patients with borderline resectable pancreatic cancer is not clear. Methodology: We analyzed the prognosis of patients with pancreatic cancer who underwent curative pancreatoduodenectomy or total pancreatectomy in combination with portal/superior mesenteric vein resection (PVR) [PVR (+) group] or without PVR [PVR(-) group]. Results: MST of the PVR (+) group was significantly shorter than that of the PVR(-) group (p=0.017). In contrast, when we focused on the patients with gemcitabine AC, there was no significant difference in MST between the PVR (+) and the PVR (-) groups (p=0.247). Furthermore, we compared MST of two subgroups in the PVR (+) group depending on gemcitabine AC status. In the PVR (+) group, MST of the patients with gemcitabine AC was significantly longer than that without gemcitabine AC (p=0.003). This was also true for the patients with pancreatic cancer which had histologically proven invasion to portal/superior mesenteric vein (PV/SMV) (p=0.001). Conclusions: The prognosis of patients with pancreatic cancer invading PV/SMV can be improved by combination therapy with PVR and gemcitabine adjuvant chemotherapy.
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| 89. |
Matsumoto H, Higashida M, Kubota H, Murakami H, Shiotani A, Haruma K, Nakamura M, Hirai T, Clinical Benefit of Non-Curative Resection for Stage IV Gastric Cancer. , Abdominal Oncology, 1, 1, 1-5, 2013.04. |
| 90. |
Mori Y, Otsuka T, Kono H, Nagayoshi Y, Ideno N, Aso T, Kozono S, Ohuchida K, Takahata S, Nakamura M, Mizumoto K, Tanaka M, A minimally invasive and simple screening test for detection of pancreatic ductal adenocarcinoma using biomarkers in duodenal juice., Pancreas, 42, 2, 187-192, 2013.04, OBJECTIVES:
The aim of this study was to establish a minimally invasive and simple screening test for detection of pancreatic ductal adenocarcinoma (PDAC) using duodenal juice (DJ).
METHODS:
Duodenal juice was collected prospectively before endoscopic retrograde cholangiopancreatography in 46 patients. A protease inhibitor was not added to the samples collected during the initial 2.5 minutes but was added in the latter 2.5 minutes. Thereafter, secretin was administered intravenously, and DJ was subsequently collected for additional 10 minutes. The sensitivities of carcinoembryonic antigen (CEA), S100 calcium-binding protein P (S100P), and interleukin 8 in DJ and pancreatic juice were assessed.
RESULTS:
There were 30 patients with PDAC and 16 with benign lesions. It was possible to collect an adequate amount of DJ without secretin administration. In the PDAC group, CEA concentrations in DJ were significantly higher than those in the benign group, even without the use of a protease inhibitor. S100P levels in DJ in the PDAC group were significantly higher than those in the benign group in the presence of the protease inhibitor.
CONCLUSIONS:
Duodenal juice collection during routine upper endoscopy and assessments of CEA and S100P in DJ might become a useful screening test for detection of PDAC.
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| 91. |
Tsuruta A, Hirai T, Nakamura M, Retrospective comparison of open versus laparoscopic ventral and incisional hernia repair, Asian J Endosc Surg, 7, 3, 246-250, 2014.04, Abstract
INTRODUCTION:
We performed a retrospective study to determine the mid-term recurrence and complication rates of patients following laparoscopic ventral and incisional hernia repair (LVHR) with DualMesh, an expanded polytetrafluoroethylene (ePTFE) mesh. Additionally, a study of the mesh contraction rate was performed postoperatively.
METHODS:
We compared open mesh repair of ventral and incisional hernias (OR) and LVHR. We also analyzed the shrinkage rate of ePTFE mesh. We included 45 patients (21 OR, 24 LVHR) who underwent mesh repair for primary ventral and incisional hernias between January 2008 and December 2012. Patients' characteristics did not significantly differ between the two groups.
RESULTS:
Mean operating time was 152.7 min for the OR group and 143.1 min for the LVHR group (P = 0.25). Mean postoperative hospital stay was 13.4 days for the OR group and 6.8 days for the LVHR groups (P = 0.01). The postoperative complication rate was 28.6% for the OR group and 12.5% for the LVHR group (P = 0.03). Among OR patients, causes of morbidity were variable: two recurrent cases, one surgical-site infection, one re-recurrence, one case of enteritis, and one case of heart failure. Among the LVHR patients, there was one surgical-site infection and two cases of seroma. No patients in the LVHR group experienced recurrence, while 14.3% of OR patients had a recurrence. In the LVHR group, the mean ePTFE mesh contraction rate was 10.6%.
CONCLUSION:
LVHR has advantages compared with OR, and the post-insertion contraction rate of ePTFE mesh was 10.6%.
© 2014 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
KEYWORDS:
DualMesh; ePTFE; laparoscopic ventral and incisional hernia repair (LVHR). |
| 92. |
Nagayoshi Y, Nakamura M, Matsuoka K, Ohtsuka T, Mori Y, Kono H, Aso T, Takahata S, Ryo A, Takeda H, Ito T, Oda Y, Endo Y, Sawasaki T, Tanaka M, Profiling of autoantibodies in sera of pancreatic cancer patients, Ann Surg Oncol, 10.1245/s10434-014-3574-0, 21, Suppl3, S459-S465, 2014.04, BACKGROUND:
Although autoantibodies to cancer antigens are candidates for biomarkers, no comprehensive studies to detect cancer-specific antibodies have been performed. This study identified autoantibodies in the sera of pancreatic cancer (PC) patients using proteomics based on a wheat germ cell-free protein production system.
METHODS:
We constructed a biotinylated protein library of 2,183 genes. Interactions between biotinylated proteins and serum antibodies were detected by AlphaScreen® assay. Relative luminescence signals of each protein in 37 PC patients and 20 healthy controls were measured, and their sensitivity and specificity for PC were calculated.
RESULTS:
Luminescence signals of nine proteins were significantly higher than those of healthy controls, with calcium and integrin binding 1 (CIB1) protein showing the greatest significance (p = 0.002). Sensitivity, specificity, positive predictive value and negative predictive value of CIB1 autoantibody alone for PC were 76, 70, 82, and 61 %, respectively, and 97, 35, 74, and 88 %, respectively, when the four most significant proteins were combined. Presence of these autoantibodies did not vary significantly with other clinicopathological characteristics.
CONCLUSION:
Several autoantibodies, including CIB1, are potential biomarkers for PC.
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| 93. |
Nakamura M, Shindo K, Ideno N, Ueda J, Takahata S, Nakashima H, Ohtsuka T, Shimizu S, Oda Y, Tanaka M, Prediction of Pancreatic Fistula by Preoperatively Assessable Factors; Retrospective Review of Unified Operations by Single Surgeon, Hepatogastroenterology, 2014, 61, 834-837, 2014.04, Abstract
BACKGROUND/AIMS: This retrospective study was conducted to find preoperatively assessable risk factors for postoperative pancreatic fistula (POPF) in patients undergoing laparoscopic distal pancreatectomy (LDP) using a slow compression method with a stapler, which we call pen-firing compression (PFC).
METHODOLOGY: Fifty-two patients underwent LDP, of whom 42 underwent PFC for pancreatic division using a stapler. The relationship between preoperatively assessable factors and the incidence of clinical POPF was statistically analyzed.
RESULTS: Overall rate of POPF was 7.1% in 42 patients. Univariate analysis showed that greater BMI (p = 0.004) and thicker pancreatic stump (0.0022) were significant risk factors for POPF. BMI and stump thickness remained significant (P CONCLUSIONS: High BMI value and thick pancreatic stump are significant risk factors for POPF after LDP. Alternative treatment of the pancreatic stump may prevent POPF in high-risk patients.
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| 94. |
Nakamura M, Ogo A, Yamura M, Yamaguchi Y, Nakashima H, Metformin suppresses sonic hedgehog expression in pancreatic cancer cells, Anticancer Res, 34, 4, 1765-1769, 2014.04, Abstract
BACKGROUND/AIM:
Metformin use has previously been associated with decreased cancer risk. The Hedgehog signaling pathway is a well-characterized early and late mediator of pancreatic cancer oncogenesis. The aim of the present study was to clarify the effect of metformin on factors involved in Hedgehog signaling.
MATERIALS AND METHODS:
BxPC3 human pancreatic cancer cells were treated with metformin, and Sonic hedgehog (Shh) mRNA and protein levels were examined by real time reverse transcription-polymerase chain reaction, immunohistochemistry and immunoblotting, respectively. The effect of metformin on Shh levels was also examined in three other cancer cell lines.
RESULTS:
Shh protein and mRNA expression was suppressed by metformin in BxPC3 cells. This phenomenon was further confirmed in three other cancer cell lines. Shh mRNA expression was inhibited by metformin in a concentration-dependent manner in two cancer cell lines.
CONCLUSION:
Metformin reduces the expression of Shh in several cancer cell lines including pancreatic cancer cell.
KEYWORDS:
Hedgehog signaling pathway; Pancreatic cancer; Sonic Hedgehog; metformin. |
| 95. |
Ueda J, Kayashima T, Mori Y, Ohtsuka T, Takahata S, Nakamura M, Tanaka M, Hepaticocholecystojejunostomy as effective palliative biliary bypass for unresectable pancreatic cancer, Hepatogastroenterology, 61, 129, 197-202, 2014.04, Abstract
BACKGROUND/AIMS:
The majority of patients with pancreatic cancer present with far advanced disease and jaundice. With the advancement of endoscopic interventional techniques, the role of surgical bypass has declined. However, surgical bypass is still considered to be appropriate in patients who are able to tolerate surgery. We performed hepaticocholecystojejunostomy consecutively as a palliative surgical biliary bypass for the purpose of long-term palliation. The aim of this study was to analyze the results of our palliative surgical biliary bypass, hepaticocholecystojejunostomy.
METHODOLOGY:
Between January 2001 through December 2009, 69 patients received palliative surgical biliary bypass (bypass group) and 33 patients received endoscopic biliary stenting (stent group) for unresectable pancreatic cancers. Mortality, morbidity and survival between the two groups were compared.
RESULTS:
There was no in-hospital death in the bypass group, but 2 patients (6%) in the stent group died in the hospital (p = 0.04). The surgical morbidity rate was 15% in the bypass group, while 20 patients (61%) in the stent group developed complications, mainly due to stent blockage. There was no significant difference in overall survival between the two groups. Among patients who underwent systemic chemotherapy but did not present with jaundice at the time of diagnosis, those who underwent prophylactic surgical biliary bypass before chemotherapy showed better survival than those who underwent systemic chemotherapy preceding biliary bypass or biliary stenting after occurrence of jaundice (p = 0.01).
CONCLUSIONS:
Hepaticocholecystojejunostomy resulted in negligible mortality, low morbidity and effective long-term palliation. Prophylactic surgical biliary bypass with gastrointestinal bypass might be a good treatment option for non-jaundiced patients undergoing chemotherapy for unresectable pancreatic cancer.. |
| 96. |
Nakamura M, Nakashima H, Abe T, Ensako T, Yoshida K, Hino K, Gemcitabine-based adjuvant chemotherapy for patients with advanced gallbladder cancer, Anticancer Res, 34, 6, 3125-3129, 2014.04, AAbstract
AIM:
We investigated effects of gemcitabine-based adjuvant chemotherapy (GEM) on prognosis of patients with gallbladder cancer.
PATIENTS AND METHODS:
We retrospectively analyzed outcomes of 36 patients who underwent radical resection for gallbladder cancer from 2001 through to 2012, using χ(2) for prognostic factors and Kaplan-Meier estimator and log-rank tests for survival data.
RESULTS:
The GEM group had higher rates of lymph node positivity and distant metastasis, higher UICC stage and fewer R0 resections; their 5-year survival rate (60%) did not significantly differ from that of the controls (70.0%), nor was GEM a significant prognostic factor in univariate analysis. However, among patients who underwent R1 and R2 resections, GEM significantly improved prognosis in both univariate and multivariate analyses. Median survival of the R1/2 GEM group (66.4 months) was significantly better than that of controls (5.4 months) (p=0.002).
CONCLUSION:
GEM improved prognosis of patients with gallbladder cancer after R1/R2 resections.
Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
KEYWORDS:
Gallbladder cancer; adjuvant chemotherapy; curability; gemcitabine (GEM). |
| 97. |
Matsumoto H, Kubota T, Higashida M, Yoden E, Hiratsuka J, Haruma K, Nakamura M, Hirai H, Docetaxel/ TS-1 with Radiation for Unresectable Squamous Cell Carcinoma of the Esophagus - A Phase II Trial, Anticancer Res, 34, 7, 3759-3763, 2014.04, Abstract
BACKGROUND:
We tried a new regimen of docetaxel / TS-1 (tegafur-gimestat-otastat potassium) combined with radiation for squamous cell carcinoma of the esophagus in a phase II trial.
PATIENTS AND METHODS:
The patients, whose tumor invaded other organs without other organ metastasis, were given TS-1 (60 mg/m2/day) from days 1 to 14, and docetaxel (20-30 mg/m2) on days 1 and 8. They received radiation in 2.0 Gy from days 1 to 21. Patients were given a seven-day rest after the first course, and then were treated with the same regimen from days 28 to 49.
RESULTS:
Seventeen cases were enrolled in the study. The response rate was 76.4% (13/17). The overall 5-year survival rate was 29.6% (5/17) and median survival time was 15.2 months. Adverse events more than grade 3 occurred in 10 cases.
CONCLUSION:
This combination therapy may be one of the most effective treatments because of its lower rate of non-hematological adverse events and higher response rate. Three cases also underwent salvage surgery when the tumor recurred, and in one case, chemoradiation to a metastatic nodule on the thoracic wall was added.
Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
KEYWORDS:
Docetaxel; TS-1; chemoradiation; unresectable squamous cell carcinoma of esophagus. |
| 98. |
Tsutsumi K, Ohtsuka T, Fujino M, Nakashima H, Aishima S, Ueda J, Takahata S, Nakamura M, Oda Y, Tanaka M, Analysis of risk factors for recurrence after curative resection of well-differentiated pancreatic neuroendocrine tumors based on the new grading classification, J Hepatobiliary Pancreat Sci, 21, 6, 418-425, 2014.04,
BACKGROUND:
It is difficult to predict the malignant potential of pancreatic neuroendocrine tumors (PNETs) precisely. This study investigated the validity of a new grading system adopted by the World Health Organization 2010 classification to determine risk factors for recurrence of PNETs.
METHODS:
Data of 70 patients with PNETs who underwent curative resection were retrospectively examined by uni- and multivariate analyses. Histopathological findings were re-reviewed by experienced pathologists. NET G1 was defined as mitotic count
RESULTS:
There were 58 patients with NET G1 and 12 with NET G2. Incidence of recurrence was 11.4%. Univariate analysis demonstrated significant risk factors for recurrence including NET G2 of histological grade (P = 0.0089), male gender (P = 0.0333), tumor size ≥ 20 mm (P = 0.0117), lymph node metastasis (P = 0.0004), liver metastasis (P
CONCLUSIONS:
This study confirmed the prognostic relevance of the new grading classification and that evaluation of perineural invasion and histological grade should be considered as prognostic predictors in well-differentiated PNETs (NET G1 and G2).
© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
KEYWORDS:
Grading classification; Neural invasion; Pancreatic neuroendocrine tumor; Predictors of recurrence; WHO 2010 classification
. |
| 99. |
Cases AI, Ohtsuka T, Kimura H, Zheng B, Shindo K, Oda Y, Mizumoto K, Nakamura M, Tanaka M, Significance of expression of glucagon-like peptide 1 receptor in pancreatic cancer, Oncol Rep, 10.3892/or.2015.4138, 34, 4, 1717-1725, 2015.04, Abstract
Glucagon-like peptide 1 (GLP-1) induces insulin secretion and proliferation of pancreatic β-cells, and inhibits their apoptosis through the GLP-1 receptor (GLP-1R), thus providing a foundation for using GLP-1-based therapies for the treatment of type 2 diabetes. However, doubts have emerged regarding the drug safety of these therapies. We investigated the potential role of GLP-1R in pancreatic ductal adenocarcinoma (PDAC). GLP-1R expression was semi-quantitatively evaluated by immunohistochemistry in 48 PDAC samples, and its correlations with clinicopathological features were investigated. CFPAC-1 cells were used for GLP-1R knockdown to evaluate its effects on cell proliferation, migration and invasion. GLP-1R expression was positive in 23 tumors and negative in 25 tumors. No correlations were found between GLP-1R expression status and clinicopathological characteristics. Furthermore, GLP-1R expression status did not affect the patient prognosis (P=0.74). The majority of lymph node metastases (11 of 15 samples examined; 73%) were positive for GLP-1R expression. Immunoreactivity for GLP-1R was also noted in sites of perineural and lymphovascular invasion. GLP-1R knockdown significantly reduced the proliferation, migration and invasion of CFPAC-1 cells (P. |
| 100. |
Tsuruta A, Itoh T, Hirai T, Nakamura M, Multi-layered intra-abdominal adhesion prophylaxis following laparoscopic colorectal surgery, Surg Endosc, 10.1007/s00464-014-3813-2 , 29, 6, 1400-1405, 2015.04, BACKGROUND:
Small bowel obstruction secondary to intra-abdominal adhesions is a frequent postoperative complication. Less invasive surgery carries a lower risk of postoperative adhesions, but adhesions may still occur after laparoscopic colorectal surgery. We present here some of our methods of adhesion prophylaxis for laparoscopic colorectal surgery.
METHODS:
The 167 patients who underwent laparoscopic colorectal surgery at our center from 2007 to 2012 were retrospectively reviewed. To prevent postoperative intra-abdominal adhesions, anti-adhesion barriers were placed using the half-overlap method. The rate of postoperative small bowel obstruction was compared among three groups: patients who received no adhesion prophylaxis (Group NP), patients who received single-layered adhesion prophylaxis adjacent to the incision (Group SP), and patients who received three layers of adhesion prophylaxis at different depths (Group MLP).
RESULTS:
The rate of postoperative ileus was significantly different among the three groups, at 9.7 % (6/62) in Group NP, 5.0 % (1/19) in Group SP, and 0 % (0/86) in Group MLP).
CONCLUSIONS:
This retrospective analysis found that placement of multi-layered anti-adhesion barriers using the half-overlap method provided the most effective prophylaxis. Prospective clinical trials are needed to further evaluate these methods of anti-adhesion prophylaxis.
. |
| 101. |
Matsumoto H, Murakami H, Kubota T, Higashida M, Nakamura M, Hirai H, Clinical Outcome of Lower Esophageal Sphincter- and Vagus Nerve-Preserving Partial Cardiectomy for Early Gastric Cancer of the Subcardia, Gastric Cancer, 18, 3, 669-674, 2015.04, Abstract
BACKGROUND:
No definitive operative method has been established for the treatment of early subcardial gastric cancer. Our newly developed technique involves local resection of the subcardia while preserving the lower esophageal sphincter and vagus nerve. A new fornix is constructed to accept the transposed esophagus.
METHODS:
Thirty patients underwent this procedure between July 2003 and December 2010. Continuous gastric pH monitoring was performed immediately after surgery, and esophageal manometry was undertaken 1 month later. Serum total protein, albumin, total cholesterol, cholinesterase, and body mass index (BMI) were recorded every 3 months. Pre- and postoperative oral intake were compared, reflux symptoms were recorded, and reflux esophagitis was assessed by endoscopy after 1 year.
RESULTS:
Twenty-five patients (86 %) reported no symptoms of reflux, and 27 (92.8 %) patients could eat 70 % or more of what they had eaten before surgery. Lower esophageal pressures were found to be >10 mmHg in 66.7 % of patients, and the fraction of time that pH CONCLUSIONS:
This surgical technique is a useful means of preserving postoperative quality of life after local gastrectomy by preventing reflux and maintaining nutritional status.. |
| 102. |
Horioka K, Ohuchida K, Sada M, Zheng B, Moriyama T, Fujita H, Manabe T, Ohtsuka T, Shimamoto M, Miyazaki T, Mizumoto K, Oda Y, Nakamura M, Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer, Int J Oncol, 48, 4, 1499-1508, 2016.04, Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P |
| 103. |
Kohno Y, Yamamoto H, Hirahashi M, Kumagae Y, Nakamura M, Oki E, Oda Y, Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia, Hum Pathol, 52, 145-152, 2016.04, 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 62years 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. . |
| 104. |
Miyasaka Y, Ohtsuka T, Tamura K, Mori Y, Shindo K, Yamada D, Takahata S, Ishigami K, Ito T, Tokunaga S, Oda Y, Mizumoto K, Nakamura M, Tanaka M, Predictive factors for the metachronous development of high-risk lesions in the remnant pancreas after partial pancreatectomy for intraductal papillary mucinous neoplasm, Ann Surg, 10.1097/SLA.0000000000001368 , 263, 6, 1180-1187, 2016.04, Abstract
OBJECTIVE:
To identify factors predicting the development of high-risk lesions in the remnant pancreas after surgery for intraductal papillary mucinous neoplasm (IPMN).
BACKGROUND:
IPMN has unique features, including multifocality, adenoma-carcinoma sequence, and the development of distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. Careful attention should, therefore, be paid to the metachronous occurrence of high-risk lesions, including high-grade dysplasia or invasive carcinoma (HGD/INV) of IPMN and concomitant PDAC in the remnant pancreas after partial pancreatectomy for IPMN.
METHODS:
Clinicopathologic and surveillance data for 195 patients who underwent partial pancreatectomy for IPMN were reviewed retrospectively.
RESULTS:
Thirteen patients exhibited metachronous development of high-risk lesions including 6 HGD/INV and 7 concomitant PDACs in the remnant pancreas. The 5- and 10-year cumulative incidences of metachronous high-risk lesions in the remnant pancreas were 7.8% and 11.8%, respectively. Twelve of 13 patients had high-risk lesions at the time of initial surgery, and 10 of the 13 IPMNs were located in the distal pancreas. The IPMN subtypes initially resected were gastric in 6 patients, intestinal in 5, and pancreatobililary in the remaining 2. Univariate and multiple regression analyses identified pathologic results of HGD/INV and IPMN located in the distal pancreas as independent predictive factors for metachronous HGD/INV of IPMN, and the pancreatobiliary subtype of IPMN and presence of concomitant PDAC for metachronous PDAC.
CONCLUSIONS:
Patients undergoing partial pancreatectomy for IPMN are at high risk of developing lesions requiring surgery in the remnant pancreas, and close, long-term surveillance should be considered in these patients.. |
| 105. |
Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, Fujita H, Maeyama R, Manabe T, Abe A, Mizuuchi Y, Oda Y, Mizumoto K, Nakamura M, Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL, Int J Oncol, 10.3892/ijo.2016.3389 , 48, 4, 1688-1700, 2016.04, Abstract
Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P. |
| 106. |
Nakamura M, Matsumoto H, Nakashima H, Ando Y, Hirai T, Yoshida K, Hino K, L-Carnitine Supplementation Improved Hepatic Steatosis After Pancreatectomy, Pancreas, 10.1097/MPA.0000000000000508 , 45, 3, e7-e9, 2016.04. |
| 107. |
Takizawa K, Yamamoto H, Taguchi K, Ohno S, Tokunaga E, Yamashita N, Kubo M, Nakamura M, Oda Y, Insulin-like growth factor II messenger RNA-binding protein-3 is an indicator of malignant phyllodes tumor of the breast, Hum Pathol, 55, 9, 30-38, 2016.04, Abstract
The aim of this study was to elucidate the clinicopathological and prognostic significance of the expressions of insulin-like growth factor II mRNA-binding protein-3 (IMP3) and epidermal growth factor receptor (EGFR) in phyllodes tumors (PTs). Immunohistochemical staining for IMP3 and EGFR was performed in 130 cases of primary PTs (83 benign, 28 borderline, 19 malignant), 34 recurrent/metastatic PTs, and 26 fibroadenomas (FAs). Among the primary tumors, a high expression of IMP3 was significantly more frequently present in malignant PTs (17/19, 89%) than in the FAs (0/26, 0%), benign PTs (0/83, 0%) and borderline PTs (3/28, 11%). The recurrent and metastatic lesions of malignant PTs also showed high IMP3 expression (3/5 [60%] and 6/6 [100%], respectively). Most malignant PTs showed strong IMP3 expression at the interductal area or more diffusely, whereas weak and focal (low) expression of IMP3 was limited to the periductal area in FAs and benign PTs. EGFR overexpression was significantly correlated with tumor grade and high IMP3 expression. Overexpressions of IMP3 and EGFR were significantly associated with shorter periods of metastasis-free and disease-free survival. The results suggest that high expressions of IMP3 and EGFR with a characteristic staining pattern may be helpful for both identifying malignant PT and predicting the prognosis of these tumors.. |
| 108. |
Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M, Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility, Cancer Lett, 10.1016/j.canlet.2016.01., 372, 2, 210-218, 2016.04, Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel-patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs abrogated para
llel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer.. |
| 109. |
Manabe T, Ueki T, Nagayoshi K, Moriyama T, Yanai K, Nagai S, Esaki M, Nakamura K, Nakamura M, Feasibility of laparoscopic surgery for complex Crohn's disease of the small intestine., Asian J Endosc Surg, 10.1111/ases.12287, 9, 4, 265-269, 2016.04, Abstract
BACKGROUND:
The laparoscopic approach for complex Crohn's disease (CD), which involves abscess formation, fistula formation, and recurrent CD, is controversial. The aim of this study was to investigate the feasibility and safety of the laparoscopic approach for complex CD.
METHODS:
Fifty-six patients who had undergone surgery for CD of the small bowel from January 2007 to August 2014 were divided into two groups: the laparoscopic approach for complex CD group (LC group, n = 31) and the laparoscopic approach for simple CD group (LS group, n = 25). The preoperative data and surgical outcomes of the LC group were compared with those of the LS groups.
RESULTS:
There were no significant differences in preoperative data and operating time between the two groups. Blood loss was not significantly different between the LC and LS groups. The incision length was longer in the LC group than the LS group (P = 0.004). The incidence of severe postoperative complications in the LC group was higher than in the LS group (P = 0.026). The length of postoperative stay was similar in the LC and LS groups.
CONCLUSIONS:
The laparoscopic approach for complex CD is feasible and provides good cosmesis that is comparable to that offered by simple CD.. |
| 110. |
Fujimoto T, Ohtsuka T, Date K, Kimura H, Matsunaga T, Mori Y, Miyasaka Y, Mochidome N, Oda Y, Nakamura M, Expression of Bcl-2 19-kDa interacting protein 3 predicts prognosis after ampullary carcinoma resection, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.367 , 23, 8, 489-496, 2016.04, Abstract
BACKGROUND:
An adequate management strategy for ampullary carcinoma (AC), a rare neoplasm, has yet to be determined. The aim of this study was to identify specific molecular markers allowing for the adequate management of AC.
METHODS:
The clinicopathological data of 41 patients who underwent curative resection of AC were reviewed retrospectively. The expression of thymidylate synthase (TS) and Bcl-2 19-kDa interacting protein 3 (BNIP3), two sensitive markers for S-1 and gemcitabine, respectively, was evaluated immunohistochemically. The relationship between the expression levels of these markers and the clinicopathological data were then investigated.
RESULTS:
The 5-year overall survival rate in the study population was 62%. In univariate and multivariate analyses, lymph node metastasis, neural invasion, lymphatic invasion, and the high-level BNIP3 expression were significant predictive factors for a poor postoperative prognosis. Neither TS nor BNIP3 expression were able to predict survival or the disease recurrence rate in patients who received postoperative adjuvant chemotherapy for AC.
CONCLUSIONS:
BNIP3 expression may serve as a prognostic marker for patients with AC, but neither TS nor BNIP3 contributes to the selection criteria for adjuvant chemotherapy for AC, at least with respect to current drug regimens.
© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
KEYWORDS:
Ampulla of Vater; BNIP3; Carcinoma; Chemotherapy; Thymidylate synthase. |
| 111. |
Ueno D, Nakashima H, Higashida M, Yoshida K, Hino K, Irei I, Moriya T, Matsumoto H, Hirai T, Nakamura M, Emergent laparoscopic cholecystectomy for acute acalculous cholecystitis revisited, Surg Today, 10.1007/s00595-015-1173-8 , 46, 3, 309-312, 2016.04, Abstract
PURPOSE:
To compare the safety of emergent laparoscopic cholecystectomy for acute acalculous cholecystitis (AAC) with surgery for acute calculous cholecystitis (ACC).
METHODS:
We retrospectively reviewed the perioperative records of 111 patients who underwent emergent laparoscopic cholecystectomy for acute cholecystitis under the care of the Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, between January 2010 and April 2014. Patients were divided into the AAC group (27 patients) and the ACC group (84 patients), and their perioperative outcomes were compared.
RESULTS:
Patients in the AAC group had significantly higher disease severity and American Society of Anesthesiologists physical status scores (p = 0.001 and 0.037, respectively), lower blood hemoglobin and albumin concentrations (p = 0.0005 and 0.017, respectively), and lower hematocrit and platelet count (p CONCLUSIONS:
Early laparoscopic cholecystectomy is safe in acute acalculous as well as acute calculous cholecystitis.
KEYWORDS:
Acute acalculous cholecystitis; Early laparoscopic cholecystectomy; Emergent operation; Short-term clinical outcomes; Ultrasound scissors. |
| 112. |
Tamura K, Ohtsuka T, Date K, Fujimoto T, Matsunaga T, Kimura H, Watanabe Y, Miyazaki T, Ohuchida K, Takahata S, Ishigami K, Oda Y, Mizumoto K, Nakamura M, Tanaka M, Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers, Pancreas, 10.1097/MPA.0000000000000563 , 45, 6, 826-835, 2016.04, OBJECTIVES:To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC).METHODS:Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients.RESULTS:KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and d
istinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components.CONCLUSIONS:It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.. |
| 113. |
Kimura H, Ohtsuka T, Fujimoto T, Date K, Matsunaga T, Cases AI, Abe A, Mizuuchi Y, Miyasaka Y, Ito T, Oda Y, Nakamura M, Tanaka M, Different hormonal expression patterns between primary pancreatic neuroendocrine tumors and metastatic sites, Pancreas, 45, 7, 947-952, 2016.04, OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) are known to have heterogeneity in terms of their ability to produce multiple hormones. The aim of this study was to evaluate the heterogeneity of PNETs from the viewpoint of hormonal expression. METHODS: The expressions of 4 representative hormones, gastrin, insulin, glucagon, and somatostatin, in both primary and metastatic lesions, were analyzed by immunohistochemical staining in 20 patients with metastatic PNETs (6 gastrinomas, 1 insulinoma, 1 glucagonoma, and 12 nonfunctioning PNETs [NF-PNETs]). Metastatic sites included lymph nodes in all 20 patients and liver metastasis in 7 patients (2 gastrinomas and 5 NF-PNETs). RESULTS: There were 6 PNETs with multiple hormone secretion (30%), and positive expression of 1 or more hormones was found in 9 of 12 patients whose primary tumors were diagnosed as NF-PNETs. The positive concordance rate of the hormonal expression pattern between primary tumors and metast
atic lymph nodes and between primary tumors and hepatic metastasis were 50% and 11%, respectively. Three patients had metastatic lesions with positive hormonal expression, whereas their primary tumors were negative. CONCLUSIONS: Hormonal expressions are often different between the primary tumors and metastatic sites of PNETs.. |
| 114. |
Yawen Y, Nakamura M, Nakashima N, Designing Health Data Management Systems:Learning From Prominent Worldwide Applications, J Health Med Inform, 7, 216, 1-3, 2016.04. |
| 115. |
Abe T, Ohuchida K, Miyasaka Y, Ohtsuka T, Oda Y, Nakamura M, Comparison of Surgical Outcomes Between Radical Antegrade Modular Pancreatosplenectomy (RAMPS) and Standard Retrograde Pancreatosplenectomy (SPRS) for Left-Sided Pancreatic Cancer, World J Surg, 10.1007/s00268-016-3526-x , 40, 9, 2267-75, 2016.04, BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) is a modification of standard retrograde pancreatosplenectomy (SRPS) used to achieve the dissection of N1 lymph nodes, early vascular control, and negative posterior margins. However, there have been few comparative studies regarding the clinical outcomes of the RAMPS and SRPS procedures.METHODS: Ninety-three patients underwent distal pancreatectomy for the treatment of pancreas body and tail adenocarcinoma between 2000 and 2014. Clinicopathologic data were retrospectively analyzed in this study. We compared short- and long-term outcomes between RAMPS and SRPS. In addition, we investigated the significance of clinicopathologic factors in left-sided pancreatic cancers.RESULTS: Fifty-three patients underwent RAMPS and 40 patients underwent SRPS. RAMPS revealed a larger number of retrieved lymph nodes [28.4 ± 11.6 vs 20.7 ± 10.1; P = 0.0016], more frequent R0 resection [90.5 vs 67.5
%; P = 0.0053], less intraoperative bleeding than SRPS [485.4 ± 63.3 vs 682.3 ± 72.8 ml; P = 0.0444], and shorter operating time (267.3 ± 11.5 vs 339.4 ± 13.2 min; P < 0.0001) as compared with SRPS. In comparing RAMPS and SRPS, RAMPS showed a tendency for improvement of the median survival times than SRPS (47 vs 34 months) (P = 0.1920). In the multivariate analysis, R1 resection, histologic grade, and vascular invasion for overall survival (OS) were found to be independent factors.CONCLUSIONS: There were a decrease of intraoperative bleeding and an increase in the number of retrieved lymph nodes and the R0 resection rate using RAMPS as compared with SRPS.. |
| 116. |
Suyama K, Onishi H, Imaizumi A, Shinkai K, Umebayashi M, Kubo M, Mizuuchi Y, Oda Y, Tanaka M, Nakamura M, Katano, M, CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells, Cancer Lett, 374, 1, 44-53, 2016.04, Hedgehog (Hh) signaling has been found to be activated in breast cancer stem cells (BCSCs). However, the precise role of the BCSCs marker, CD24, remains unclear. Here, we describe a relationship between CD24 and Sonic Hedgehog (SHH), and reveal a role for this relationship in the induction of a malignant phenotype of breast cancer. CD24 siRNA-transfected breast cancer cells (BCCs) demonstrated higher expression of SHH and GLI1, increased anchorage-independent proliferation, and enhanced invasiveness and superior tumorigenicity compared with control. Conversely, CD24 forced-expressing BCCs possessed decreased SHH and GLI1 expression, anchorage-independent proliferation, and invasiveness. Suppression of SHH decreased invasiveness through inhibition of matrix metalloproteinase (MMP)-2 expression, GLI1 expression, anchorage-independent proliferation, tumorigenicity, and tumor volume in vivo in CD24 siRNA transfected BCCs. DNA microarray analysis identified STAT1 as a relationship between CD24 and SHH. CD24 siRNA-transfected BCCs with concurrent STAT1 inhibition exhibited decreased SHH expression, invasiveness, anchorage-independent proliferation, tumorigenicity, and tumor volume in vivo. These results suggest that CD24 suppresses development of a malignant phenotype by down-regulating SHH transcription through STAT1 inhibition. CD24 gene transfer or STAT1 inhibition may represent new effective therapeutic strategies to target refractory breast cancer.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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| 117. |
Zheng B, Ohuchida K, Chijiiwa Y, Zhao M, Mizuuchi Y, Cui L, Horioka K, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Tanaka M, CD146 Attenuation in Cancer-Associated Fibroblasts Promotes Pancreatic Cancer Progression, Mol Carcinog, 10.1002/mc.22409, 55, 11, 1560-1572, 2016.04. |
| 118. |
Yoshida M, Miyasaka Y, Ohuchida K, Okumura T, Zheng B, Torata N, Fujita H, Nabae T, Manabe T, Shimamoto M, Ohtsuka T, Mizumoto K, Nakamura M, Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model., Cancer Sci, 10.1111/cas.13024 , 107, 10, 1443-1452, 2016.04, Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. C
alpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction.. |
| 119. |
Mori H, Kubo M, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Miyazaki T, Oda Y, Otsuka T, Nakamura M, BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer, PLoS One, 10.1371/journal.pone.0167016 , 11, 12, e0167016, 2016.04, BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. MethodsThe BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. ResultsOf the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter
recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.ConclusionsThe 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.. |
| 120. |
Kawamoto M, Onishi H, Ozono K, Yamasaki A, Imaizumi A1, Kamakura S, Nakano K, Oda Y, Sumimoto H, Nakamura M, Tropomyosin-related kinase B mediated signaling contributes to the induction of malignant phenotype of gallbladder cancer, Oncotarget, 10.18632/oncotarget.16063, 8, 22, 36211-36224, 2017.04, Abstract
This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0.0363). In vitro experiment, we used five TrkB-expressing GBC cell lines with or without K-ras mutation. TrkB-mediated signaling increased proliferation and the invasiveness by inducing epithelial mesenchymal transition, and activating matrix metalloproteinases-2 (MMP-2) and MMP-9. Inhibition of TrkB-mediated signaling also decreased hypoxia-inducible factor-1α, vascular endothelial growth factor A (VEGF-A), VEGF-C, and VEGF-D expression. In vivo experiment, inhibition of TrkB-mediated signaling suppressed tumorigenicity and tumor growth in GBC. These findings demonstrate that TrkB-mediated signaling contributes to the induction of malignant phenotypes (proliferation, invasiveness, angiogenesis, lymphangiogenesis, and tumorigenesis) in GBC, and could be a promising therapeutic target regardless of K-ras mutation status.. |
| 121. |
Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M, The combination of PD-L1 expression and decreased tumor- infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer, Oncotarget, 8, 9, 15584-15592, 2017.04, This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD- L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs- low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-
L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.. |
| 122. |
Matsunaga T, Ohtsuka T, Asano K, Kimura H, Ohuchida K, Kitada H, Ideno N, Mori Y, Tokunaga S, Oda Y, Guha S, Raimondo M, Nakamura M, Tanaka M, S100P in Duodenal Fluid Is a Useful Diagnostic Marker for Pancreatic Ductal Adenocarcinoma, Pancreas, 10.1097/MPA.0000000000000940, 46, 10, 1288-1295, 2017.04, Abstract
OBJECTIVES:
The development of an effective screening method for pancreatic ductal adenocarcinoma (PDAC) is of paramount importance. This study assessed the diagnostic utility in pancreatic diseases of duodenal markers during upper gastrointestinal endoscopy (GIE) or endoscopic ultrasonography.
METHODS:
This study prospectively enrolled 299 consecutive participants, including 94 patients with PDACs, 144 patients with other pancreatic diseases, and 61 normal individuals as control subjects. All subjects underwent upper GIE or endoscopic ultrasonography either at Kyushu University Hospital (Fukuoka, Japan) or the Mayo Clinic (Jacksonville, Fla) from October 2011 to July 2014. Duodenal fluid (DF) was collected without secretin stimulation and of carcinoembryonic antigen and S100 calcium-binding protein P (S100P) concentrations were measured.
RESULTS:
Concentrations of S100P in DF were significantly higher in patients with PDAC and chronic pancreatitis than in control subjects (P
CONCLUSIONS:
Analysis of S100P concentration in DF, in combination with routine screening upper GIE, may facilitate the detection of PDAC.. |
| 123. |
Miyasaka Y, Mori Y, Nakata K, Ohtsuka T, Nakamura M, Prophylactic biliary and gastrointestinal bypass for unresectable pancreatic head cancer: A retrospective case series, JOP, 18, 6, 470-474, 2017.04. |
| 124. |
Date K, Ohtsuka, T Fujimoto, T Tamura K, Kimura H, Matsunaga T, Mochidome N, Miyazaki T, Mori Y, Oda Y, Nakamura M Tanaka M, Molecular Evidence for Monoclonal Skip Progression in Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas, Ann Surg, 10.1097/SLA.0000000000001755, 265, 5, 969-977, 2017.04, Objective:
To clarify clonality of distinct multisegmental main duct (MD)-intraductal papillary mucinous neoplasms (IPMNs) using microarray analysis.
Background:
IPMNs represent a pancreatic ductal cell field defect, which causes multiple occurrences of lesions. In addtion, it has been speculated that MD-IPMNs display features of monoclonal skip progression.
Methods:
Total RNA was extracted from fresh-frozen tissue samples of metachronous MD-IPMNs and nonneoplastic pancreas tissue from the same pancreas from two individuals, and whole human genome microarray analysis was performed. Formalin-fixed paraffin-embedded tissue specimens from 28 distinct IPMNs were then collected from 12 patients, genomic DNA was extracted, and GNAS/KRAS mutational status was investigated. Immunohistochemical analysis was performed to validate the expression pattern of the indicated proteins.
Results:
Microarray analysis revealed that metachronous MD-IPMNs from the same individual displayed pair-wise correlation coefficients of 0.9523 and 0.9512. In contrast, MD-IPMNs of the same histological grade from different individuals displayed coefficients of 0.8092 and 0.8211. Scatter plot analysis revealed that metachronous MD-IPMNs from the same individual displayed a closer linear relationship. Furthermore, heat map and hierarchical cluster analyses revealed that metachronous MD-IPMNs from the same individual were classified in the same branch, and the gene expression patterns were similar. The GNAS/KRAS mutational statuses of distinct MD-IPMNs were consistent with each other. Immunohistochemical assessment of five specific proteins demonstrated that the same expression pattern between two lesions was observed in 95% of the samples.
Conclusions:
These findings using molecular analyses indicate that MD-IPMNs might display features of monoclonal skip progression.
. |
| 125. |
Miyazaki T, Ohishi Y, Miyasaka Y, Oda Y, Aishima S, Ozono K, Abe A, Nagai E, Nakamura M, Oda Y, Molecular Characteristics of Pancreatic Ductal Adenocarcinomas with High-Grade Pancreatic Intraepithelial Neoplasia (PanIN) Are Different from Those without High-Grade PanIN, Pathobiology, 10.1159//000455194, 84, 4, 192-201, 2017.04, We reported that pancreatic ductal adenocarcinomas (PDACs) without high-grade pancreatic intraepithelial neoplasia (PanIN) in the vicinity had worse prognoses than PDACs with high-grade PanIN. However, the molecular characteristics of PDACs with and without high-grade PanIN have not been compared. The aim of this study is to clarify the molecular characteristics of PDACs with and without high-grade PanIN.. |
| 126. |
Date S, Noguchi H, Kaku K, Kurihara K, Miyasaka Y, Okabe Y, Nakamura U, Ohtsuka T, Nakamura M, Laparoscopy-Assisted Spleen-Preserving Distal Pancreatectomy for Living-Donor Pancreas Transplantation, Transplant Proc, 10.1016/j.transproceed.2017.03.037, 49, 5, 1133-1137, 2017.04, BACKGROUND:Living pancreas transplantation plays an important role in the treatment of patients with severe type 1 diabetes. However, pancreatectomy is very invasive for the donor, and less-invasive surgical procedures are needed. Although some reports have described hand-assisted laparoscopic surgery for distal pancreatectomy in living-donor operations, less-invasive laparoscopy-assisted (LA) procedures are expected to increase the donor pool. We herein report the outcomes of four cases of LA spleen-preserving distal pancreatectomy (Warshaw technique [WT]) in living pancreas donors.PATIENTS AND METHODS:Four living pancreas donors underwent LA-WT at our institution from September 2010 to January 2013. All donors fulfilled the donor criteria established by the Japan Society for Pancreas and Islet Transplantation.RESULTS:The median donor age was 54 years. Two donors underwent left nephrectomy in addition to LA-WT for simultaneous pancreas-kidney transpl
antation. The median donor operation time for pancreatectomy was 340.5 minutes. The median pancreas warm ischemic time was 3 minutes. The median donor blood loss was 246 g. All recipients immediately achieved insulin independence. One donor required reoperation because of obstructive ileus resulting from a port-site hernia. Another donor developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), which was controlled with conservative management. After a maximum follow-up of 73 months, no clinically relevant adverse events had occurred. These results were comparable with those of previous studies concerning living-donor pancreas transplantation.CONCLUSION:The LA-WT is a safe and acceptable operation for living-donor pancreas transplantation.. |
| 127. |
Manabe T, Koba R, Nagayoshi K, Sadakari Y, Fujita H, Nagai S, Ueki T, Nagai E, Nakamura M, Laparoscopic excision of neurogenic retrorectal tumors, Asian J Endosc Surg, 10.1111/ases.12337., 10, 2, 223-226, 2017.04, Abstract
Retrorectal tumors (RT) are uncommon and usually managed by open surgical excision. Laparoscopic excision for RT has been reported in only a small number of papers. We aimed to assess the laparoscopic approach for RT and to discuss the factors that made this procedure difficult. We performed laparoscopic excision using a five-trocar technique for neurogenic RT in three patients. Tumors were successfully excised laparoscopically in two patients. However, the third patient required open conversion because the tumor was strongly adhered to the sacrum and could not be mobilized by dissection, resulting in poor visualization of the dissected site. Laparoscopic excision for RT provides excellent intraoperative visualization and good cosmesis in selected patients, but firm adherence to the sacrum may cause difficulty with this procedure.. |
| 128. |
Ohuchida K, Nagai E, Moriyama T, Shindo K, Manabe T, Ohtsuka T, Shimizu S, Nakamura M, Feasibility and safety of modified inverted T-shaped method using linear stapler with movable cartridge fork for esophagojejunostomy following laparoscopic total gastrectomy, Transl Gastroenterol Hepatol, 23, 2, 50, 2017.04, Abstract
BACKGROUND:
We previously reported the use of an inverted T-shaped method to obtain a suitable view for hand sewing to close the common entry hole when the linear stapler was fired for esophagojejunostomy after laparoscopic total gastrectomy (LTG). This conventional method involved insertion of the fixed cartridge fork to the Roux limb and the fine movable anvil fork to the esophagus to avoid perforation of the jejunum. However, insertion of the movable anvil fork to the esophagus during this procedure often requires us to strongly push down the main body of the stapler with the fixed cartridge fork to bring the direction of the anvil fork in line with the direction of the long axis of the esophagus while controlling the opening of the movable anvil fork. We therefore modified this complicated inverted T-shaped method using a linear stapler with a movable cartridge fork. This modified method involved insertion of the movable cartridge fork into the Roux limb followed by natural, easy insertion of the fixed anvil fork into the esophagus without controlling the opening of the movable cartridge fork.
METHODS:
We performed LTG in a total of 155 consecutive patients with gastric cancer from November 2007 to December 2015 in Kyushu University Hospital. After LTG, we performed the conventional inverted T-shaped method using a linear stapler with a fixed cartridge fork in 61 patients from November 2007 to July 2011 (fixed cartridge group). From August 2011, we used a linear stapler with a movable cartridge fork and performed the modified inverted T-shaped method in 94 patients (movable cartridge group). We herein compare the short-term outcomes in 94 cases of LTG using the modified method (movable cartridge fork) with those in 61 cases using the conventional method (fixed cartridge fork).
RESULTS:
We found no significant differences in the perioperative or postoperative events between the movable and fixed cartridge groups. One case of anastomotic leakage occurred in the fixed cartridge group, but no anastomotic leakage occurred in the movable cartridge group.
CONCLUSIONS:
Although there were no remarkable differences in the short-term outcomes between the movable and fixed cartridge groups, we believe that the modified inverted T-shaped method is technically more feasible and reliable than the conventional method and will contribute to the improved safety of LTG.. |
| 129. |
Okumura T, Ohuchida K, Sada M, Abe T, Endo S, Koikawa K, Iwamoto C, Miura D, Mizuuchi Y, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells, Oncotarget, 10.18632/oncotarget.15430., 8, 11, 18280-18295, 2017.04, Abstract
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.
KEYWORDS:
adipose microenvironment; extra-pancreatic invasion; fatty acids; lipolysis; pancreatic cancer. |
| 130. |
Yamauchi A, Yamamura M, Katase N, Itadani M, Okada N, Kobiki K, Nakamura M, Yamaguchi Y, Kuribayashi F, Evaluation of pancreatic cancer cell migration with multiple parameters in vitro by using an optical real-time cell mobility assay device, BMC Cancer, 10.1186/s12885-017-3218-4., 17, 1, 234-234, 2017.04, Abstract
BACKGROUND:
Migration of cancer cell correlates with distant metastasis and local invasion, which are good targets for cancer treatment. An optically accessible device "TAXIScan" was developed, which provides considerably more information regarding the cellular dynamics and less quantity of samples than do the existing methods. Here, we report the establishment of a system to analyze the nature of pancreatic cancer cells using TAXIScan and we evaluated lysophosphatidic acid (LPA)-elicited pancreatic cell migration.
METHODS:
Pancreatic cancer cell lines, BxPC3, PANC-1, AsPC1, and MIAPaCa-2, were analyzed for adhesion as well as migration towards LPA by TAXIScan using parameters such as velocity and directionality or for the number of migrated cells by the Boyden chamber methods. To confirm that the migration was initiated by LPA, the expression of LPA receptors and activation of intracellular signal transductions were examined by quantitative reverse transcriptase polymerase reaction and western blotting.
RESULTS:
Scaffold coating was necessary for the adhesion of pancreatic cancer cells, and collagen I and Matrigel were found to be good scaffolds. BxPC3 and PANC-1 cells clearly migrated towards the concentration gradient formed by injecting 1 μL LPA, which was abrogated by pre-treatment with LPA inhibitor, Ki16425 (IC50 for the directionality ≈ 1.86 μM). The LPA dependent migration was further confirmed by mRNA and protein expression of LPA receptors as well as phosphorylation of signaling molecules. LPA1 mRNA was highest among the 6 receptors, and LPA1, LPA2 and LPA3 proteins were detected in BxPC3 and PANC-1 cells. Phosphorylation of Akt (Thr308 and Ser473) and p42/44MAPK in BxPC3 and PANC-1 cells was observed after LPA stimulation, which was clearly inhibited by pre-treatment with a compound Ki16425.
CONCLUSIONS:
We established a novel pancreatic cancer cell migration assay system using TAXIScan. This assay device provides multiple information on migrating cells simultaneously, such as their morphology, directionality, and velocity, with a small volume of sample and can be a powerful tool for analyzing the nature of cancer cells and for identifying new factors that affect cell functions.
KEYWORDS:
Chemotaxis; Inhibitor; Lipid mediator; Metastasis; Migration; TAXIScan. |
| 131. |
Fujimoto T, Ohtsuka T, Nakashima Y, Gotoh Y, Date K, Mori Y, Sadakari Y, Takahata S, Oda Y, Nakamura M, Elevated bile amylase level without pancreaticobiliary maljunction is a risk factor for gallbladder carcinoma, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.421., 24, 2, 103-108, 2017.04, Background: Elevated bile amylase level in patients with pancreaticobiliary maljunction (PBM) or high confluence of pancreaticobiliary ducts (HCPBD) is well known as a risk factor for gallbladder carcinoma (GBC) development. However, the effects of occult pancreaticobiliary reflux (OPR), a condition characterized by high bile amylase level in the presence of an anatomically normal pancreaticobiliary junction, on GBC development remain unclear. The aim of this study was to assess the relationship between OPR and GBC.Methods: Clinicopathological data of 52 patients who were preoperatively diagnosed with gallbladder (GB) tumor (22 malignant, 30 benign) were retrospectively reviewed. All of the patients underwent preoperative endoscopic retrograde cholangiopancreatography to evaluate pancreaticobiliary junction morphology and bile amylase level. The relationship between the histological diagnosis of GB lesions, and pancreaticobiliary junction morphology a
nd bile amylase level were investigated.Results: PBM, HCPBD, and normal pancreaticobiliary junction (NPJ) were identified in 12, 9, and 31 patients, respectively. The rates of GBC in patients with PBM, HCPBD, and NPJ were 58% (7/12), 67% (6/9), and 29% (9/31), respectively. Of the 31 patients with NPJ, 22 had OPR and 9 of these had GBC. None of the patients with NPJ and normal bile amylase level had GBC. Additionally, among patients with NPJ, bile amylase level was significantly higher in patients with GBC than in patients with benign tumors.Conclusions: OPR, like PBM and HCPBD, is a risk factor for GBC development.. |
| 132. |
Nakayama H, Ohuchida K, Yoshida M, Miyazaki T, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Moriyama T, Nakata K, Miyasaka Y, Shirahane K, Manabe T, Ohtsuka T, Toma H, Tominaga Y, Nagai E, Mizumoto K, Oda Y, Nakamura M, Degree of desmoplasia in metastatic lymph node lesions is associated with lesion size and poor prognosis in pancreatic cancer patients, Oncol Lett, 10.3892/ol.2017.6549, 14, 3, 3141-3147, 2017.04, Abstract
Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10-70%) and low (KEYWORDS:
desmoplasia; locally extranodal invasion; lymph node metastasis; pancreatic cancer; prognostic factor. |
| 133. |
Ohtsuka T, Mori Y, Ishigami K, Fujimoto T, Miyasaka Y, Nakata K, Ohuchida K, Nagai E, Oda Y, Shimizu S, Nakamura M, Clinical significance of circumportal pancreas, a rare congenital anomaly, in pancreatectomy, Am J Surg, 214, 2, 267-272, 2017.04, Abstract
BACKGROUND:
Circumportal pancreas is a rare congenital pancreatic anomaly. The aim of this study was to clarify the clinical characteristics of patients with circumportal pancreases undergoing pancreatectomy.
METHODS:
The medical records of 508 patients who underwent pancreatectomy were retrospectively reviewed. The prevalence of circumportal pancreas and related anatomical variations were assessed. Surgical procedures and postoperative outcomes were compared in patients with and without circumportal pancreas.
RESULTS:
Circumportal pancreas was observed in 9 of the 508 patients (1.7%). In all nine patients, the portal vein was completely encircled by the pancreatic parenchyma above the level of the splenoportal junction, and the main pancreatic duct ran dorsal to the portal vein. The rate of variant hepatic artery did not differ significantly in patients with and without circumportal pancreas. Pancreatic fistula developed more frequently in patients with than without circumportal pancreas (44% vs. 14%, p = 0.03), but other clinical parameters did not differ significantly in these two groups.
CONCLUSIONS:
Despite being rare, circumportal pancreas may increase the risk of postoperative pancreatic fistula in patients undergoing pancreatectomy. However, a prospective, large-cohort study is necessary to determine the real incidence of relevant anatomical variations and the definitive clinical significance of this rare anomaly.. |
| 134. |
Abe T, Ohuchida K, Endo S, Ookubo F, Mori Y, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Oda Y, Nakamura M, Clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer, Surgery, 161, 4, 951-958, 2017.04, BACKGROUND:The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood.METHODS:Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors.RESULTS:Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P < .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ pat
ients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P < .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival.CONCLUSION:Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy.. |
| 135. |
Abe T, Ohuchida K, Koikawa K, Endo S, Okumura T, Sada M, Horioka K, Zheng B, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination, Int J Oncol, 50, 2, 457-467, 2017.04, The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues
of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.. |
| 136. |
Ozono K, Ohishi Y, Onishi H, Nakamura K, Motoshita J, Kato M, Nakanishi R, Nakamura M, Oda Y, Brain-derived neurotrophic factor/tropomyosin-related kinase B signaling pathway contributes to the aggressive behavior of lung squamous cell carcinoma, Lab Invest, 10.1038/labinvest.2017.45
[Indexed for MEDLINE], 97, 11, 1332-1342, 2017.04, Abstract
The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P |
| 137. |
Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice, Gastroenterology, 10.1053/j.gastro.2017.01.010, 152, 6, 1492-1506, 2017.04, BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) changefrom a quiescent to activated state in the tumor environmentand secrete extracellular matrix (ECM) molecules and cytokinesto increase the aggressiveness of tumors. However, it is notclear how PSCs are activated to produce these factors, orwhether this process can be inhibited. PSCs have morphologicand functional similarities to hepatic stellate cells, whichundergo autophagy to promote fibrosis and tumor growth. Weinvestigated whether autophagy activates PSCs, which promotesdevelopment of the tumor stroma and growth ofpancreatic tumors in mice. METHODS: We used immunofluorescencemicroscopy and immunohistochemistry to analyzepancreatic tumor specimens from 133 patients who underwentpancreatectomy in Japan from 2000 to 2009. PSCs werecultured from pancreatic tumor tissues or tissues of patientswith chronic pancreatitis; these were analyzed by immunofluorescencemicroscopy, immunoblots, quantitative
reversetranscription polymerase chain reaction, and in assays forinvasiveness, proliferation, and lipid droplets. Autophagy wasinhibited in PSCs by administration of chloroquine or transfectionwith small interfering RNAs. Proteins were knockeddown in immortalized PSCs by expression of small hairpinRNAs. Cells were transplanted into pancreatic tails of nudemice, and tumor growth and metastasis were quantified. RESULTS:Based on immunohistochemical analyses, autophagywas significantly associated with tumor T category (P ｼ .018),histologic grade (P ｼ .001), lymph node metastases (P < .001),stage (P ｼ .009), perilymphatic invasion (P ｼ .001), and perivascularinvasion (P ｼ .003). Autophagy of PSCs was associatedwith shorter survival times of patients with pancreatic cancer.PSC expression of microtubule-associated protein 1 lightchain 3, a marker of autophagosomes, was associated with pooroutcomes (shorter survival time, disease recurrence) forpati
ents with pancreatic cancer (relative risk of shorter survivaltime, 1.56). Immunoblots showed that PSCs from pancreatictumor samples expressed higher levels of markers of autophagythan PSCs from chronic pancreatitis samples. Inhibitorsof autophagy increased the number of lipid droplets of PSCs,indicating a quiescent state of PSCs, and reduced their productionof ECM molecules and interleukin 6, as well as theirproliferation and invasiveness in culture. PSCs exposedto autophagy inhibitors formed smaller tumors in nude mice(P ｼ .001) and fewer liver metastases (P ｼ .018) with lessperitoneal dissemination (P ｼ .018) compared to PSCs notexposed to autophagy inhibitors. CONCLUSIONS: AutophagicPSCs produce ECM molecules and interleukin 6 and areassociated with shorter survival times and disease recurrencein patients with pancreatic cancer. Inhibitors of PSC autophagymight reduce pancreatic tumor invasiveness by altering thetumor stroma.. |
| 138. |
Endo S, Nakata K, Sagara A, Koikawa K, Ando Y, Kibe S, Takesue S, Nakayama H, Abe T, Okumura T, Moriyama T, Miyasaka Y, Ohuchida K, Ohtsuka T, Mizumoto K, Nakamura M, Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells, Pancreatology, 10.1016/j.pan.2017.08.009, 17, 6, 990-996, 2017.04, Background: Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy.However, it has not been clarified whether autophagy induced by salinomycin treatment has a protectiveor cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells andwhether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells.Methods: We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigatedeffect on proliferation and the CD133 positive fraction using flow cytometry. In addition, wemonitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining,western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was usedto investigate the impact of autophagy inhibition on sensitivity to salinomycin.Results: Salinomycin suppressed the proliferation of pancreatic cancer cells in a co
ncentration dependentmanner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cellsin a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitiveto salinomycin.Conclusions: Our data provide the first evidence indicating that autophagy induced by salinomycin havea protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin,autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.. |
| 139. |
Nakamura M, Nakata K, Matsumoto H, Ohtsuka T, Yoshida K, Tokunaga S, Hino K, Acyl/free carnitine ratio is a risk factor for hepatic steatosis after pancreatoduodenectomy and total pancreatectomy, Pancreatology, 17, 1, 135-138, 2017.04, Abstract
OBJECTIVES:
Hepatic steatosis, one of the most frequent long-term complications of pancreatectomy, influences not only hepatic function but also survival rate. However, its risk factors and pathogenesis have not been established. The purpose of this study was to clarify the risk factors for hepatic steatosis after pancreatectomy.
METHODS:
In this retrospective study of 21 patients who had undergone pancreatectomy (19 cases of pancreatoduodenectomy and 2 cases of total pancreatectomy), serum carnitine concentrations, fractions of carnitine, and hepatic attenuation on computed tomography images were analyzed with the aim of identifying risk factors for hepatic steatosis.
RESULTS:
Thirteen (61.9%) of the 21 patients were diagnosed as having hypocarnitinemia after pancreatectomy. Average hepatic attenuation was as low as 42.2HU (±21.3 SD). A high ratio of acyl/free carnitine was associated with less pronounced hepatic attenuation according to both univariate (P CONCLUSIONS:
The serum carnitine concentrations were low after pancreatectomy in some patients. The statistical analyses suggest that a high ratio of acyl/free carnitine is an independent risk factor for hepatic steatosis after pancreatectomy.. |
| 140. |
Torata N, Kubo M, Miura D, Ohuchida K, Mizuuchi Y, Fujimura Y, Hayakawa E, Kai M, Oda Y, Mizumoto K, Hashizume M, Nakamura M, Visualizing Energy Charge in Breast Carcinoma Tissues by MALDI Mass-spectrometry Imaging Profiles of Low-molecular-weight Metabolites, Anticancer Res, doi:10.21873/anticanres.12723, 38, 7, 4267-4272, 2018.04, Abstract
BACKGROUND/AIM:
Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass-spectrometry imaging (MALDI-MSI).
MATERIALS AND METHODS:
A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue.
RESULTS:
Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences.
CONCLUSION:
Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma.
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| 141. |
Wakabayashi G, Iwashita Y, Hibi T, Takada T, Strasberg SM, Asbun HJ, Endo I, Umezawa A, Asai K, Suzuki K, Mori Y, Okamoto K, Pitt HA, Han HS, Hwang TL, Yoon YS, Yoon DS, Choi IS, Huang WS, Gimenez ME, Garden OJ, Gouma DJ, Belli G, Dervenis C, Jagannath P, Chan ACW, Lau WY, Liu KH, Su CH, Misawa T, Nakamura M, Horiguchi A, Tagaya N, Fujioka S, Higuchi R, Shikata S, Noguchi Y, Ukai T, Yokoe M, Cherqui D, Honda G, Sugioka A, de Santibanes E, Supe AN, Tokumura H, Kimura T, Yoshida M, Mayumi T, Kitano S, Inomata M, Hirata K, Sumiyama Y, Inui K, Yamamoto M, Tokyo Guidelines 2018: surgical management of acute cholecystitis: safe steps in laparoscopic cholecystectomy for acute cholecystitis (with videos), J Hepatobiliary Pancreat Sci, 10.1002/jhbp.517, 25, 1, 73-86, 2018.04. |
| 142. |
Okamoto K, Suzuki K, Takada T, Strasberg SM, Asbun HJ, Endo I, Iwashita Y, Hibi T, Pitt HA, Umezawa A, Asai K, Han HS, Hwang TL, Mori Y, Yoon YS, Huang WS, Belli G, Dervenis C, Yokoe M, Kiriyama S, Itoi T, Jagannath P, Garden OJ, Miura F, Nakamura M, Horiguchi A, Wakabayashi G, Cherqui D, de Santibanes E, Shikata S, Noguchi Y, Ukai T, Higuchi R, Wada K, Honda G, Supe AN, Yoshida M, Mayumi T, Gouma DJ, Deziel DJ, Liau KH, Chen MF, Shibao K, Liu KH, Su CH, Chan ACW, Yoon DS, Choi IS, Jonas E, Chen XP, Fan ST, Ker CG, Gimenez ME, Kitano S, Inomata M, Hirata K, Inui K, Sumiyama Y, Yamamoto M, Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.516, 25, 1, 55-72, 2018.04. |
| 143. |
Date K, Ohtsuka T, Nakamura S, Mochidome N, Mori Y, Miyasaka Y, Oda Y, Nakamura M, Surveillance of patients with intraductal papillary mucinous neoplasm with and without pancreatectomy with special reference to the incidence of concomitant pancreatic ductal adenocarcinoma, Surgery, 10.1016/j.surg.2017.09.040, 163, 2, 291-299, 2018.04, Abstract
BACKGROUND:
The presence of an intraductal papillary mucinous neoplasm is important in the detection of concomitant pancreatic ductal adenocarcinoma. The aim of this study was to elucidate the incidence and timing of development of concomitant pancreatic ductal adenocarcinoma in patients with and without pancreatectomy for intraductal papillary mucinous neoplasm.
METHODS:
We reviewed retrospectively the surveillance data for 22 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm (pancreatic ductal adenocarcinoma-resection group), 180 who underwent pancreatectomy for intraductal papillary mucinous neoplasm (intraductal papillary mucinous neoplasm-resection group), and 263 whose intraductal papillary mucinous neoplasms were left untreated (nonresection group). The incidence and timing of the development of a concomitant pancreatic ductal adenocarcinoma during the surveillance of patients with and without partial pancreatectomy for intraductal papillary mucinous neoplasm were investigated using the Kaplan-Meier method.
RESULTS:
During a median surveillance period of 40 months (range 6-262 months), 5 patients in the pancreatic ductal adenocarcinoma-resection group, 6 in the intraductal papillary mucinous neoplasm-resection group, and 8 in the nonresection group developed concomitant pancreatic ductal adenocarcinoma. The estimated 5-year (17%) and 10-year (56%) cumulative incidences of secondary pancreatic ductal adenocarcinoma in the pancreatic ductal adenocarcinoma-resection group were significantly greater than those in the other two groups (P
CONCLUSION:
Long-term (≥5-year) surveillance in patients with intraductal papillary mucinous neoplasm is necessary and important because of the potential for development of concomitant pancreatic ductal adenocarcinoma. Those with a history of resection of concomitant pancreatic ductal adenocarcinoma at the time of the initial operation are at quite high risk for the development of secondary pancreatic ductal adenocarcinoma.. |
| 144. |
Yamada S, Fujii T, Kawai M, Shimokawa T, Nakamura M, Murakami Y, Satoi S, Eguchi H, Nagakawa Y, Kodera Y, Yamaue H, Splenic vein resection together with the pancreatic parenchyma versus separated resection after isolation of the parenchyma during distal pancreatectomy (COSMOS-DP trial): study protocol for a randomised controlled trial, Trials, 10.1186/s13063-018-2756-7 , 19, 1, 369, 2018.04, Abstract
BACKGROUND:
In distal pancreatectomy (DP), it is customary to ligate and divide the splenic vein after isolating it from the pancreatic parenchyma. This is considered essential to prevent disruption of the stump of the splenic vein and consequent intra-abdominal haemorrhage in the event of pancreatic fistula (PF). However, this procedure can be technically demanding, especially when the vein is firmly embedded in the pancreatic parenchyma. The objective of the COSMOS-DP trial is to confirm the non-inferiority of resection of the splenic vein embedded in the pancreatic parenchyma compared with the conventional technique of isolating the splenic vein before resection during DP using a mechanical stapler.
METHODS:
Patients with diseases of the pancreatic body and tail whose pancreatic parenchyma and splenic vein can be divided concurrently during open or laparoscopic DP are considered eligible for inclusion. This study is designed as a multicentre prospective randomised phase III trial. Eligible patients will be centrally randomised to either Arm A (resection of the splenic vein after isolation from the pancreatic parenchyma) or Arm B (co-resection of the vein together with the pancreas). This study aims to establish the non-inferiority of the safety of Arm B compared with that of Arm A; the primary endpoint is the incidence of PF (ISGPF grade B/C).
DISCUSSION:
The COSMOS-DP trial will establish the safety of this procedure, such that it can be recommended with more confidence. The use of this procedure will likely result in significant reductions in operative time and blood loss during DP.
TRIAL REGISTRATION:
ClinicalTrials.gov, NCT02871804 . Registered on 27 July 2016.
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| 145. |
Kurata K, Kai M, Kubo M, Mori H, Yamada M, Nakafusa Y, Nakamura M, Significance of Endocrine Therapy for Unresected Primary Breast Cancer, Gan To Kagaku Ryoho, 45, 11, 1645-1647, 2018.04. |
| 146. |
Kameda C, Watanabe M, Suehara N, Watanabe Y, Nishihara K, Nakano T, Nakamura M, Safety of laparoscopic distal gastrectomy for gastric cancer when performed by trainee surgeons with little experience in performing open gastrectomy, Surg Today, 10.1007/s00595-017-1569-8, 48, 2, 211-216, 2018.04, Purpose: This study aimed to evaluate the surgical outcomes and clinical safety of laparoscopic distal gastrectomy (LDG) when performed by trainee surgeons with little prior experience in performing open gastrectomy, under the guidance of trainer surgeons.Methods: From January 2008 until March 2015, 17 trainee surgeons and 5 trainer surgeons performed LDGs to treat 371 patients with clinical stage T1-T3 gastric cancer. Of these patients, 140 and 231 underwent LDG performed by trainee surgeons and trainer surgeons, respectively. We retrospectively analyzed the surgical outcomes of the two groups.Results: Trainee surgeons required significantly longer operation times than the trainer surgeons, with respective mean operation times of 262 and 223 minutes (p < 0.001). However, the mean blood loss volumes, average numbers of retrieved lymph nodes, postoperative complications, and postoperative hospital stay lengths did not differ significantly between LD
Gs performed by trainee surgeons and trainer surgeons. Conclusions: The study findings suggest that, under the guidance of trainer surgeons, trainee surgeons with little experience with open gastrectomy and even without prior experience with LDG can perform radical surgeries safely.. |
| 147. |
Ohtsuka T, Gotoh Y, Nakashima Y, Okayama Y, Nakamura S, Morita M, Aly MYF, Velasquez VVDM, Mori Y, Sadakari Y, Nakata K, Miyasaka Y, Ishigami K, Fujimori N, Mochidome N, Oda Y, Shimizu S, Nakamura M, Role of SpyGlass-DStm in the preoperative assessment of pancreatic intraductal papillary mucinous neoplasm involving the main pancreatic duct, Pancreatology, 10.1016/j.pan.2018.04.012, 18, 5, 566-571, 2018.04, Abstract
BACKGROUND/OBJECTIVES:
It is often difficult to determine an adequate resection line during pancreatectomy for intraductal papillary mucinous neoplasm involving the main pancreatic duct during partial pancreatectomy. The aim of this study was to evaluate the usefulness of improved peroral pancreatoscopy using SpyGlass-DStm in the preoperative assessment of intraductal papillary mucinous neoplasm involving the main pancreatic duct.
METHODS:
We collected and retrospectively analyzed clinicopathological data from seven consecutive patients who underwent preoperative assessment of intraductal papillary mucinous neoplasm involving the main duct using SpyGlass-DStm.
RESULTS:
Good imaging quality of the intraductal protruding lesion was obtained in all seven patients, and only one adverse event was noted wherein a patient had mild pancreatitis. Six patients underwent pancreatectomy. In one patient, masked-type concomitant pancreatic ductal adenocarcinoma and low-length dysplastic lesion was found near the surgical margin, which was not detected by preoperative imaging modalities including SpyGlass-DStm. The sensitivity of targeting biopsy during SpyGlass-DStm to diagnose high-grade dysplasia was 0%.
CONCLUSIONS:
SpyGlass-DStm can be safely performed in patients with intraductal papillary mucinous neoplasm involving the main duct, and has excellent visualization of the target lesion. However, challenges include poor diagnostic ability of targeting biopsy, and, therefore, intraoperative frozen section is still needed to obtain negative surgical margins
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| 148. |
Abe T, Nakata K, Kibe S, Mori Y, Miyasaka Y, Ohuchida K, Ohtsuka T, Oda Y, Nakamura M, Prognostic Value of Preoperative Nutritional and Immunological Factors in Patients with Pancreatic Ductal Adenocarcinoma, Ann Surg Oncol, 10.1245/s10434-018-6761-6, 25, 13, 3996-4003, 2018.04. |
| 149. |
Noguchi H, Miyasaka Y, Kaku K, Nakamura U, Okabe Y, Ohtsuka T, Ishigami K, Nakamura M, Preoperative Muscle Volume Predicts Graft Survival after Pancreas Transplantation: A Retrospective Observational Cohort Study, Transplant Proc, 10.1016/j.transproceed.2018.03.018, 50, 5, 1482-1488, 2018.04, Abstract
Background
Several studies have suggested that decreased muscle volume is associated with attenuation of immune function. The recipient’s immune system is responsible for rejection of transplanted organs, which is a major cause of graft loss after transplantation. We aimed to determine whether muscle volume is correlated with graft survival after pancreas transplantation (PT).
Methods
Forty-three patients underwent PT for type 1 diabetes mellitus at our institution from August 2001 to May 2016. The quantity of skeletal muscle was evaluated using the psoas muscle mass index (PMI). The correlation between the PMI and outcome after PT was assessed.
Results
A total of 32 and 11 recipients underwent simultaneous pancreas–kidney transplantation (SPK) and PT alone/pancreas after kidney transplantation, respectively. Patients with a surviving graft showed a significantly lower PMI than those with graft loss (P = 0.0451). We divided the recipients into two groups according to the PMI cutoff values which were established using receiver operating characteristic curves. The cumulative graft survival rate was significantly higher in patients with a low than normal PMI (P = 0.0206). A multivariate Cox regression analysis revealed that a low PMI (P= 0.0075) is an independent predictive factor for better graft survival. A low PMI was not a significant predictive factor for acute rejection, but was an independent predictive factor for graft survival after the first acute rejection (P= 0.0025).
Conclusions
Our data suggest that muscle volume could be a predictor of graft survival after PT.
Key words
pancreas transplantation; sarcopenia; graft rejection; graft survival
Abbreviations
AR, acute rejection; ATG, rabbit antithymocyte globulin; BMI, body mass index; CI, confidence interval; CT, computed tomography; DM, diabetes mellitus; HR, hazard ratio; IL, interleukin; ND, not done; PAK, pancreas-after-kidney transplantation; PMI, psoas muscle mass index; PT, pancreas transplantation; PTA, pancreas transplantation alone; SPK, simultaneous pancreas–kidney transplantation; TNF-α, tumor necrosis factor-alpha; Tregs, regulatory T cells. |
| 150. |
Okabe Y, Noguchi H, Miyamoto K, Kaku K, Tsuchimoto A, Masutani K, Nakamura M, Preformed C1q-binding Donor-specific Anti-HLA Antibodies and Graft Function After Kidney Transplantation, Transplantation Proceedings, 10.1016/j.transproceed.2018.07.033, 50, 10, 3460-3466, 2018.04, Abstract
Background: De novo complement-binding donor-specific anti-human leukocyte antigen antibodies (DSAs) are reportedly associated with an increased risk of kidney graft failure, but there is little information on preformed complement-binding DSAs. This study investigated the correlation between preformed C1q-binding DSAs and medium-term outcomes in kidney transplantation (KT).
Methods: We retrospectively studied 44 pretransplant DSA-positive patients, including 36 patients who underwent KT between April 2010 and October 2016. There were 17 patients with C1q-binding DSAs and 27 patients without C1q-binding DSAs. Clinical variables were examined in the 2 groups.
Results: Patients with C1q-binding DSAs had significantly higher blood transfusion history (53.0% vs 18.6%; P = .0174), complement-dependent cytotoxicity crossmatch (CDC-XM)-positivity (29.4% vs 0%; P = .0012), and DSA median fluorescence intensity (MFI) (10,974 vs 2764; P = .0009). Among patients who were not excluded for CDC-XM-positivity and underwent KT, there was no significant difference in cumulative biopsy-proven acute rejection rate (32.5% vs 33.5%; P = .8354), cumulative graft survival, and 3-month and 12-month protocol biopsy results between patients with and without C1q-binding DSAs. Although patients with C1q-binding DSAs showed a higher incidence of delayed graft function (54.6% vs 20.0%; P = .0419), multivariate logistic regression showed that DSA MFI (P = .0124), but not C1q-binding DSAs (P = .2377), was an independent risk factor for delayed graft function.
Conclusions: In patients with CDC-XM-negativity, preformed C1q-binding DSAs were not associated with incidence of antibody-mediated rejection and medium-term graft survival after KT. C1q-binding DSAs were highly correlated with DSA MFI and CDC-XM-positivity.. |
| 151. |
Sadakari Y, Date S, Murakami S, Ichimiya S, Nishimura S, Kawaji H, Sagara A, Castillo JR, Ishikawa M, Kamimura T, Uchiyama A, Nakamura M, Prediction of Negative Outcomes in Non-Surgical Treatment for Appendiceal Abscess in Adults, J Anus Rectum Colon, 10.23922/jarc.2017-051 , 2, 2, 59-65, 2018.04, Abstract: Objectives: Non-surgical treatment is an acceptable approach for managing appendiceal abscess in adults.
However, it is only applicable for selected patients, and conversion to surgery is mandatory for failed conservative
treatment. This study aimed to determine the predictive factors for unsuccessful outcomes. Methods:
Of 594 patients with acute appendicitis, 34 (5.7%) diagnosed with appendiceal abscess were initially
treated conservatively. Patients were divided into two groups: the conservative group, which was successfully
treated with antibiotics and percutaneous abscess drainage, and the conversion group, which comprised
patients who had surgical conversion despite conservative treatment. Risk factors for the conversion
group were investigated by comparing clinical and radiological parameters between the two groups. Results:
Eight (23.4%) patients were converted to surgical management at an average of 5.5 days of non-surgical
treatment. An abscess size greater than 40 mm and a lower rate of improvement in the white blood cell
(WBC) count were significant factors for predicting conversion in multivariate analysis. The conversion
group had a long operative time and high morbidity and operative conversion rates (change of proposed initial
operation). Early conversion to operation group, i.e., less than 5 days of treatment, contributed to a significantly
shorter hospital stay, lower hospital cost, and relatively shorter operative time (p = 0.02, p = 0.04,
and p = 0.11, respectively). Conclusions: Contributing factors in predicting unsuccessful outcomes for nonsurgical
treatment include an abscess size greater than 40 mm and a low rate of improvement in WBC
count on the first day of antibiotic treatment.
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| 152. |
Koikawa K, Ohuchida K, Takesue S, Ando Y, Kibe S, Nakayama H, Endo S, Abe T, Okumura T, Horioka H, Sada M, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohuchida R, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180, Cancer lett, 10.1016/j.canlet.2017.10.010, 1, 412, 143-154, 2018.04, Specific cell populations leading the local invasion of cancer are called “leading cells”. However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and deter- mined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co- cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs
suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.. |
| 153. |
Saeki K, Ohishi Y, Matsuda R, Mochidome N, Miyasaka Y, Yamamoto H, Koga Y, Maehara Y, Nakamura M, Oda Y
, “Pancreatic Mucoepidermoid Carcinoma” Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features, Am J Pathol, 10.1097/PAS.0000000000001135, 42, 11, 1419-1428, 2018.04, Abstract“Mucoepidermoid carcinoma (MEC)” has been accepted as a synonym for pancreatic adenosquamous carcinoma (ASC). Pancreatic ASC can show salivary gland-type MEC-like morphology. CRTC1/3-MAML2 fusion gene is a characteristic molecular feature of MEC of the salivary gland. We conducted this study to clarify whether the pancreatic ASC with salivary gland-type MEC-like morphology (Pan-MEC) is a pancreatic counterpart of salivary gland-type MEC (Sal-MEC). We retrospectively analyzed 37 pancreatic ASCs including 16 Pan-MECs and 21 tumors without MEC-like features (ASC-NOS [not otherwise specified]), and we investigated (1) clinicopathologic features, (2) the presence of CRTC1/3-MAML2 fusion gene by reverse transcription polymerase chain reaction, (3) the presence of rearrangement of MAML2 gene by fluorescence in situ hybridization, and (4) mucin core proteins by immunohistochemistry. We also compared 16 Pan-MECs with 20 Sal-MECs by immunohistochemistry for mucin core protein. There were no significant differences of any clinicopathologic characteristics and survival analysis between the Pan-MECs and ASCs-NOS. Of note, the pancreatic ASCs (including Pan-MEC and ASC-NOS) were significantly more aggressive than conventional pancreatic ductal adenocarcinoma. In addition, all Pan-MECs were histologically high-grade. CRTC1/3-MAML2 fusion gene and MAML2 gene rearrangement were not detected in any ASCs including Pan-MECs. There were significant differences of MUC5AC and MUC6 between the Pan-MECs and Sal-MECs, but no significant differences of mucin core protein between the Pan-MECs and pancreatic ASCs-NOS. Pan-MEC is histologically and biologically high-grade and unrelated to CRTC1/3-MAML2 fusion gene, unlike Sal-MEC which is related to CRTC1/3-MAML2 fusion gene. Pan-MEC is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related Sal-MEC.
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| 154. |
Kanno A, Masamune A, Hanada K, Maguchi H, Shimizu Y, Ueki T, Hasebe O, Ohtsuka T, Nakamura M, Takenaka M, Kitano M, Kikuyama M, Gabata T, Yoshida K, Sasaki T, Serikawa M, Furukawa T, Yanagisawa A, Shimosegawa T, Multicenter study of early pancreatic cancer in Japan, Pancreatology, 10.1016/j.pan.2017.11.007, 18, 1, 61-67, 2018.04, Abstract
BACKGROUND/OBJECTIVES:
The diagnosis of early-stage pancreatic ductal adenocarcinoma (PDAC) is still challenging. We conducted a multicenter study to clarify the clinical features of early-stage PDAC in Japan.
METHODS:
We collected patients with stage 0 and stage I PDAC according to the sixth edition of the Japanese Classification of Pancreatic Carcinoma. We retrospectively analyzed the clinical profiles including opportunities for medical examination, imaging modalities and findings, methods of cytological diagnosis, and prognosis according to the stages at diagnosis.
RESULTS:
Two hundred cases with Stage 0 and stage I PDAC were reported from 14 institutions, which accounted for approximately 0.7% and 3% of all PDAC cases, respectively. Overall, 20% of the early-stage PDAC cases were symptomatic. Indirect imaging findings such as dilatation of the main pancreatic duct were useful to detect early-stage PDAC. In particular, local fatty changes may be specific to early-stage PDAC. For preoperative pathologic diagnosis, cytology during endoscopic retrograde cholangiopancreatography was more commonly applied than endoscopic ultrasound fine-needle aspiration. Although the overall prognosis was favorable, new PDAC lesions developed in the remnant pancreas in 11.5% cases.
CONCLUSIONS:
This multicenter study revealed several key points concerning the diagnosis and management of early-stage PDAC, including screening of asymptomatic cases, importance of indirect imaging findings, application of cytology during endoscopic retrograde cholangiopancreatography, and the risk of carcinogenesis in the remnant pancreas.. |
| 155. |
Nakata K, Shikata S, Ohtsuka T, Ukai T, Miyasaka Y, Mori Y, Velasquez VVDM, Gotoh Y, Ban D, Nakamura Y, Nagakawa Y, Tanabe M, Sahara Y, Takaori K, Honda G, Misawa T, Kawai M, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Chinnusamy P, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M, Minimally invasive preservation versus splenectomy during distal pancreatectomy: a systematic review and meta-analysis, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.569 , 25, 11, 476-488, 2018.04, Abstract
BACKGROUND:
Minimally invasive distal pancreatectomy (MIDP) has gained in popularity recently. However, there is no consensus on whether to preserve the spleen or not. In this study, we compared MIDP outcomes between spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS); as well as outcomes between splenic vessel preservation (SVP) and Warshaw's technique (WT).
METHODS:
A systematic search of PubMed (MEDLINE) and Cochrane Library was conducted and the reference lists of review articles were hand-searched.
RESULTS:
Fifteen relevant studies with 769 patients were selected for meta-analyses of DPS and SPDP, while another 15 studies with 841 patients were used for the analysis between SVP and WT. Compared with the DPS group, SPDP patients had significantly lower incidences of infectious complications (P = 0.006) and pancreatic fistula (P = 0.002), shorter operative time (P CONCLUSIONS:
Based on this study, SPDP has significantly superior outcomes compared to DPS. When a spleen is preserved, SVP has better outcomes over WT for reducing splenic complications.
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| 156. |
Abe A, Ohishi Y, Miyazaki T, Ozono K, Mochidome N, Saeki K, Nakamura M, Oda Y, 'Microcystic pattern' should be recognised as part of the morphological spectrum of solid-pseudopapillary neoplasm of the pancreas, Histopathology, 10.1111/his.13376 , 72, 2, 216-226, 2018.04, Abstract AIM: Solid pseudopapillary neoplasm (SPN) is an uncommon pancreatic tumour characterised by solid and pseudopapillary growth patterns. We have observed SPNs can show a microcystic pattern (microcystic SPN), which has been poorly described and may be confused with microcystic neoplasms. We conducted the present study to clarify the clinicopathological and immunohistochemical features of microcystic SPNs.
METHODS AND RESULTS: We examined a consecutive series of 44 SPNs and 10 serous cystadenomas (SCAs), and classified them into 13 microcystic SPNs (29.5%) and 31 conventional SPNs (70.5%). Clinicopathological analysis, immunohistochemical staining and mucin histochemistry were performed. Clear cell change, hyalinised stroma and haemorrhage were observed significantly more frequently in the microcystic SPNs compared to the conventional SPNs. Immunohistochemically, the microcystic SPNs showed significantly lower frequencies of CD10 (0%) and CD56 expression (62%) compared to the conventional SPNs (87%; P . |
| 157. |
Inui K, Masamune A, Igarashi Y, Ohara H, Tazuma S, Sugiyama M, Suzuki Y, Miyoshi H, Yamamoto S, Takeyama Y, Nakano E, Takuma K, Sakagami J, Hayashi K, Kogure A, Ito T, Mukai T, Maetani I, Nagahama M, Serikawa M, Ueki T, Furuya K, Isayama H, Moriyama I, Shigeno M, Mizukami K, Nanashima A, Oana S, Ikehata A, Watanabe N, Hirooka Y, Ogoshi K, Sasaki Y, Iwata Y, Kudo Y, Nakayama A, Nakamura M, Management of Pancreatolithiasis: A Nationwide Survey in Japan, Pancreas, 10.1097/MPA.0000000000001071., 47, 6, 708-714, 2018.04, Abstract
OBJECTIVES:
The aim of this study was to assess prevailing treatment of pancreatolithiasis in Japan.
METHODS:
We surveyed clinical data from 1834 patients (1479 men and 355 women) at 125 hospitals.
RESULTS:
Extracorporeal shock-wave lithotripsy (ESWL) was performed alone in 103 patients (5.6%), ESWL plus an endoscopic procedure in 446 (24.3%), endoscopic treatment alone in 261 (14.2%), and surgery in 167 (9.1%). Other treatments were given to 358 (19.5%), whereas 499 (27.2%) received no treatment. Symptoms were relieved in 85.7% after ESWL, 80.8% after endoscopic treatment alone, and 92.8% after surgery. Early complication rates within 3 months after ESWL, endoscopic treatment alone, and surgery were 8%, 4.5%, and 27.1%, respectively. Late complications after ESWL, endoscopic procedures alone, and surgery were 1.7%, 2.5%, and 8.2%, respectively. Symptom relief but also early and late complications were greater after surgery than after ESWL and endoscopic treatment. Among 417 patients undergoing ESWL, 61 (14.6%) required surgery, as did 32 (16%) of 200 patients treated endoscopically. Surgery was required less frequently following initial operative treatment (11/164 patients [6.7%]). Nonsurgical initial treatments were chosen more frequently.
CONCLUSIONS:
First-line treatment of pancreatolithiasis should be ESWL with or without endoscopy because of minimal invasiveness and fewer complications.
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| 158. |
Nagakawa Y, Nakamura Y, Honda G, Gotoh Y, Ohtsuka T, Ban D, Nakata K, Sahara Y, Velasquez VVDM, Takaori K, Misawa T, Kuroki T, Kawai M, Morikawa T, Yamaue H, Tanabe M, Mou Y, Lee WJ, Shrikhande SV, Conrad C, Han HS, Tang CN, Palanivelu C, Kooby DA, Asbun HJ, Wakabayashi G, Tsuchida A, Takada T, Yamamoto M, Nakamura M, Learning curve and surgical factors influencing the surgical outcomes during the initial experience with laparoscopic pancreaticoduodenectomy, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.586 , 25, 11, 498-507, 2018.04, Abstract
BACKGROUND:
Laparoscopic pancreaticoduodenectomy (LPD) requires sufficient laparoscopic training for optimal outcomes. Our aim is to determine the learning curve and investigate the factors influencing surgical outcomes during the learning curve.
METHODS:
We analyzed surgical results of 150 consecutive cases of LPD performed by three hepatopancreatobiliary surgeons during their 50 first cases. Learning curves were constructed by cumulative sum (CUSUM) analysis. Preoperative factors influencing resection time and blood loss were investigated in the introductory and stable periods. RESULTS : The learning curve could be divided into three phases: initial (1-20 cases), plateau (21-30), and stable (31-50). Resection time with lymph node dissection was significantly longer during the introductory period (initial and plateau periods) (P CONCLUSIONS:
Hepatopancreatobiliary surgeons need more than 30 cases until LPD becomes stable. Lymph node dissection and patients with high visceral fat area and concomitant pancreatitis should be avoided during the introductory period of the learning curve.. |
| 159. |
Aly MYF, Mori Y, Miyasaka Y, Ohtsuka T, Sadakari Y, Nakata K, Oda Y, Shimizu S, Nakamura M, Laparoscopic surgery for congenital biliary dilatation: a single-institution experience, Surg Today, 10.1007/s00595-017-1545-3, 48, 1, 44-50, 2018.04, Abstract
PURPOSE:
Laparoscopic surgery as a treatment for congenital biliary dilatation is uncommon. We herein present a series of laparoscopic surgeries for congenital biliary dilatation performed in our institution and review our experience with this approach over a long period of time.
METHODS:
Medical records of 36 consecutive patients who underwent laparoscopic surgery for congenital biliary dilatation from 1996 to 2015 were retrospectively reviewed. Data on patient demographics, operative time, blood loss, hospital stay, and complications were evaluated. A comparison between the former period (Group A, 1996-2005) and the latter period (Group B, 2006-2015) was performed.
RESULTS:
The patients comprised 23 females and 13 males with a median age of 34 years. The median operative time, blood loss, and hospital stay was 493 min, 154 g, and 11 days, respectively. Total early and late complications occurred in 7 (19%) and 2 (5%) patients, respectively. A comparison between Groups A and B revealed no significant difference in operative time or complications, but operative blood loss, open conversion, and hospital stay were significantly lower in Group B than in Group A (P
CONCLUSION:
Laparoscopic surgery for congenital biliary dilatation is feasible and provides acceptable results. Further prospective studies of larger numbers of patients are needed.. |
| 160. |
Yamada S, Arase H, Tachibana S, Tomita K, Eriguchi M, Fujisaki K, Okabe Y, Nakamura M, Nakano T, Tsuruya K, Kitazono T, Immobilization-induced severe hypercalcaemia successfully treated with reduced dose of zoledronate in a maintenance haemodialysis patient, Nephrology, 10.1111/nep.13246 , 23, 10, 963-964, 2018.04. |
| 161. |
Ideno N, Yamaguchi H, Ghosh B, Gupta S, Okumura T, Steffen DJ, Fisher CG, Wood LD, Singhi AD, Nakamura M, Gutkind JS, Maitra A, GNASR201C Induces Pancreatic Cystic Neoplasms in Mice That Express Activated KRAS by Inhibiting YAP1 Signaling, Gastroenterology, 10.1053/j.gastro.2018.08.006 , 155, 5, 1593-1607, 2018.04, Abstract
BACKGROUND & AIMS:
Mutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.
METHODS:
We generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNASR201C) upon doxycycline administration. Mice that were not given doxycycline were used as controls, and survival times were compared by Kaplan-Meier analysis. Pancreata were collected at different time points after doxycycline administration and analyzed by histology. Pancreatic ductal adenocarcinomas (PDACs) were isolated from mice and used to generate cell lines, which were analyzed by reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and colony formation and invasion assays. Full-length and mutant forms of yes-associated protein (YAP) were expressed in PDAC cells. IPMN specimens were obtained from 13 patients with IPMN undergoing surgery and analyzed by immunohistochemistry.
RESULTS:
All Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNASR201C did not accelerate the development of PDACs compared with control mice. However, the neoplasms observed in Kras;Gnas mice were more differentiated, and expressed more genes associated with ductal phenotypes, than in control mice. PDACs isolated from Kras;Gnas mice had activation of the Hippo pathway; in cells from these tumors, phosphorylated YAP1 was sequestered in the cytoplasm, and this was also observed in human IPMNs with GNAS mutations. Sequestration of YAP1 was not observed in PDAC cells from control mice.
CONCLUSIONS:
In mice that express activated KRAS in the pancreas, we found expression of GNASR201C to cause development of more differentiated tumors, with gene expression pattern associated with the ductal phenotype. Expression of mutant GNAS caused phosphorylated YAP1 to be sequestered in the cytoplasm, altering tumor progression.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| 162. |
Ohtsuka T, Mori Y, Fujimoto T, Miyasaka Y, Nakata K, Ohuchida K, Nagai E, Oda Y, Shimizu S, Nakamura M, Feasibility of Prophylactic Pancreatojejunostomy in Possible High-Risk Patients for Prevention of Pancreatic Fistula during Enucleation or Limited Pancreatic Resection, Am Surg, 84, 1, 149-153, 2018.04, Abstract
The aim of this study was to assess the feasibility of prophylactic pancreatojejunostomy after enucleation or limited pancreatic resection regarding the risk of postoperative pancreatic fistula (PF). We retrospectively reviewed the medical records of 32 patients who underwent enucleation or limited pancreatic resection and compared the clinical parameters between patients with (n = 10) and without (n = 22) prophylactic pancreatojejunostomy. Prophylactic pancreatojejunostomy was performed in patients with a possible high risk ofPF. No operation-related mortality occurred. Operation time was significantly longer (P |
| 163. |
Fujimoto T, Mori Y, Nakashima Y, Ohtsuka T, Nakamura S, Gotoh Y, Date K, Sadakari Y, Nakata K, Miyasaka Y, Osoegawa T, Aso A, Ihara E, Nakamura K, Ogawa Y, Shimizu S, Nakamura M, Endoscopic Retrograde Cholangiopancreatography in Patients With Surgically Altered Gastrointestinal Anatomy: A Retrospective Study, Int Surg, 10.9738/INTSURG-D-17-00137.1 , 103, 3-4, 184-190, 2018.04, Article Citation:
Takaaki Fujimoto, Yasuhisa Mori, Yohei Nakashima, Takao Ohtsuka, So Nakamura, Yoshitaka Gotoh, Kenjiro Date, Yoshihiko Sadakari, Kohei Nakata, Yoshihiro Miyasaka, Takashi Osoegawa, Akira Aso, Eikichi Ihara, Kazuhiko Nakamura, Yoshihiro Ogawa, Shuji Shimizu, and Masafumi Nakamura (2019) Endoscopic Retrograde Cholangiopancreatography in Patients With Surgically Altered Gastrointestinal Anatomy:. |
| 164. |
Mori H, Kubo M, Kai M, Kurata K, Yamada M, Nakamura M, Efficacy and Safety of Bi-weekly Pegfilgrastim for Dose-dense Chemotherapy-induced Neutropenia in Breast Cancer Patients, Anticancer Res, 10.21873/anticanres.12740 , 38, 7, 4381-4386, 2018.04, Abstract
BACKGROUND/AIM:
The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens.
PATIENTS AND METHODS:
This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA.
RESULTS:
Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays.
CONCLUSION:
Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients.
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| 165. |
Tamura S, Isobe T, Ariyama H, Nakano M, Kikushige Y, Takaishi S, Kusaba H, Takenaka K, Ueki T, Nakamura M
, Akashi K, Baba E, E‑cadherin regulates proliferation of colorectal cancer stem cells through NANOG
, Oncol Rep, 10.3892/or.2018.6464 , 40, 2, 693-703, 2018.04, Cancer stem cells (CSCs) possess a self‑renewal ability and display tumorigenic potential in immunodeficient mice. Colorectal CSCs are thought to be a uniform population and no functionally distinct subpopulations have been identified. Because E‑cadherin is an essential molecule for self‑renewal of embryonic stem cells, we examined E‑cadherin expression, which may play a role in maintaining the properties of CSCs, in EpCAMhigh/CD44+ colorectal CSCs from human primary colorectal cancers. We obtained 18 surgical specimens of human primary colorectal cancer. CD44, EpCAM, and E‑cadherin expression were analyzed by fluorescence‑activated cell sorting. Sorted EpCAMhigh/CD44+ colorectal CSCs were injected into immunodeficient mice to estimate the tumorigenic potential. Genetic profiles were analyzed by cDNA microarray. Notably, colorectal CSCs could be divided into two populations based on the E‑cadherin expression status, and they exhibited different pathological characteristics. Compared to E‑cadherin‑negative colorectal CSCs, E‑cadherin‑positive (EC+) colorectal CSCs demonstrated higher tumor growth potential in vivo. EC+ colorectal CSCs revealed a higher expression of the pluripotency factor NANOG, which contributed to the higher tumor growth potential of EC+ colorectal CSCs through control of cyclin D1 expression. These findings are the first demonstration of functionally distinct subpopulations of colorectal CSCs in human clinical samples.. |
| 166. |
Ohtsuka T, Ban D, Nakamura Y, Nagakawa Y, Tanabe M, Gotoh Y, Velasquez VVDM, Nakata K, Sahara Y, Takaori K, Honda G, Misawa T, Kawai M, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Palanivelu C, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M, Difficulty scoring system in laparoscopic distal pancreatectomy, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.578, 25, 11, 489-497, 2018.04, Abstract
BACKGROUND:
Several factors affect the level of difficulty of laparoscopic distal pancreatectomy (LDP). The purpose of this study was to develop a difficulty scoring (DS) system to quantify the degree of difficulty in LDP.
METHODS:
We collected clinical data for 80 patients who underwent LDP. A 10-level difficulty index was developed and subcategorized into a three-level difficulty index; 1-3 as low, 4-6 as intermediate, and 7-10 as high index. The automatic linear modeling (LINEAR) statistical tool was used to identify factors that significantly increase level of difficulty in LDP.
RESULTS:
The operator's 10-level DS concordance between the 10-level DS by the reviewers, LINEAR index DS, and clinical index DS systems were analyzed, and the weighted Cohen's kappa statistic were at 0.869, 0.729, and 0.648, respectively, showing good to excellent inter-rater agreement. We identified five factors significantly affecting level of difficulty in LDP; type of operation, resection line, proximity of tumor to major vessel, tumor extension to peripancreatic tissue, and left-sided portal hypertension/splenomegaly.
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| 167. |
Fujimoto H, Saito Y, Ohuchida K, Kawakami E, Fujiki S, Watanabe T, Ono R, Kaneko A, Takagi S, Najima Y, Hijikata A, Cui L, Ueki T, Oda Y, Hori S, Ohara O, Nakamura M, Saito T, Ishikawa F, Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+ T Cells in Human Colorectal Cancer, J Immunol, 10.4049/jimmunol.1701222 , 200, 9, 3291-3303, 2018.04, Abstract
Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8+ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3+ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.
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| 168. |
Kawamoto M, Umebayashi M, Tanaka H, Koya N, Nakagawa S, Kawabe K, Onishi H, Nakamura M, Morisaki T, Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma, Anticancer Res, 10.21873/anticanres.12516, 38, 5, 2739-2748, 2018.04, Abstract
BACKGROUND/AIM:
Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA).
MATERIALS AND METHODS:
We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity.
RESULTS:
MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1).
CONCLUSION:
MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA.. |
| 169. |
Nakano K, Yamamoto H, Fujiwara M, Koga Y, Tsuruta S, Ihara E, Oki E, Nakamura M, Ogawa Y, Oda Y, Clinicopathologic and Molecular Characteristics of Synchronous Colorectal Carcinoma With Mismatch Repair Deficiency, Am J Surg Pathol, 10.1097/PAS.0000000000000947, 42, 2, 172-182, 2018.04, Abstract
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.
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| 170. |
Kubo M, Umebayashi M, Kurata K, Mori H, Kai M, Onishi H, Katano M, Nakamura M, Morisaki T, Catumaxomab with Activated T-cells Efficiently Lyses Chemoresistant EpCAM-positive Triple-negative Breast Cancer Cell Lines, Anticancer Res38, 10.21873/anticanres.12724., 38, 7, 4273-4279, 2018.04. |
| 171. |
Mori H, Kubo M, Kai M, Velasquez VV, Kurata K, Yamada M, Okido M, Kuroki S, Oda Y, Nakamura M, BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations, Clin Breast Cancer, 10.1016/j.clbc.2018.05.008, 18, 5, e1217-e1227, 2018.04. |
| 172. |
Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Endo S, Abe T, Okumura T, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma, Cancer Lett, 10.1016/j.canlet.2018.03.031
, 1, 425, 65-77, 2018.04, Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruct
ion and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.. |
| 173. |
Nagakawa Y, Hosokawa Y, Sahara Y, Takishita C, Hijikata Y, Osakabe H, Nakajima T, Shirota T, Katsumata K, Nakamura M, Tsuchida A, Approaching the superior mesenteric artery from the right side using the proximal-dorsal jejunal vein preisolation method during laparoscopic pancreaticoduodenectomy, Surg Endosc, 10.1007/s00464-018-6118-z , 32, 9, 4044-4051, 2018.04, Abstract
BACKGROUND:
Although the artery-first approach is widely used in open pancreaticoduodenectomy, it is difficult to laparoscopically expose the origin of the inferior pancreaticoduodenal artery (IPDA) from the left side of the superior mesenteric artery (SMA). By contrast, damaging the inferior pancreaticoduodenal veins (IPDVs) is possible when approaching the IPDA from the right side of the SMA. To facilitate the artery-first approach in laparoscopic pancreaticoduodenectomy (LPD), we focused on the proximal-dorsal jejunal vein (PDJV) that branched from the superior mesenteric vein (SMV) dorsal side and drained the IPDVs. This study aimed to clarify the usefulness of the right SMA approach using the PDJV preisolation method.
METHODS:
The PDJV was first isolated, and the IPDVs were divided along the PDJV on the right side of the SMA. Then, the IPDA was divided at the root without first separating the pancreatic head from the portal vein and the SMV. Overall, 21 patients underwent this approach, and the results were retrospectively compared with those of 21 patients who underwent the artery-first approach, which was performed on the left side of the SMA. Anatomical characteristics of the PDJV were evaluated using multidetector computed tomography for the two groups.
RESULTS:
Operative times and resection times were significantly lower for the PDJV preisolation group than for the conventional LPD group (489.3 vs. 541.7 min, respectively; p = 0.002). During anatomical evaluation, 41 patients (97.6%) had a PDJV that drained from the SMV dorsally and was in contact with the anterior aspect of the uncinate process. The PDJV was confirmed as the first jejunal vein in 31 patients (73.8%) and as the second jejunal vein in 10 patients (23.8%).
CONCLUSIONS:
This approach facilitates dissection of the IPDA on the right side of the SMA, thereby reducing operative times. |
| 174. |
Sadakari Y, Nagai S, Velasquez VV, Nagayoshi K, Fujita H, Ohuchida K, Manabe T, Ohtsuka T, Nakamura M, Application of ultrasonography to high-tie and low-tie vascular ligation of the inferior mesenteric artery in laparoscopic colorectal cancer surgery: technical notes., Surg Endosc, 10.1007/s00464-018-6302-1, 33, 1, 309-314, 2018.04, Abstract
BACKGROUND:
Two ligation techniques can be applied in laparoscopy for left-sided colorectal cancer: (1) high-tie (HT), transection at the level of the inferior mesenteric artery (IMA); and (2) low-tie (LT), transection below the IMA, at the level of superior rectal artery (SRA), preserving the left colic artery (LCA). However, even with preoperative images, it can still be a challenge to identify these structures due to intraoperative individual conditions. In this study, we assess the use intraoperative ultrasonography (IOUS) to aid us in identifying the IMA and its branches to the SRA, LCA, and sigmoid artery.
METHODS:
We performed IOUS in 18 patients diagnosed with left-sided colorectal cancer. Preoperatively, a three-dimensional computed tomography (3D-CT) angiography was obtained in majority of the patients, to visualize the IMA and its branches. Two patients were contraindicated to receive a contrast study, hence, was unable to undergo 3D-CT angiography. The resected specimen was grossly examined for the study. The bifurcation types were identified and compared using different modalities: preoperative 3D-CT, IOUS, and gross examination of the resected specimen.
RESULTS:
The branching of the IMA revealed by IOUS was consistent to the findings preoperatively by the 3D-CT and postoperatively by the resected specimen. The IOUS result of the two patients without preoperative 3D-CT evaluation was also consistent with the post-operative bifurcation type.
CONCLUSIONS:
IOUS is an easy and feasible modality which aids in detecting the branching of the IMA during LT and HT ligation in laparoscopic left-sided colorectal surgery. It can serve as an adjunct modality for 3D-CT angiography and can also be considered a safe alternative option for cases wherein 3D-CT angiography is unavailable
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| 175. |
Okumura T, Ohuchida K, Kibe S, Iwamoto C, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Sada M, Horioka K, Mochidome N, Arita M, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix, Int J Cancer, 10.1002/ijc.31775 , 144, 6, 1401-1413, 2018.04, Abstract
Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.
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| 176. |
Morisaki T, Kubo M, Umebayashi M, Yuan Y, Tsuyada A, Tanaka H, Koya N, Nakagawa S, Morisaki T, Nakamura M, Usefulness of the nCounter Analysis System to Monitor Immune-related Biomarkers in PBMCs During Anti-PD-1 Therapy, Anticancer Res, 10.21873/anticanres.13628, 39, 8, 4517-4523, 2019.04. |
| 177. |
Mori H, Kubo M, Kai M, Yamada M, Kurata K, Kawaji H, Kaneshiro K, Osako T, Nishimura R, Arima N, Okido M, Kishimoto J, Oda Y, Nakamura M, T-bet+ lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer, Breast Cancer Res Treat, 10.1007/s10549-019-05256-2, 176, 3, 569-577, 2019.04, Purpose T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells.Methods This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10－3 mm2.Results Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet+ tumors had longer overall survival (OS) compared with patients with T-bet－ tumors (p = 0.047). The combination of CD8+ and T-b
et+ was associated with a better recurrence-free survival (RFS) and OS compared to CD8+/T-bet－ tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet+ tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12–0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07–0.95, p = 0.039 for OS).Conclusions OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC.. |
| 178. |
Kurahara H, Shinchi H, Ohtsuka T, Miyasaka Y, Matsunaga T, Noshiro H, Adachi T, Eguchi S, Imamura N, Nanashima A, Sakamoto K, Nagano H, Ohta M, Inomata M, Chikamoto A, Baba H, Watanabe Y, Nishihara K, Yasunaga M, Okuda K, Natsugoe S, Nakamura M, Significance of neoadjuvant therapy for borderline resectable pancreatic cancer: a multicenter retrospective study, Langenbecks Arch Surg, 10.1007/s00423-019-01754-5, 404, 2, 167-174, 2019.04, Abstract
PURPOSE:
Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study.
METHODS:
Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A).
RESULTS:
The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles.
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| 179. |
Nakayama H, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Shido K, Miyoshi K, Nakata K, Moriyama T, Miyasaka Y, Inoue S, Ohtsuka T, Mizumoto K, Nakamura M, S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer, Int J Oncol, 10.3892/ijo.2019.4812, 55, 1, 211-222, 2019.04, Abstract
Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.
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| 180. |
Moriyama T, Han HS, Kudo K, Sadakari Y, Moriyama T, Nakashima N, Nakamura M, Shimizu S, Role of international tele-education with live surgery for pre-clinical medical students , Proceedings of the APAN – Research Workshop 2019
, 48-53, 2019.04. |
| 181. |
Noguchi H, Kakuta Y, Okumi M, Omoto K, Okabe Y, Ishida H, Nakamura M, TanabeK, Pure versus hand-assisted retroperitoneoscopic live donor nephrectomy: a retrospective cohort study of 1508 transplants from two centers, Surg Endosc, doi: 10.1007/s00464-019-06697-y, 33, 12, 4038-4047, 2019.04. |
| 182. |
Senoh M, Kato H, Honda H, Fukuda T, Tagashira Y, Horiuchi H, Chiba H, Suzuki D, Hosokawa N, Kitazono H, Norisue Y, Kume H, Mori N, Morikawa H, Kashiwagura S, Higuchi A, Kato H, Nakamura M, Ishiguro S, Morita S, Ishikawa H, Watanabe T, Kojima K, Yokomaku I, Bando T, Toimoto K, Moriya K, Kasahara K, Kitada S, Ogawa J, Saito H, Tominaga H, Shimizu Y, Masumoto F, Tadera K, Yoshida J, Kikuchi T, Yoshikawa I, Watanabe T, Honda M, Yokote K, Toyokawa T, Miyazato H, Nakama M, Mahe C, Reske K, Olsen MA, Dubberke ER, Performance of laboratory tests for detection for Clostridioides difficile: A multicenter prospective study in Japan, Anaerobe, 60, 102107, 2019.04. |
| 183. |
Nakamura S, Sadakari Y, Ohtsuka T, Okayama T, Nakashima Y, Gotoh Y, Saeki K, Mori Y, Nakata K, Miyasaka Y, Onishi H, Oda Y, Goggins M, Nakamura M, Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma, Ann Surg Oncol, 10.1245/s10434-019-07269-z, 26, 7, 2104-2111, 2019.04, Abstract
BACKGROUND:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC.
METHODS:
Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients.
RESULTS:
A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p CONCLUSIONS:
We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC
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| 184. |
Noguchi H, Tsuchimoto A, Ueki K, Kaku K, Okabe Y, Nakamura M, One-year Outcome of Everolimus With Standard doseTacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants, TrDirectansplant , 10.1097/TXD.0000000000000962, 6, 1, e514, 2019.04. |
| 185. |
Miyasaka Y, Ohtsuka T, Kimura R, Matsuda R, Mori Y, Nakata K, Kakihara D, Fujimori N, Ohno T, Oda Y, Nakamura M, Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer Potentially Improves Survival and Facilitates Surgery, Ann Surg Oncol, 10.1245/s10434-019-07309-8, 26, 5, 1528-1534, 2019.04. |
| 186. |
Yan Z, Ohuchida K, Fei S, Zheng B, Guan W, Feng H, Kibe S, Ando Y, Koikawa K, Abe T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Hashizume M, Nakamura M, Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis, J Exp Clin Cancer Res, 10.1186/s13046-019-1226-8 , 38, 1, 221, 2019.04, Abstract
BACKGROUND:Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction.
METHODS:Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor.
RESULTS:Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model.
CONCLUSIONS: These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.
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| 187. |
Gotoh Y, Ohtsuka T, Nakamura S, Shindo K, Ohuchida K, Miyasaka Y, Mori Y, Mochidome N, Oda Y, Nakamura M, Genetic assessment of recurrent pancreatic high-risk lesions in the remnant pancreas: Metachronous multifocal lesion or local recurrence?, Surgery, 10.1016/j.surg.2018.10.025 , 165, 4, 767-774, 2019.04, Abstract
BACKGROUND: It is difficult to determine whether a second high-risk lesion, including pancreatic ductal adenocarcinoma or high-grade pancreatic intraepithelial neoplasm, is a metachronous multifocal lesion or represents local recurrence after resection of the first high-risk lesion. This study attempts to clarify the characteristics of second high-risk lesions in the remnant pancreas using genetic analyses.
METHODS: Clinicopathologic data were collected from 12 patients who underwent pancreatectomy for a second high-risk lesion in the remnant pancreas. We performed mutational and immunohistochemical analyses of 4 major genes-KRAS, TP53, CDKN2A, and SMAD4-associated with pancreatic ductal adenocarcinoma progression, as well as targeted next-generation sequencing.
RESULTS: Mutations in the four genes in the second high-risk lesion were consistent with the first lesion in four patients but were inconsistent in the remaining eight patients, and thus we considered that the latter eight patients likely had metachronous multifocal high-risk lesions and the other four patients had local recurrence. The estimated cumulative recurrence rate after resection of the second high-risk lesion was greater in the local recurrence group compared with the metachronous multifocal group, and the estimated cumulative disease-specific survival rate was greater in the metachronous multifocal group. Targeted next-generation sequencing demonstrated that the second lesions in the metachronous multifocal high-risk lesion group showed differences in founder mutations compared with the first lesion. In the local recurrence group, the founder mutations in the second lesion were common with those in the first lesion.
CONCLUSION: Genetic assessment might help discriminate metachronous multifocal high-risk lesions from local recurrence.
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| 188. |
Miura Y, Noguchi H, Okabe Y, Masutani K, Tokunaga S, Nakamura M, Effects of Telmisartan and Candesartan on the Metabolism of Lipids and Glucose in Kidney Transplantat Patients: A prospective, Randomized Crossover Study, Transplantation Direct, 10.1097/TXD.000000000000861, 5, 2, e423, 2019.04, Background. The risk of cardiovascular events remains after kidney transplantation (KT). Abnormal glucose metabolism and
hyperlipidemia contribute partly to this risk. Among angiotensin II type-1 receptor blockers, telmisartan alone has been shown
to ameliorate these effects on glucose and lipid metabolism (GLM). We investigated the effects of telmisartan on GLM in KT patients.
Methods. This trial had a crossover design. Forty-six KT patients with well-controlled hypertension under angiotensin II
type-1 receptor blockers were randomized into telmisartan and candesartan groups. After a 12-week treatment, crossover was
initiated, and additional 12-week treatment was administered without a washout period. We examined the laboratory parameters
of GLM, blood pressure and graft function before and after each treatment period. Results. Forty patients completed the scheduled
treatment regimen. Serum levels of triglyceride were significantly lower (114.3 ± 50.8 mg/dL vs 136.5 ± 66.8 mg/dL;
P = 0.019), and the estimated glomerular filtration rate was significantly higher (50.4 ± 15.1 mL/min per 1.73 m2 vs
48.5 ± 12.5mL/min per 1.73m2; P = 0.038) after telmisartan treatment than after candesartan treatment. Therewere no significant
differences between the 2 treatment groups with regard to the other parameters studied (including serum adiponectin levels and
parameters of glucose metabolism). Conclusions. These data suggest that telmisartan can improve serum triglyceride levels
and graft function for KT patients better than candesartan.. |
| 189. |
Nakano M, Kikushige Y, Miyawaki K, Kunisaki Y, Mizuno S, Takenaka K, Tamura S, Okumura Y, Ito M, Ariyama H, Kusaba H, Nakamura M, Maeda T, Baba E, Akashi K, Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer, Oncogene, 10.1038/s41388-018-0480-0 , 38, 6, 780-793, 2019.04, Abstract
Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial-mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44+ CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44+ CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44- non-CSCs into the undifferentiated CD44+ CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.
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| 190. |
Kato H, Senoh M, Honda H, Fukuda T, Tagashira Y, Horiuchi H, Chiba H, Suzuki D, Hosokawa N, Kitazono H, Norisue Y, Kume H, Mori N, Morikawa H, Kashiwagura S, Higuchi A, Kato H, Nakamura M, Ishiguro S, Morita S, Ishikawa H, Watanabe T, Kojima K, Yokomaku I, Bando T, Toimoto K, Moriya K, Kasahara K, Kitada S, Ogawa J, Saito H, Tominaga H, Shimizu Y, Masumoto F, Tadera K, Yoshida J, Kikuchi T, Yoshikawa I, Watanabe T, Honda M, Yokote K, Toyokawa T, Miyazato H, Nakama M, Mahe C, Reske K, Olsen MA, Dubberke ER, Clostridioides (Clostridium) difficile infection burden in Japan: A multicenter prospective study, Anaerobe, 10.1016/j.anaerobe.2019.03.007, 60, 102011, 2019.04. |
| 191. |
Nakashima Y, Ohtsuka T, Nakamura S, Mori Y, Nakata K, Miyasaka Y, Ishigami K, Matsuda R, Oda Y, Nakamura M, Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors, Pancreatology, 10.1016/j.pan.2018.11.010, 19, 1, 50-56, 2019.04, Abstract
BACKGROUND/OBJECTIVES:
The biological features of cystic pancreatic neuroendocrine tumors (PNETs) remain unclear. The aim of this study was to clarify the clinicopathological characteristics of non-functioning PNETs (NF-PNETs) with a cystic component.
METHODS:
The medical records of 75 patients with NF-PNETs who had undergone resection in our institution were retrospectively reviewed. Clinicopathological factors were compared between PNETs with and without a cystic component. Expression of somatostatin 2 receptor (SSTR-2) was also analyzed.
RESULTS:
Cystic PNETs were diagnosed in 14 patients (19%). The proportion of men was significantly higher for cystic than solid PNETs (79% vs. 44%, P CONCLUSIONS:
Although cystic PNETs were larger upon diagnosis than solid PNETs in this study, prognosis after surgical resection did not differ significantly between these types of PNET. Somatostatin receptor scintigraphy and somatostatin analogues may be more useful for diagnosing and treating cystic PNETs, respectively.
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| 192. |
Miki M, Oono T, Fujimori N, Takaoka T, Kawabe K, Miyasaka Y, Ohtsuka T, Saito D, Nakamura M, Ohkawa Y, Oda Y, Suyama M, Ito T, Ogawa Y, CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors, Cancer Med, 10.1002/cam4.2232 , 8, 8, 3748-3760, 2019.04, Abstract
Although the postoperative recurrence rate for pancreatic neuroendocrine tumors (PNETs) is reported to be 13.5%-30%, the paucity of valuable biomarkers to predict recurrence poses a problem for the early detection of relapse. Hence, this study aimed to identify new biomarkers to predict the recurrence of PNETs. We performed RNA sequencing (RNA-Seq) on RNA isolated from frozen primary tumors sampled from all localized G1/G2 PNETs resected curatively from 1998 to 2015 in our institution. We calculated differentially expressed genes (DEGs) in tumor with and without recurrence (≥3 years) for the propensity-matched cohort. Gene ontology analysis for the identified DEGs was also performed. Furthermore, we evaluated the expression levels of candidate genes as recurrence predictors via immunostaining. Comparison of transcriptional levels in tumors with and without recurrence identified 166 DEGs. Up- and downregulated genes with high significance in these tumors were mainly related to extracellular organization and cell adhesion, respectively. We observed the top three upregulated genes, C-type lectin domain family 3 member A (CLEC3A), matrix metalloproteinase-7 (MMP7), and lipocalin2 (LCN2) immunohistochemically and compared their levels in recurrent and nonrecurrent tumors. Significantly higher recurrence rate was shown in patients with positive expression of CLEC3A (P = 0.028), MMP7 (P = 0.003), and LCN2 (P = 0.040) than that with negative expression. We identified CLEC3A, MMP7, and LCN2 known to be associated with the phosphatidylinositol-3-kinase/Akt pathway, as potential novel markers to predict the postoperative recurrence of PNETs
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| 193. |
Yan Z, Ohuchida K, Zheng B, Okumura T, Takesue S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis, J Cancer Res Clin Oncol, 10.1007/s00432-019-02860-z , 145, 5, 1147-1164, 2019.04, Abstract
PURPOSE:This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer.
METHODS:We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin-CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model.
RESULTS:CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK-MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model.
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| 194. |
Kibe S, Ohuchida K, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Shimamoto M, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M, Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion, Cancer Lett, 10.1016/j.canlet.2018.12.005, 1, 444, 70-81, 2019.04, Abstract
The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.
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| 195. |
Miyasaka Y, Nakamura M, ASO Author Reflections: Impact of Neoadjuvant Chemotherapy With Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer on Surgical Outcomes , Ann Surg Oncol, 10.1245/s10434-019-07857-z
, 26, 3, 739-740, 2019.04. |
| 196. |
Valencia S, Shindo K, Moriyama T, Ohuchida K, Tsurumaru D, Chua M, Chen HC, Yao L, Ohtsuka T, Shimizu S, Nakamura M, Subcutaneous fat area as a risk factor for extraction site incisional hernia following gastrectomy for gastric cancer, Surg Today, 10.1007/s00595-020-02039-x
, 50, 11, 1418-1426, 2020.04, Abstract
Purpose: To identify the incidence of extraction site incisional hernia following gastrectomy for gastric cancer and its significant risk factors, including the subcutaneous fat area.
Methods: We reviewed data gathered prospectively on patients with gastric cancer, who underwent gastrectomy between 2008 and 2012 at Kyushu University Hospital, Fukuoka, Japan. The subcutaneous fat area (SFA) and visceral fat area (VFA) were measured using axial computed tomography at the level of the L4 and L3 transverse processes, and the L2-L3 intervertebral disc. The primary endpoint of the rate of extraction site incisional hernia was based on the computed tomography and clinical data including hospital follow-up reports.
Results: After applying the inclusion and exclusion criteria, 320 patients were included in this retrospective analysis: 3.1% (10/320) had extraction site incisional hernias after a mean follow-up of 11 months. Multivariate analysis revealed that age and the SFA were independent risk factors (age ≥ 70.5 years: P = .013, odds ratio: 9.116, 95% confidence interval 1.581-52.553; L4 SFA ≥ 124 cm2: P = .004, odds ratio: 13.752, 95% confidence interval 2.290-82.582).
Conclusion: Age and the SFA were independent risk factors for extraction site incisional hernia in patients undergoing gastrectomy for gastric cancer.
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| 197. |
Noguchi H, Tsuchimoto A, Ueki K, Kaku K, Okabe Y, Nakamura M, Reduced Recurrence of Primary IgA Nephropathy in Kidney Transplant Recipients Receiving Everolimus With Corticosteroid: A Retrospective, Single-Center Study of 135 Transplant Patients, Transplantation Proceedings, 10.1016/j.transproceed.2020.05.022, 52, 10, 3118-3124, 2020.04. |
| 198. |
Hirono S, Shimizu Y, Ohtsuka T, Kin T, Hara K, Kanno A, Koshita S, Hanada K, Kitano M, Inoue H, Itoi T, Ueki T, Shimokawa T, Hijioka S, Yanagisawa A, Nakamura M, Okazaki K, Yamaue H, Recurrence Patterns After Surgical Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas; A Multicenter, Retrospective Study of 1074 IPMN Patients by the Japan Pancreas Society , Journal of Gastroenterology, 10.1007/s00535-019-01617-2 , 55, 1, 86-99, 2020.04, Abstract
Background: Although there are numerous reports focusing on surgical indication for intraductal papillary mucinous neoplasm (IPMN), the recurrence patterns following surgery are less widely reported. To ascertain optimal treatment and postoperative surveillance for IPMN patients, we analyzed patterns and risk factors for recurrence after surgery for IPMN.
Methods: This study is a retrospective, multi-institutional, observational study, including 1074 patients undergoing surgery for IPMN at 11 academic institutions. We analyzed the risk factors for recurrence after classifying postoperative recurrences into metachronous high-risk lesions (malignant progression of IPMN and/or metachronous pancreatic ductal adenocarcinoma) in the remnant pancreas and extra-pancreatic recurrence.
Results: Of 1074 patients undergoing surgery for IPMN, 155 patients (14.4%) developed postoperative recurrence. We found that 34.3% of 70 high-risk lesions in the remnant pancreas occurred over 5 years after surgery, and survival of 36 patients undergoing second operation for high-risk lesions was better than that of 34 patients who did not (P = 0.04). We found four independent risk factors for metachronous high-risk lesions in remnant pancreas: symptoms [P = 0.005, hazard ratio (HR) 1.988], location of pancreatic body/tail (P Conclusion: We suggest that life-time continuous surveillance might be necessary for IPMN patients. Second surgery for metachronous high-risk lesions in remnant pancreas should be considered to improve survival.
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| 199. |
Koba R, Fujita H, Nishibori M, Saeki K, Nagayoshi K, Sadakari Y, Nagai S, Sekizawa O, Nitta K, Manabe T, Ueki T, Ishida T, Oda Y, Nakamura M, Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry, Int J Cancer, 10.1002/ijc.32592, 146, 9, 2498-2509, 2020.04, Oxaliplatin, a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, non-destructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received oxaliplatin-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85�11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in non-degenerated area (p < 0.001). Co
nversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (Odds Ratio; 19.99, 95% confidence interval; 2.04�196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of oxaliplatin-based chemotherapy by quantifying the distribution of platinum.. |
| 200. |
Kawai M, Yamaue H, Jang JY, Uesaka K, Unno M, Nakamura M, Fujii T, Satoi S, Choi HS, Sho M, Fukumoto T, Kim CS, Hong HT, Izumo W, Yoon SD, Amano R, Park SJ, Choi BS, Yu CH, Kim SJ, Ahn JY, Kim H, Ashida R, Hirono S, Heo SJ, Song BK, Park SJ, Yamamoto M, Shimokawa T, Kim SW, Propensity score-matched analysis of internal stent vs external stent for pancreatojejunostomy during pancreaticoduodenectomy: Japanese-Korean cooperative project , Pancreatology, 10.1016/j.pan.2020.06.014
, 20, 5, 984-991, 2020.04, Abstract
Background: Several studies comparing internal and external stents have been conducted with the aim of reducing pancreatic fistula after PD. There is still no consensus, however, on the appropriate use of pancreatic stents for prevention of pancreatic fistula. This multicenter large cohort study aims to evaluate whether internal or external pancreatic stents are more effective in reduction of clinically relevant pancreatic fistula after pancreaticoduodenectomy (PD).
Methods: We reviewed 3149 patients (internal stent n = 1,311, external stent n = 1838) who underwent PD at 20 institutions in Japan and Korea between 2007 and 2013. Propensity score matched analysis was used to minimize bias from nonrandomized treatment assignment. The primary endpoint was the incidence of clinically relevant pancreatic fistula. This study was registered on the UMIN Clinical Trials Registry (UMIN000032402).
Results: After propensity score matched analysis, clinically relevant pancreatic fistula occurred in more patients in the external stents group (280 patients, 28.7%) than in patients in the internal stents group (126 patients, 12.9%) (OR 2.713 [95% CI, 2.139-3.455]; P Conclusion: Propensity score matched analysis showed that, regarding clinically relevant pancreatic fistula after PD, internal stents are safer than external stents for pancreaticojejunostomy.
Keywords: External stent; Internal stent; Pancreatic fistula; Pancreaticoduodenectomy.
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| 201. |
Yasuhiro Oyama, Hideya Onishi, Satoko Koga, Mutsunori Murahashi, Shu Ichimiya, Kazunori Nakayama, Akiko Fujimura, Makoto Kawamoto, Akira Imaizumi, Masayo Umebayashi, Kenoki Ohuchida, Takashi Morisaki, Masafumi Nakamura, Patched 1-interacting Peptide Represses Fibrosis in Pancreatic Cancer to Augment the Effectiveness of Immunotherapy, J Immunother, 10.1097/CJI.0000000000000305, 43, 4, 121-133, 2020.04, Abstract
Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor β1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.. |
| 202. |
Matsuda R, Miyasaka Y, Ohishi Y, Yamamoto T, Saeki K, Mochidome N, Abe A, Ozono K, Shindo K, Ohtsuka T, Kikutake C, Nakamura M, Oda Y, Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas, Ann Surg, 10.1097/SLA.0000000000003060, 271, 5, 941-948, 2020.04. |
| 203. |
Nakayama K, Onishi H, Fujimura A, Imaizumi A, Kawamoto M, Oyama Y, Ichimiya S, Koga S, Fujimoto Y, Nakashima K, Nakamura M, NFκB and TGFβ contribute to the expression of PTPN3 in activated human lymphocytes , Cell Immunol, 10.1016/j.cellimm.2020.104237, 358, 104237, 2020.04, Abstract
We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFκB activation as well as increased PTPN3 expression. NFκB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFκB enhanced PTPN3 expression and tyrosine kinase activation. TGFβ reduced PTPN3 expression and NFκB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.
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| 204. |
Takesue S, Ohuchida K, Shinkawa T, Otsubo Y, Matsumoto S, Sagara A, Yonenaga A, Ando Y, Kibe S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Toma H, Tominaga Y, Mizumoto K, Hashizume M, Nakamura M, Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts, Int J Oncol, 10.3892/ijo.2019.4951, 56, 2, 596-605, 2020.04, Abstract
Cancer‑associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor‑stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.
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| 205. |
Ando Y, Ohuchida K, Otsubo Y, Kibe S, Takesue S, Abe T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Oda Y, Nakamura M, Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5, Plos one, 10.1371/journal.pone.0228015, 15, 1, e0228015, 2020.04, Abstract
Background: Necroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer.
Methods: We used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells.
Results: RIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis.
Conclusion: These findings indicate that necroptosis at the pancreatic cancer invasion front can promote cancer cell migration and invasion via the CXCL5-CXCR2 axis.. |
| 206. |
Fujimori N, Miki M, Lee L, Matsumoto K, Takamatsu Y, Takaoka T, Teramatsu K, Suehiro Y, Murakami M, Igarashi H, Oono T, Ohtsuka T, Nakamura M, Koga Y, Oda Y, Ito T, Ogawa Y, Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years, Pancreatology, 10.1016/j.pan.2020.04.003, 20, 4, 709-715, 2020.04, a b s t r a c t
Background/Objectives: This single-center study aimed to evaluate treatment outcomes and long-term
prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World
Health Organization (WHO) 2017 classification.
Methods: We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between
January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or
further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and
prognostic factors were retrospectively analyzed.
Results: The number of PanNENs, especially non-functioning PanNENs, has increased over the last
decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1
(n . 145, MST . 261 months) relative to NET G2 (n . 72, 132 months), NET G3 (n . 3, 34 months) and
NEC G3 (n . 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly
better than in those with drug therapy. However, 26% of patients who underwent curative resection
developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n . 97), the MST
and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of
>10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line
therapy (stable disease/partial response) and three or more treatment regimens were significant
favorable predictors for unresectable PanNENs according to multivariate analyses (p Conclusions: We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical
setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.
© 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved. |
| 207. |
Kurata K, Kubo M, Kai M, Mori H, Kawaji H, Kaneshiro K, Yamada M, Nishimura R, Osako T, Arima N, Okido M, Oda Y, Nakamura M, Microsatellite instability in Japanese female patients with triple-negative breast cancer, Breast Cancer, 10.1007/s12282-019-01043-5 , 27, 3, 490-498, 2020.04, Abstract
Background: It is important to identify biomarkers for triple-negative breast cancers (TNBCs). Recently, pembrolizumab, an immune checkpoint inhibitor (ICI) for programmed cell death 1 (PD-1), was approved as a treatment strategy for unresectable or metastatic tumor with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency, such as malignant melanoma, non-small cell lung cancer, renal cell cancer and urothelial cancer. In addition, results from clinical trials suggested that ICI was a promising treatment for TNBCs with accumulated mutations. However, the frequency of MSI in Japanese TNBCs still remains unclear. We aimed to analyze the presence of MSI-H in TNBCs as a biomarker for ICI therapy.
Methods: In this study, we retrospectively evaluated the MSI of 228 TNBCs using an innovative method, MSI Analysis System Version 1.2 (Promega), consisting of 5 microsatellite markers: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 without a normal tissue control.
Results: Among 228 tumors, 222 (97.4%) were microsatellite stable, 4 (1.7%) low-frequency MSI and 2 (0.9%) MSI-H, respectively. Two MSI-H tumors were potentially aggressive pathologically as indicated by nuclear grade 3 and high Ki-67 (> 30%), and were classified as basal-like and non-BRCA-like, but were not consistent regarding tumor-infiltrating lymphocytes, CD8 and PD-L1 expression.
Conclusions: Although we found that MSI-H was uncommon (0.9%) in TNBCs, potential targets for ICIs exist in TNBCs. Therefore, MSI-H breast cancer patients should be picked up using not only conventional methods but also platforms for comprehensive genomic profiling.
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| 208. |
Miyasaka Y, Ohtsuka T, Kimura R, Matsuda R, Mori Y, Nakata K, Watanabe M, Oda Y, Nakamura M, Is remnant pancreatic cancer after pancreatic resection more frequent in early-stage pancreatic cancer than in advanced-stage cancer? , Ann Gastroenterol Surg, 10.1002/ags3.12340
, 4, 4, 448-454, 2020.04, Abstract
Aim: As the prognosis of patients who undergo resection for pancreatic cancer has improved, reports of remnant pancreatic cancer after pancreatic cancer resection have been increasing. Previous studies regarding early-stage pancreatic cancer showed a high incidence of remnant pancreatic cancer in these patients. The aim of this study was to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer.
Methods: Patients who underwent partial pancreatic resection for primary pancreatic cancer were retrospectively reviewed and divided into an early-stage group and an advanced-stage group according to the stage of the initial cancer. Patient characteristics and long-term outcomes, including development of remnant pancreatic cancer, were compared between the two groups.
Results: This study included 321 patients who underwent partial pancreatectomy for pancreatic cancer; 32 patients in the early-stage group and 289 patients in the advanced-stage group. Remnant pancreatic cancer developed in 19 patients (5.9%); seven patients (21.9%) in the early-stage group and 12 patients (4.5%) in the advanced-stage group. The cumulative incidence of remnant pancreatic cancer according to the Kaplan-Meier method was comparable between the two groups (5-year cumulative incidence: 20.6% vs 9.9%, early-stage group vs advanced-stage group; P = .1827).
Conclusion: Our results suggested that the potential for developing remnant pancreatic cancer was comparable between the early-stage and the advanced-stage groups. Therefore, the incidence of remnant pancreatic cancer may increase along with improved pancreatic cancer treatment.
Keywords: neoplasm; neoplasm staging; pancreatectomy; pancreatic cancer; recurrence; second primary.
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| 209. |
Miyasaka Y, Ohtsuka T, Matsuda R, Mori Y, Nakata K, Ohuchida K, Nakamura M, High-risk lesions in the remnant pancreas: fate of the remnant pancreas after pancreatic resection for pancreatic cancer and intraductal papillary mucinous neoplasms, Surg Today, 10.1007/s00595-019-01852-3, 50, 8, 832-840, 2020.04, Abstract:Progress in diagnostic modalities, surgical procedures, and multidisciplinary treatment for pancreatic diseases has increased the number of long-term survivors after pancreatic resection. Several reports have focused on high-risk lesions (HRLs), including high-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma, high-grade intraductal papillary mucinous neoplasm (IPMN), and IPMN with an associated invasive carcinoma, in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The etiology of HRLs in the remnant pancreas is thought to be either isolated local recurrence of the initial lesion in the remnant pancreas or a newly developed primary lesion. Although it is difficult to distinguish between local recurrence and a new primary lesion, comparison of genetic alterations between two lesions may help with this distinction. Early detection of HRLs in the remnant pancreas may improve the prognosis of patients, and several investigators have proposed predictive factors for HRLs in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The reported short- and long-term outcomes of surgical resection of HRLs in the remnant pancreas are relatively favorable. Life-long surveillance of the remnant pancreas is recommended after partial pancreatic resection for pancreatic cancer or IPMN.
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| 210. |
Mei T, Noguchi H, Hisadome Y, Kaku K, Nishiki T, Okabe Y, Nakamura M, Hepatitis B virus reactivation in kidney transplant patients with resolved hepatitis B virus infection: Risk factors and the safety and efficacy of preemptive therapy, Transplant Infectious disease, doi.org/10.1111/tid.13234, 22, 2, e13234, 2020.04, BackgroundHepatitis B virus (HBV) reactivation is associated with complications and adverse outcomes in patients with clinically resolved HBV infection who are seronegative for hepatitis B surface antigen (HBs Ag), and seropositive for hepatitis B core antibody (HBc Ab) and/or hepatitis B surface antibody (HBs Ab) before kidney transplantation (KT).MethodsWe retrospectively analyzed 52 patients with resolved HBV infection who were HBV‐DNA negative. HBV‐DNA after KT was evaluated, and the occurrence of HBV reactivation and outcomes were monitored. We defined HBV reactivation as seropositivity for HBV‐DNA at or above the minimal detection level of 1.0 log IU/mL and treated preemptively (using entecavir) when the HBV‐DNA level was at or above 1.3 log IU/mL, in accordance with the Japanese Guidelines for HBV treatment.ResultsAmong the 52 patients, the mean age was 57.2 ± 10.8 years. The median HBc Ab titer was 12.8 (inte
rquartile range, 4.6‐42.6) cutoff index, and five (9.6%) cases of HBV reactivation occurred. No patients developed graft loss and died due to HBV reactivation. Statistical analysis showed that age and HBc Ab titer were significant risk factors for HBV reactivation (P = .037 and P = .042, respectively). No significant differences were found between graft survival and the presence or absence of HBV reactivation.ConclusionThese results suggest that HBc Ab titer and age could be significant risk factors for HBV reactivation. Resolution of HBV infection did not appear to be associated with patient or graft survival, regardless of whether HBV reactivation occurred, when following our preemptive strategy.. |
| 211. |
Yamaguchi K, Ito M, Ohmura H, Hanamura F, Nakano M, Tsuchihashi K, Nagai S, Ariyama H, Kusaba H, Yamamoto H, Oda Y, Nakamura M, Akashi K, Baba E, Helper T Cell-Dominant Tertiary Lymphoid Structures Are Associated With Disease Relapse of Advanced Colorectal Cancer , Oncolmmunology, 10.1080/2162402X.2020.1724763
, 9, 1, e1724763-1-e1724763-11, 2020.04, Abstract
Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient's prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3+ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.
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| 212. |
Araki T, Noguchi H, Kaku K, Okabe Y, Nakamura M, Hand-assisted Laparoscopic versus Hand-Assisted retroperitoneoscopic living-donor Nephrectomy: a retrospective, single-center, propensity-score analysis of 840 transplants using 2 techniques, Transplantation Proceedings, 10.1016/j.transproceed.2020.01.134, 52, 6, 1655-1660, 2020.04, ABSTRACT
Introduction. Living-donor kidney transplantation (LDKT) is the most realistic option for
patients with end-stage kidney disease because of a severe shortage of deceased donors.
Hand-assisted laparoscopic donor nephrectomy (HALDN) and hand-assisted
retroperitoneoscopic donor nephrectomy (HARDN) have been undertaken at our
institute. We compared these 2 surgical procedures with respect to donor outcome and
the graft function of recipients.
Methods. We reviewed data from 840 consecutive live-donor kidney transplants from
October 2003 to April 2019. Propensity scores were calculated for each patient using
bivariate logistic regression.
Results. After propensity-score matching, the 2 groups each contained 205 patients.
Donors in the HALDN group had a longer procedure time (217 minutes, P less estimated blood loss (51 mL, P postoperative day (POD) 1 (7.9 mg/dL, P There were 22 modified Clavien-classifiable complications among the study groups. A
significantly higher conversion to open surgery was noted in the HARDN group (P .
.0181) than in the HALDN group, but there was no significant difference in the
prevalence of complications in either group. There was no significant difference in the
estimated glomerular filtration rate of recipients at POD14 between the 2 groups.
Conclusions. Safety and early graft function of HALDN in LDKT are comparable to or
even better than that of HARDN.. |
| 213. |
Mei T, Noguchi H, Suetsugu K, Hisadome Y, Kaku K, Okabe Y, Masuda S, Nakamura M, Effects of Concomitant Administration of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Kidney Transplant Recipients, Biological and Pharmaceutical Bulletin, https://doi.org/10.1248/bpb.b20-00361, 43, 10, 1600-1603, 2020.04, Vonoprazan fumarate (vonoprazan) is a new kind of acid suppressant with potent acid inhibitoryeffects. Therefore, it has been administered to kidney transplant recipients for treatment or prophylaxis ofsteroid ulcers, refractory peptic ulcers, and gastroesophageal reflux disease. Because tacrolimus, which is awell-established immunosuppressant for kidney transplantation, and vonoprazan share the CYP3A4 systemfor metabolism, drug interactions are anticipated upon simultaneous administration. We retrospectivelyanalyzed 52 kidney transplant recipients who were converted from rabeprazole, which has a small effecton the tacrolimus trough blood concentration (C0), to vonoprazan between August 2016 and July 2019. Wecompared the tacrolimus C0/tacrolimus dose (C0/D) before and after conversion and serum liver enzymes,serum total bilirubin, and the estimated glomerular filtration rate (eGFR). As a result, mean tacrolimus C0/Dbefore and after conversion was 1.98
1.02 and 2.19 1.15 (ng/mL)/(mg/d), respectively, (p < 0.001). Additionally,mean aspartate transaminase (AST) before and after conversion was 18.6 4.2 and 19.6 5.2 IU/L,respectively, (p 0.037). Mean alanine transaminase (ALT) before and after conversion was 15.8 5.5and 17.6 7.1 IU/L, respectively, (p 0.007). Mean eGFR before and after conversion was 50.6 14.4 and51.4 14.7 mL/min/1.73 m2, respectively (p 0.021). Mean AST, ALT, and eGFR were slightly but significantlyelevated within normal ranges after conversion. In conclusion, our study suggests that the mean tacrolimusC0/D was elevated significantly by converting from rabeprazole to vonoprazan, but it had little clinicalsignificance. Vonoprazan can be administered safely to kidney transplant recipients receiving tacrolimus.. |
| 214. |
Nakata K, Yamamoto H, Miyata H, Kakeji Y, Seto Y, Yamaue H, Yamamoto M, Nakamura M, Definition of the Objective Threshold of Pancreatoduodenectomy With Nationwide Data Systems , J Hepatobiliary Pancreat Sci, 10.1002/jhbp.704
, 27, 3, 107-113, 2020.04, Abstract
Background: This study aimed to define an objective evidence-based threshold of high-volume hospitals (HVHs) for pancreatoduodenectomy (PD) using nationwide data systems.
Methods: A total of 36,453 patients underwent PD in 1,499 hospitals from 2012 to 2015 were collected from the National Clinical Database in Japan. Restricted cubic spline model with risk adjustment was used for definition of an objective evidence-based threshold of HVHs.
Results: The restricted cubic spline curve of 30-day and in-hospital mortality showed a continuous decrease with an increase in hospital volume and plateau phase of mortality was detected between approximately 30 and 50 PDs/year. On the basis of this curve, we defined hospitals ≥30 PDs/year as HVHs and ≤29 PDs/year as non-HVHs. We also sub-classified hospitals Conclusions: We consider that this concept is applicable to other high-risk procedures for reducing mortality after these procedures, which could improve medical care and health services.
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| 215. |
Mori Y, Nakata K, Ideno N, Ikenaga N, Okabe Y, Ishigami K, Oda Y, Nakamura M, Congenital biliary dilatation in the era of laparoscopic surgery, focusing on the high incidence of anatomical variations of the right hepatic artery, J Hepatobiliary Pancreat Sci, 10.1002/JHBP.819, 27, 11, 870-876, 2020.04, Abstract
Background: The present study aimed to evaluate anatomical variations of the right hepatic artery (RHA) in patients with congenital biliary dilatation (CBD) and the appropriate approach in laparoscopic surgery for CBD.
Methods: The medical records of 36 patients who underwent laparoscopic or open surgery for CBD from 1996 to 2018 were retrospectively reviewed. Radiological evaluation of the origin and course of the RHA in these 36 patients were compared with 195 control patients without CBD.
Results: The incidence of the RHA crossing anterior to the common hepatic duct (CHD) was significantly higher in patients with CBD than in those without CBD (33% versus 10%, P = .0001). There was no intraoperative injury of the RHA, irrespective of the course of the RHA. The CHD was divided at the caudal side of the RHA in 11 of 12 patients (92%) with the anterior type of RHA, and in 13 of 24 patients (54%) with the posterior type of RHA (P = .03).
Conclusions: Patients with CBD had a higher incidence of the RHA crossing anterior to the CHD than patients without CBD. Preservation of the RHA in each situation is necessary during surgery for CBD in the era of laparoscopic surgery.
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| 216. |
Matsuda R, Miyasaka Y, Ohishi Y, Yamamoto T, Saeki K, Mochidome N, Abe A, Ozono K, Shindo K, Ohtsuka T, Kikutake C, Nakamura M, Oda Y, Concomitant Intraductal Papillary Mucinous Neoplasm in Pancreatic Ductal Adenocarcinoma Is an Independent Predictive Factor for the Occurrence of New Cancer in the Remnant Pancreas, Ann Surg, 10.1097/SLA.0000000000003060. , 271, 5, 941-948, 2020.04, OBJECTIVE:
To determine the factors predicting the subsequent development of pancreatic ductal adenocarcinoma in remnant pancreas (PDAC-RP) after partial pancreatectomy for PDAC.
SUMMARY BACKGROUND DATA:
PDAC-RP after partial pancreatectomy for PDAC is currently not so rare because of improved prognosis of PDAC patients due to recent advances in surgical techniques and adjuvant therapy. However, the predictive factors related to PDAC-RP remain unknown.
METHODS:
We retrospectively reviewed the clinicopathological data of a consecutive series of 379 patients with PDAC treated by partial pancreatectomy between 1992 and 2015; 14 patients (3.69%) had PDAC-RP. Clinicopathological variables were compared between PDAC-RP and non-PDAC-RP.
RESULTS:
In univariate analysis, concomitant intraductal papillary mucinous neoplasm (IPMN) (P = 0.0005), cancer location (body/tail) (P = 0.0060), and lower T factor in UICC (P = 0.0039) were correlated with PDAC-RP development. Multivariate analysis revealed concomitant IPMN (P = 0.0135) to be an independent predictive factor for PDAC-RP. PDAC concomitant with IPMN had higher cumulative incidence of PDAC-RP (47.5%/10 yrs) than PDAC without IPMN (9.96%/10 yrs) (P = 0.0071). Moreover, the density of pancreatic intraepithelial neoplasia lesions in the background pancreas of cases of PDAC concomitant with IPMN (1.86/cm) was higher than that of cases of PDAC without IPMN (0.91/cm) (P = 0.0007).
CONCLUSIONS:
Concomitant IPMN in PDAC is an independent predictive factor for the development of new PDAC in remnant pancreas. Cancer susceptibility of remnant pancreas after resection for PDAC concomitant with IPMN is probably due to an increased density of pancreatic intraepithelial neoplasia lesions.
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| 217. |
Kawaji H, Kubo M, Yamashita N, Yamamoto H, Kai M, Kajihara A, Yamada M, Kurata K, Kaneshiro K, Harada Y, Hayashi S, Shimazaki S, Mori H, Akiyoshi S, Oki E, Oda Y, Baba E, Mori M, Nakamura M, Comprehensive molecular profiling broadens treatment options for breast cancer patients, Cancer Medicine, 10.1002/cam4.3619., 10, 2, 529-539, 2020.04. |
| 218. |
Kubota K, Jang JY, Nakanuma Y, Jang KT, Haruyama Y, Fukushima N, Furukawa T, Hong SM, Sakuraoka Y, Kim H, Matsumoto T, Lee BK, Zen Y, Kim J, Miyazaki M, Choi WD, Heo SJ, Endo I, Hwang S, Nakamura M, Han HS, Uemoto S, Park JS, Hong KE, Nanashima A, Kim DS, Kim JY, Ohta T, Kang JK, Fukumoto T, Nah WY, Seo IH, Inui K, Yoon DS, Unno M, Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a Japan‐Korea collaborative study, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.785
, 27, 9, 581-597, 2020.04, Abstract
Background
The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location.
Methods
IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid‐tubular components. Medical data were evaluated.
Results
Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P Conclusion
Type 1 and Type 2 IPNBs differ in their clinicopathological features and prognosis. This classification may help to further understand IPNB.
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| 219. |
Okusaka T, Nakamura M, Yoshida M, Kitano M, Uesaka K, Ito Y, Furuse J, Hanada K, Okazaki K, Clinical Practice Guidelines for Pancreatic Cancer 2019 From the Japan Pancreas Society A Synopsis, Pancreas, 10.1097/MPA.0000000000001513, 49, 326-335, 2020.04, Abstract
Objectives
Clinical Practice Guidelines for Pancreatic Cancer were first published in 2006 by the Japan Pancreas Society, and they were revised in 2009, 2013, and 2016. In July 2019, the Clinical Practice Guidelines for Pancreatic Cancer 2019 were newly revised in Japanese.
Methods
For this version, we developed the new guidelines according to the Minds Manual for Guideline Development 2017, which includes the concepts of GRADE (Grading Recommendations Assessment, Development, and Evaluation), to enable a better understanding of the current guidelines.
Results
The guidelines show algorithms for the diagnosis, treatment, and chemotherapy of pancreatic cancer and address 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive and palliative medicine. They include 56 clinical questions and 84 statements. There are statements corresponding to clinical questions, evidence levels, recommendation strengths, and agreement rates.
Conclusions
These guidelines represent the most standard clinical and practical management guidelines at this time in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2019 in Japanese and is an attempt to disseminate the Japanese guidelines worldwide for introducing the Japanese approach for clinical management of pancreatic cancer.
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| 220. |
Matsuda R, Miyasaka Y, Yamada Y, Kawata J, Sakihama K, Yamamoto T, Saeki K, Yamamoto H, Ohishi Y, Koga Y, Nakamura M, Oda Y, Chronic Inflammatory Changes and Oxidative Stress in the Background of "Pancreatic Ductal Adenocarcinoma Concomitant With Intraductal Papillary Mucinous Neoplasm”, Virchows Arch, 10.1007/s00428-020-02844-2
, 477, 6, 799-806, 2020.04, Abstract
Cases of "pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm" (IPMN) have multiple PDAC lesions more frequently than cases of "PDAC without IPMN". However, the mechanism of carcinogenesis in this former disease category remains unknown. The main objective of this work was thus to investigate the effects of chronic inflammation on carcinogenesis in PDAC cases. We selected 31 "PDAC concomitant with IPMN" patients and 58 "PDAC without IPMN" patients and pathologically evaluated their background pancreatic parenchyma. Fibrosis and inflammation scores of background pancreas were higher in "PDAC concomitant with IPMN" than in "PDAC without IPMN" (P . |
| 221. |
Hisadome Y, Noguchi H, Nakafusa Y, Sakihama K, Mei T, Kaku K, Okabe Y, Masutani K, Ohara Y, Ikeda K, Oda Y, Nakamura M, Association of Pretransplant BK Polyomavirus Antibody Status with BK Polyomavirus Infection After Kidney Transplantation: A Prospective Cohort Pilot Study of 47 Transplant Recipients, Transplantation Proceedings, 10.1016/j.transproceed.2020.01.164, 52, 6, 1762-1768, 2020.04. |
| 222. |
Ohtsuka T, Nagakawa Y, Toyama H, Takeda Y, Maeda A, Kumamoto Y, Nakamura Y, Hashida K, Honda G, Fukuzawa K, Toyoda E, Tanabe M, Gotohda N, Matsumoto I , Ryu T, Uyama I , Kojima T, Unno M, Ichikawa D, Inoue Y, Matsukawa H, Sudo T, Takaori K, Yamaue H, Eguchi S, Tahara M, Shinzeki M, Eguchi H, Kurata M, Morimoto M, Hayashi H, Marubashi S , Inomata M, Kimura K, Amaya K, Sho M, Yoshida R, Murata A, Yoshitomi H, Hakamada K, Yasunaga M, Abe N, Hioki M Tsuchiya M, Misawa T, Seyama Y, Noshiro H, Sakamoto E, Hasegawa K, Kawabata Y, Uchida Y, Kameyama S, Ko S, Takao T, Kitahara K, Nakahira S, Baba H, Watanabe M, Yamamoto M, Nakamura M, A Multicenter Prospective Registration Study on Laparoscopic Pancreatectomy in Japan: Report on the Assessment of 1,429 Patients , J Hepatobiliary Pancreat Sci, 10.1002/jhbp.695
, 27, 2, 47-55, 2020.04, Abstract
Background: Prospective studies are needed to understand the safety and feasibility of laparoscopic pancreatectomy. The aim of the present study was to describe laparoscopic pancreatectomy currently undertaken in Japan, using a prospective registration system.
Methods: Patient characteristics and planned operations were registered preoperatively, and then the performed operation and outcomes were reported using an online system. Collected data were also compared between institutions based on their level of experience. This study was registered with UMIN000022836.
Results: Available data were obtained from 1,429 patients at 100 Japanese institutions, including 1,197 laparoscopic distal pancreatectomies (LDPs) and 232 laparoscopic pancreatoduodenectomies (LPDs). The rates of completion for planned operations were 92% for LDP and 91% for LPD. Postoperative complication rates after LDP and LPD were 17% and 30%, and 90-day mortality rates were 0.3% and 0.4%, respectively. Shorter operation time, less blood loss, and lower incidence of pancreatic fistula were observed in institutions experienced in LDP. A higher rate of pure laparoscopic procedure and shorter operation time were noted in institutions experienced with LPD.
Conclusion: LDPs and LPDs are performed safely in Japan, especially in experienced institutions. Our data could support the next challenges in the field of laparoscopic pancreatectomy.
Keywords: Distal pancreatectomy; Laparoscopic pancreatectomy; Pancreatoduodenectomy; Prospective registration.
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| 223. |
Karen Zaguirre, Masaya Kai, Makoto Kubo, Mai Yamada, Kanako Kurata, Hitomi Kawaji, Kazuhisa Kaneshiro, Yurina Harada, Saori Hayashi, Akiko Shimazaki, Takafumi Morisaki, Hitomi Mori, Yoshinao Oda, Sanmei Chen, Taiki Moriyama, Shuji Shimizu, Masafumi Nakamura, Validity of the prognostication tool PREDICT version 2.2 in Japanese breast cancer patients, Cancer Medicine, 10.1002/cam4.3713, 10, 5, 1605-1613, 2021.04, Introduction: PREDICT is a prognostication tool that calculates the potential benefit of various postsurgical treatments on the overall survival (OS) of patients with nonmetastatic invasive breast cancer. Once patient, tumor, and treatment details have been entered, the tool will show the estimated 5-, 10-, and 15-year OS outcomes, both with and without adjuvant therapies. This study aimed to conduct an external validation of the prognostication tool PREDICT version 2.2 by evaluating its predictive accuracy of the 5- and 10-year OS outcomes among female patients with nonmetastatic invasive breast cancer in Japan.
Methods: All female patients diagnosed from 2001 to 2013 with unilateral, nonmetastatic, invasive breast cancer and had undergone surgical treatment at Kyushu University Hospital, Fukuoka, Japan, were selected. Observed and predicted 5- and 10-year OS rates were analyzed for the validation population and the subgroups. Calibration and discriminatory accuracy were assessed using Chi-squared goodness-of-fit test and area under the receiver operating characteristic curve (AUC).
Results: A total of 636 eligible cases were selected from 1, 213 records. Predicted and observed OS differed by 0.9% (p = 0.322) for 5-year OS, and 2.4% (p = 0.086) for 10-year OS. Discriminatory accuracy results for 5-year (AUC = 0.707) and 10-year (AUC = 0.707) OS were fairly well.
Conclusion: PREDICT tool accurately estimated the 5- and 10-year OS in the overall Japanese study population. However, caution should be used for interpretation of the 5-year OS outcomes in patients that are ≥65 years old, and also for the 10-year OS outcomes in patients that are ≥65 years old, those with histologic grade 3 and Luminal A tumors, and in those considering ETx or no systemic treatment.. |
| 224. |
Kiyoshi Chinen, Naoaki Sakata, Gumpei Yoshimatsu, Masafumi Nakamura, Shohta Kodama, Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation, Scientific Reports, 10.1038/s41598-021-00740-6, 11, 1, 21239, 2021.04, Abstract
Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. Trials aiming to improve the function of transplanted islets have also been challenging. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. The therapeutic effects of DLS were assessed in terms of the expression/production of endocrine genes/proteins, insulin-releasing function under glucose stimulation of mouse islets, and outcomes of syngeneic murine islet transplantation with systemic DLS administration. DLS treatment promoted insulin production and suppressed somatostatin production, suggesting that cancelation of the binding between ghrelin and GHS-R1a on β or δ cells improved insulin expression. DLS also promoted the glucose-dependent insulin-releasing function of β cells. However, the therapeutic effect of DLS in islet transplantation was fractional. In conclusion, the GHS-R1a antagonist showed preferable effects in improving the therapeutic outcomes of islet transplantation, including the promotion of insulin-releasing function.. |
| 225. |
Atsushi Fujii, Takaaki Masuda, Michio Iwata, Taro Tobo, Hiroaki Wakiyama, Kensuke Koike, Keisuke Kosai, Takafumi Nakano, Shotaro Kuramitsu, Akihiro Kitagawa, Kuniaki Sato, Yuta Kouyama, Dai Shimizu, Yoshihiro Matsumoto, Tohru Utsunomiya, Takao Ohtsuka, Yoshihiro Yamanishi, Masafumi Nakamura, Koshi Mimori, The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer, Cancer Sci, 10.1111/cas.14858, 112, 4, 1655-1668, 2021.04, Abstract
Targeting mutated oncogenes is an effective approach for treating cancer. The 4 main driver genes of pancreatic ductal adenocarcinoma (PDAC) are KRAS, TP53, CDKN2A, and SMAD4, collectively called the "big 4" of PDAC, however they remain challenging therapeutic targets. In this study, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (ASAP2), one of the ArfGAP family, was identified as a novel driver gene in PDAC. Clinical analysis with PDAC datasets showed that ASAP2 was overexpressed in PDAC cells based on increased DNA copy numbers, and high ASAP2 expression contributed to a poor prognosis in PDAC. The biological roles of ASAP2 were investigated using ASAP2-knockout PDAC cells generated with CRISPR-Cas9 technology or transfected PDAC cells. In vitro and in vivo analyses showed that ASAP2 promoted tumor growth by facilitating cell cycle progression through phosphorylation of epidermal growth factor receptor (EGFR). A repositioned drug targeting the ASAP2 pathway was identified using a bioinformatics approach. The gene perturbation correlation method showed that niclosamide, an antiparasitic drug, suppressed PDAC growth by inhibition of ASAP2 expression. These data show that ASAP2 is a novel druggable driver gene that activates the EGFR signaling pathway. Furthermore, niclosamide was identified as a repositioned therapeutic agent for PDAC possibly targeting ASAP2.
Keywords: ASAP2; driver gene; drug repositioning; niclosamide; pancreatic cancer.. |
| 226. |
Kazuhiro Koikawa, Shin Kibe, Futoshi Suiz, Nobufumi Sekino, Nami Kim, Theresa D Manz, Benika J Pinch, Dipikaa Akshinthala, Ana Verma, Giorgio Gaglia, Yutaka Nezu, Shizhong Ke, Chenxi Qiu, Kenoki Ohuchida, Yoshinao Oda, Tae Ho Lee, Babara Wegiel, John G Clohessy, Nir London, Sandro Santagata, Gerburg M Wulf, Manuel Hidalgo, Senthil K Muthuswamy, Masafumi Nakamura, Nathanael S Gray, Xiao Zhen Zhou, Kun Ping Lu, Targeting Pin1 renders pancreatic cancereradicable by synergizing with immunochemotherapy, Cell, 10.1016/j.cell.2021.07.020, 184, 18, 4753-4771, 2021.04, Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
Keywords: Pin1; cancer immune evasion; cancer-associated fibroblasts; chemotherapy; combination therapy; immuni checkpoint therapy; pancreatic cancer; targeted therapy; tumor immune microenvironment; tumor microenvironment.. |
| 227. |
Kaneyasu Nakagawa, Akihiro Tsuchimoto, Kenji Ueki, Yuta Matsukuma, Yasuhiro Okabe, Kosuke Masutani, Kohei Unagami, Yoichi Kakuta, Masayoshi Okumi, Masafumi Nakamura, Toshiaki Nakano, Kazunari Tanabe, Takanari Kitazono, Significance of Revised Criteria for Chronic Active T Cell-Mediated Rejection in the 2017 Banff Classification: Surveillance by 1-year Protocol Biopsies for Kidney Transplantation , American Journal of Transplantation, 10.1111/ajt.16093, 21, 1, 174-185, 2021.04, Abstract
Diagnostic criteria for chronic active T‐cell mediated rejection (CA‐TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1‐year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the three diagnosticians showed a substantial agreement rate of 0.68 in Fleiss’s kappa coefficient. Thirty‐three patients (8%) were classified as CA‐TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA‐TCMR according to Banff 2015 criteria. Determinant factors of CA‐TCMR were cyclosporine use (vs. tacrolimus), previous acute rejection, and BK polyomavirus‐associated nephropathy. In survival analysis, the new diagnosis of CA‐TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death‐censored graft loss (log‐rank test, P |
| 228. |
Kazuki Tomihara, Yu Hisadome, Hiroshi Noguchi, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Serum pancreatic enzymes in the early postoperative period predict complications associated with pancreatic fluid after pancreas transplantation: A retrospective, single-center, observational cohort study, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.895, 28, 4, 365-375, 2021.04, Abstract
Background: Pancreas transplantation (PT) is a radical treatment for diabetes mellitus (DM). Although the results of PT have been improving, surgical complications remain. Few reports have focused on complications associated with pancreatic fluid (CAPF) after PT. We aimed to investigate the risk factors and predictors for CAPF after PT.
Methods: Sixty-nine patients, who underwent deceased-donor PT for type 1 DM at our institution from August 2001 to May 2020, were retrospectively studied. We identified CAPF from those with Clavien-Dindo Classification ≥ grade III, and assessed risk factors by univariate and multivariate analyses using logistic regression.
Results: Twenty-one (30.4%) patients had complications with Clavien-Dindo Classification ≥ grade III. Eleven (16.0%) patients were diagnosed with CAPF. Median serum pancreatic amylase (P-AMY) levels with CAPF on postoperative day (POD)1 and POD2 were significantly higher than those without CAPF (P=0.019 and P=0.027, respectively). In multivariable analysis, serum P-AMY levels on POD1 were an independent predictive factor for CAPF (odds ratio 1.83, 95% confidence interval 1.07-3.14, P=0.008).
Conclusions: CAPF after PT is associated with high serum P-AMY in the early postoperative period. Serum pancreatic enzymes in the first few postoperative days after PT may be a significant predictive factor for CAPF.
Keywords: amylase; complications associated with pancreatic fluid; lipase; pancreas transplantation; pancreatic fistula.. |
| 229. |
Kinuko Nagayoshi, Shuntaro Nagai, Karen P. Zaguirre, Kyoko Hisano, Masafumi Sada, Yusuke Mizuuchi, Masafumi Nakamura, Securing the surgical field for mobilization of right?sided colon cancer using the duodenum?first multidirectional approach in laparoscopic surgery, Techniques in Coloproctology, 10.1007/s10151-021-02444-5, 25, 7, 865-874, 2021.04. |
| 230. |
Yu Hisadome, Takanori Mei, Hiroshi Noguchi, Toshiaki Ohkuma, Yu Sato, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Safety and Efficacy of Sodium-glucose Cotransporter 2 Inhibitors in Kidney Transplant Recipients With Pretransplant Type 2 Diabetes Mellitus: A Retrospective, Single-center, Inverse Probability of Treatment Weighting Analysis of 85 Transplant Patients, Transplant Direct, 10.1097/TXD.0000000000001228, 7, 11, e772, 2021.04, Abstract
Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can be used effectively and safely in kidney transplant (KT) recipients with pretransplant type 2 diabetes as the primary cause of end-stage renal disease (ESRD) remains unclear. In this study, we retrospectively analyzed the efficacy and safety of SGLT2 inhibitors compared with other oral hypoglycemic agents (OHAs) in KT recipients with pretransplant type 2 diabetes as the primary cause of ESRD.
Methods: In this retrospective, observational, single-center, inverse probability of treatment weighting (IPTW) analysis study, we compared the outcomes of SGLT2 inhibitors (SGLT2 group) and other OHAs (control group) following KT. A total of 85 recipients with type 2 diabetic nephropathy as the major cause of ESRD before KT who were treated at our institute between October 2003 and October 2019 were screened and included. The variables considered for IPTW were recipient age, sex, body mass index, history of cardiovascular disease, ABO incompatibility, insulin therapy, estimated glomerular filtration rate (eGFR), and hemoglobin A1c (HbA1c) at the initiation of additional OHAs. Primary endpoints were changes in HbA1c, body weight, and eGFR 1 y after the initiation of additional OHAs.
Results: After IPTW analysis, there were 26 patients in the SGLT2 group and 59 patients in the control group (n = 85 overall). The body weights were significantly reduced in the SGLT2 group. There was no statistical difference in changes in HbA1c and eGFR. Similarly, there was no significant difference in the incidence of urinary infection, acute rejection, or other side effects between the groups.
Conclusions: Our findings suggested that SGLT2 inhibitors reduced the body weight of KT recipients and were used safely without increasing side effects.. |
| 231. |
Ryuichiro Kimura, Taiki Moriyama, Kenoki Ohuchida, Koji Shindo, Shuntaro Nagai, Takao Ohtsuka, Masafumi Nakamura, Risk factors for postoperative pneumonia after laparoscopic gastrectomy in patients aged 75 years and over with gastric cancer, Asian Journal of Endoscopic Surgery, 10.1111/ases.12883, 14, 3, 408-416, 2021.04, Abstract
Introduction: The proportion of patients aged 75 years and over who undergo minimally invasive surgery for gastric cancer is increasing. However, the safety and feasibility of laparoscopic gastrectomy (LG) in this age group is controversial. This study aimed to evaluate whether LG is safe and effective in patients aged 75 years and over.
Methods: The study included 728 patients with early and advanced gastric cancer who underwent curative LG between 2009 and 2017; 166 of these patients (22.8%) were aged 75 or over. All surgeries were performed laparoscopically. Selected clinical factors were compared between the 166 patients aged 75 years and over and the 562 patients aged under 75 years.
Results: There were significant differences in presence of comorbidity, respiratory function and American Society of Anesthesiologists physical status scores between the older and younger groups. The older patients more frequently developed complications than the younger ones, particularly postoperative pneumonia. According to multivariate analyses of all participants, age, chronic obstructive pulmonary disease (COPD), and D2 lymphadenectomy were independent risk factors for postoperative pneumonia. Advanced stage and D2 lymphadenectomy were independent risk factors in the older group, whereas only COPD was an independent risk factor in the younger group.
Conclusions: LG for gastric cancer can be safely performed in patients aged over 75 years with an acceptable complication rate. However, the present data suggest that care should be taken in selecting LG with D2 lymphadenectomy to treat advanced cancer in these patients because the risk of postoperative complications, especially postoperative pneumonia, increases.
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| 232. |
Shigeru Ishida, Yoko Makihara, Hiroyuki Watanabe, Takafumi Nakashima, Kenichiro Nagata, Kimitaka Suetsugu, Toshikazu Tsuji, Kojiro Hata, Munehiko Ikeda, Mio Ikebe, Haruna Minami, Hitomi Watanabe, Kohei Nakata, Masafumi Nakamura, Nobuaki Egashira, Ichiro Ieiri, Risk Factors for Gemcitabine-Induced Vascular Pain in Patients With Pancreatic Cancer, The Annanls of Pharmacotheraphy
, 10.1177/1060028020969354 , 55, 6, 738-744, 2021.04, Objectives:
This study focused on identifying predictive factors for gemcitabine-induced vascular pain.
Methods:
We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses.
Results:
Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose (P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine (P = 0.025), and hot pack use (P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m2), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%).
Conclusions and Relevance:
High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.
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| 233. |
Takanori Mei, Hiroshi Noguchi, Kanae Otsu, Yuki Shimada, Yu Sato, Yu Hisadome, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Risk Factors and Optimal Methods for Incisional Hernias After Kidney Transplantation: A Single-Center Experience From Asia, Transplantation Proceedings, 10.1016/j.transproceed.2021.02.012, 53, 3, 1048-1054, 2021.04. |
| 234. |
Akiko Sagara, Kohei Nakata, Sokichi Matsumoto, Weiyu Guan, Tomohiko Shinkawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Repositioning of duloxetine to target pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.13005, 22, 4, 744, 2021.04, Abstract
Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.
Keywords: drug repositioning; duloxetine; pancreatic cancer; pancreatic stellate cells; tumor microenvironment.. |
| 235. |
Takeo Yamamoto, Kenichi Kohashi, Yutaka Yamada, Jun Kawata, Kukiko Sakihama, Ryota Matsuda, Yutaka Koga, Shinichi Aishima, Masafumi Nakamura, Yoshinao Oda, Relationship between cellular morphology and abnormality of SWI/SNF complex subunits in pancreatic undifferentiated carcinoma, J Cancer Res Clin Oncol, 10.1007/s00432-021-03860-8, 148, 11, 2945-2957, 2021.04, Purpose: Pancreatic undifferentiated carcinoma (UDC) is a rare tumor with a worse prognosis than pancreatic ductal adenocarcinoma (PDAC). Recent study showed that UDC exhibits loss of SMARCB1, which is one of the subunits of the SWI/SNF complex. However, whether there are abnormalities of other SWI/SNF complex subunits in UDC has remained unknown. In this study, we attempted to clarify whether the loss of SWI/SNF complex subunits is related to the pathogenesis of UDC by comparing undifferentiated component (UC) and ductal adenocarcinoma component (DAC).
Methods: Genetic analysis of the ten UCs and six DACs was performed. The expression of ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCC1, and SMARCC2 in formalin-fixed, paraffin-embedded tumor tissues collected by surgical resection from 18 UDC patients was evaluated immunohistochemically. Moreover, two pancreatic cell lines were evaluated for the effects of siARID1A on the mRNA and protein expression of E-cadherin, vimentin, and epithelial-mesenchymal transition (EMT)-related markers by qRT-PCR, western blotting, and immunofluorescence staining.
Results: UCs tended to have a higher frequency of mutation in ARID1A, SMARCA4, and SMARCC2 than DACs. Immunohistochemically, UCs revealed reduced/lost expression of ARID1A (72%), SMARCB1 (44%), SMARCC1 (31%), and SMARCC2 (67%). Reduced/lost expression of ARID1A, SMARCB1, and SMARCC2 was significantly more frequently observed in UCs than in DACs. In the pancreatic cell lines, western blotting and qRT-PCR showed that the downregulation of ARID1A increased the expression of vimentin and EMT-related markers.
Conclusion: Our results suggest that the abnormality of SWI/SNF complex subunits, especially ARID1A, is one of the factors behind the morphological change of UDC.
Keywords: ARID1A; Epithelial-mesenchymal transition; Pancreatic undifferentiated carcinoma; SWI/SNF complex.. |
| 236. |
Satoko Koga, Hideya Onishi, Shogo Masuda, Akiko Fujimura, Shu Ichimiya, Kazunori Nakayama, Akira Imaizumi, Kenichi Nishiyama, Masayuki Kojima, Kei Miyoshi, Katsuya Nakamura, Masayo Umebayashi, Takashi Morisaki, Masafumi Nakamura, PTPN3 is a potential target for a new cancer immunotherapy that has a dual effect of T cell activation and direct cancer inhibition in lung neuroendocrine tumor, Translational Oncology, 10.1016/j.tranon.2021.101152, 14, 9, 101152, 2021.04, Abstract
In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.. |
| 237. |
Naoki Mochidome, Yutaka Koga, Yoshihiro Ohishi, Tetsuyuki Miyazaki, Ryota Matsuda, Yuichi Yamada, Shinichi Aishima, Masafumi Nakamura, Yoshinao Oda, Prognostic implications of the coexisting precursor lesion types in invasive gallbladder cancer, Hum Pathol, 10.1016/j.humpath.2021.05.001, 114, 44-53, 2021.04, Abstract
Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P Keywords: Biliary intraepithelial neoplasia; Gallbladder carcinoma; Intracholecystic papillary neoplasms; p16; p53.. |
| 238. |
Yusuke Mizuuchi, Yoshitaka Tanabe, Masafumi Sada, Yoshiki Kitaura, Shuntaro Nagai, Yusuke Watanabe, Sadafumi Tamiya, Kinuko Nagayoshi, Kenoki Ohuchida, Toru Nakano, Masafumi Nakamura, Predictive factors associated with relapse of stage II/III colon cancer treated with peroral anti-cancer agents in the adjuvant setting, Mol Clin Oncol, 10.3892/mco.2021.2284., 14, 6, 122, 2021.04. |
| 239. |
Keizo Kaku, Yasuhiro Okabe, Yu Sato, Yu Hisadome, Takanori Mei, Hiroshi Noguchi, Masafumi Nakamura, Predicting Operation Time and Creating a Difficulty Scoring System in Donor Nephrectomy, J Endourol
., 10.1089/end.2020.1181, 35, 11, 1623-1630, 2021.04. |
| 240. |
Akiko Sagara, Kohei Nakata, Tomohiro Yamashita, Weiyu Guan, Pingshan Zhong, Sokichi Matsumoto, Sho Endo, Chika Iwamoto, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kenoki Ohuchida, Kazuhiro Mizumoto, Masafumi Nakamura, New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth, Pancreatology, 10.1016/j.pan.2021.04.002, 21, 6, 1071-1080, 2021.04, Abstract
Background/objectives: Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer.
Methods: Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo.
Results: Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine.
Conclusions: A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.
Keywords: Cell-based screen; Dopamine antagonist; Pancreatic cancer; Pancreatic stellate cell; Stromal targeting therapy.. |
| 241. |
Takafumi Morisaki, Makoto Kubo, Masayo Umebayashi, Poh Yin Yew, Sachiko Yoshimura, Jae-Hyun Park, Kazuma Kiyotani, Masaya Kai, Mai Yamada1, Yoshinao Oda, Yusuke Nakamura, Takashi Morisaki, Masafumi Nakamura, Neoantigens elicit T cell responses in breast cancer, scientific reports, 10.1038/s41598-021-91358-1., 11, 1, 13590-13590, 2021.04, Abstract
Neoantigens are tumour-specific antigens that arise from non-synonymous mutations in tumour cells. However, their effect on immune responses in the tumour microenvironment remains unclear in breast cancer. We performed whole exome and RNA sequencing of 31 fresh breast cancer tissues and neoantigen prediction from non-synonymous single nucleotide variants (nsSNVs) among exonic mutations. Neoantigen profiles were determined by predictive HLA binding affinity (IC50 |
| 242. |
Yoshihiro Miyasaka, Takao Ohtsuka, Susumu Eguchi, Masafumi Inomata, Kazuyoshi Nishihara, Hiroyuki Shinchi, Koji Okuda, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Masafumi Nakamura, Neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel regimen for borderline resectable pancreatic cancer with arterial involvement: A prospective multicenter single-arm phase II study protocol, Int J Surg Protoc, 10.29337/ijsp.142., 25, 1, 55-60, 2021.04, Abstract
Introduction: Although neoadjuvant treatment is recommended for patients with borderline resectable pancreatic cancer (BRPC), no standard neoadjuvant regimen has been established for BRPC with arterial involvement (BRPC-A), which is associated with a higher risk of margin-positive resection and poorer prognosis than BRPC with only venous involvement. Gemcitabine plus nab-paclitaxel (GnP) has been reported to significantly reduce tumor size in metastatic pancreatic cancer, and some retrospective studies suggested that neoadjuvant GnP for BRPC improved resectability and survival.
Methods and analysis: A prospective multicenter single-arm phase II study is conducted to evaluate the safety and efficacy of GnP as neoadjuvant chemotherapy for BRPC-A. The primary endpoint is the R0 resection rate. The secondary endpoints are the neoadjuvant chemotherapy response rate, resection rate, pathological response rate, incidence rate of adverse events, and quality of life.
Ethics and dissemination: This study protocol was approved by the institutional review board of Kyushu University (no. 181). The results will be published in a peer-reviewed journal and will be presented at medical meetings.
Highlights: Strategy for borderline resectable pancreatic cancer involving arteries (BRPC-A).There is no standard regimen for neoadjuvant chemotherapy for BRPC-A.Gemcitabine plus nab-paclitaxel (GnP) shows significant tumor shrinkage.Neoadjuvant GnP for BRPC-A increases resectability and margin-negative resection.
Keywords: borderline resectable pancreatic cancer; gemcitabine; nab-paclitaxel; neoadjuvant.. |
| 243. |
Haimin Feng, Taiki Moriyama, Kenoki Ohuchida, Nan Sheng, Chika Iwamoto, Koji Shindo, Kengo Shirahane, Naoki Ikenaga, Shuntaro Nagai, Kohei Nakata, Kazuhiro Mizumoto, Masafumi Nakamura, N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions, J Exp Clin Cancer Res, 10.1186/s13046-021-01939-1, 40, 133, 1-19, 2021.04, Background: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions.
Method: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models.
Results: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level.
Conclusion: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.. |
| 244. |
Kohei Nakata, Yasuhisa Mori, Naoki Ikenaga, Noboru Ideno, Yusuke Watanabe, Yoshihiro Miyasaka, Takao Ohtsuka, Masafumi Nakamura, Management of postoperative pancreatic fistula after pancreatoduodenectomy: Analysis of 600 cases of pancreatoduodenectomy patients over a 10-year period at a single institution, Surgery., 10.1016/j.surg.2021.01.010, 169, 6, 1446-1453, 2021.04, Abstract
Background: Although postoperative pancreatic fistula (POPF) is a common and critical complication of pancreatoduodenectomy (PD), effective strategies to prevent POPF have not yet been completely developed. Because appropriate management of POPF is important to reduce the mortality rate after PD, in this study we aimed to evaluate our approach for the management of POPF after PD, including the postoperative course.
Methods: This retrospective study included 605 consecutive patients who underwent PD at our hospital between 2010 and 2020. All patients who developed POPF were first managed conservatively, with drainage tubes placed during surgery retained to manage POPF. In cases wherein conservative treatment was unsuccessful, open drainage, followed by continuous negative pressure and continuous irrigation, was used. For open drainage, the surgical wound was opened bluntly (approximate length, 5 cm) under local anesthesia, and the fluid was directly and completely drained.
Results: The prevalence of POPF of grades B and C was 15.4% (n = 93) and 0.33% (n = 2), respectively. Of these patients, 1 required reoperation, 43 recovered with conservative management only, 47 required open drainage, and 4 required image-guided percutaneous drainage. Postoperative hemorrhage with a pseudoaneurysm was identified in 3 (0.66%) patients. The postoperative in-hospital mortality rate was low (n = 1, 0.16%). The rate of successful POPF management was 98.9%.
Conclusion: Based on our high success rate in POPF management, we consider open drainage to be a safe primary management method for POPF.. |
| 245. |
Yoshihiko Sadakari, Kyoko Hisano, Masafumi Sada, Yusuke Mizuuchi, Kinuko Nagayoshi, Hayato Fujita, Shuntaro Nagai, Tatsuya Manabe, Takashi Ueki, Masafumi Nakamura, Long-term effects of laparoscopic lateral pelvic lymph node dissection on urinary retention in rectal cancer, Surgical Endoscopy, 10.1007/s00464-021-08364-7, 36, 2, 999-1007, 2021.04, Abstract
Background: The addition of lateral pelvic lymph node dissection (LPLND) in rectal cancer surgery has been reported to increase the incidence of post-operative urinary retention. Here, we assessed the predictive factors and long-term outcomes of urinary retention following laparoscopic LPLND (L-LPLND) with total mesorectal excision (TME) for advanced lower rectal cancer.
Methods: This retrospective single-institutional study reviewed post-operative urinary retention in 71 patients with lower rectal cancer who underwent L-LPLND with TME. Patients with preoperative urinary dysfunction or who underwent unilateral LPLND were excluded. Detailed information regarding patient clinicopathologic characteristics, post-void residual urine volume, and the presence or absence of urinary retention over time was collected from clinical and histopathologic reports and telephone surveys. Urinary retention was defined as residual urine > 100 mL and the need for further treatment.
Results: Post-operative urinary retention was observed in 25/71 patients (35.2%). Multivariate analysis revealed that blood loss ≥ 400 mL [odds ratio (OR) 4.52; 95% confidence interval (CI) 1.24-16.43; p = 0.018] and inferior vesical artery (IVA) resection (OR 8.28; 95% CI 2.46-27.81; p Conclusion: We identified the predictive factors of urinary retention following L-LPLND with TME, including increased blood loss (≥ 400 mL) and IVA resection. Urinary retention associated with unilateral IVA resection improved relatively quickly. L-LPLND with unilateral IVA resection is a feasible and safe procedure to improve oncological curability. However, if oncological curability is guaranteed, bilateral IVA resection should be avoided to prevent irreversible urinary retention.
Keywords: Inferior vesical artery; Laparoscopy; Lateral pelvic lymph node dissection; Long-term effects; Rectal cancer; Urinary retention.. |
| 246. |
Biao Zheng, Jianhua Qu, Kenoki Ohuchida, Haimin Feng, Stephen Jun Fei Chong, Zilong Yan, Yicui Piao, Peng Liu, Nan Sheng, Daiki Eguchi, Takao Ohtsuka, Kazuhiro Mizumoto, Zhong Liu, Shazib Pervaiz, Peng Gong, Masafumi Nakamura, LAMA4 upregulation is associated with high liver metastasis potential and poor survival outcome of Pancreatic Cancer
, Theranostics, 70.7150/thno.68023., 11, 20, 10171-10172, 2021.04. |
| 247. |
Hitomi Mori, Kohei Saeki, Gregory Chang, Jinhui Wang, Xiwei Wu, Pei-Yin Hsu, Noriko Kanaya, Xiaoqiang Wang, George Somlo, Masafumi Nakamura, Andrea Bild, Shiuan Chen, Influence of Estrogen Treatment on ESR1+ and ESR1－ Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models, Cancers, /10.3390/cancers13246375 , 13, 24, 6375, 2021.04, A 100% ER positivity is not required for an endocrine therapy response. Furthermore, while estrogen typically promotes the progression of hormone-dependent breast cancer via the activation of estrogen receptor (ER)-α, estrogen-induced tumor suppression in ER+ breast cancer has been clinically observed. With the success in establishing estrogen-stimulated (SC31) and estrogen-suppressed (GS3) patient-derived xenograft (PDX) models, single-cell RNA sequencing analysis was performed to determine the impact of estrogen on ESR1+ and ESR1? tumor cells. We found that 17β-estradiol (E2)-induced suppression of GS3 transpired through wild-type and unamplified ERα. E2 upregulated the expression of estrogen-dependent genes in both SC31 and GS3; however, E2 induced cell cycle advance in SC31, while it resulted in cell cycle arrest in GS3. Importantly, these gene expression changes occurred in both ESR1+ and ESR1? cells within the same b
reast tumors, demonstrating for the first time a differential effect of estrogen on ESR1? cells. E2 also upregulated a tumor-suppressor gene, IL-24, in GS3. The apoptosis gene set was upregulated and the G2M checkpoint gene set was downregulated in most IL-24+ cells after E2 treatment. In summary, estrogen affected pathologically defined ER+ tumors differently, influencing both ESR1+ and ESR1? cells. Our results also suggest IL-24 to be a potential marker of estrogen-suppressed tumors.. |
| 248. |
Yu Sato, Hiroshi Noguchi, Takanori Mei, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Impact of the Mayo Adhesive Probability score on donor and recipient outcomes after living-donor kidney transplantation: a retrospective, single-center study of 782 transplants
, Transplant Direct, 10.1097/TXD.0000000000001185, 7, 8, e728, 2021.04, Abstract
Background: This study was performed to assess the impact of the Mayo Adhesive Probability (MAP) score on donor and recipient outcomes after living-donor kidney transplantation (LDKT).
Methods: We retrospectively analyzed 782 transplants involving LDKT between February 2008 and October 2019 to assess the correlation between the MAP score and outcome after LDKT. We divided the transplants into 2 groups according to the donor MAP score: 0 (MAP0) and 1-5 (MAP1-5).
Results: Compared with the MAP0 group, donors in the MAP1-5 group were significantly older, had higher body mass index, and were more likely to be men. The prevalences of hypertension, hyperlipidemia, and diabetes were also higher among donors in the MAP1-5 group than among donors in the MAP0 group. Operative time, estimated blood loss during donor nephrectomy, and percentage of glomerular sclerosis were significantly greater in the MAP1-5 group than in the MAP0 group. Donor and recipient perioperative complications were comparable between the 2 groups; death-censored graft survival rates also did not significantly differ between groups. Although the recipient mean estimated glomerular filtration rate (eGFR) from postoperative d 1 to 7 was significantly higher in the MAP0 group than in the MAP1-5 group (P = 0.007), eGFR reductions within 5 y after transplantation were similar between groups. There were no significant differences between groups in recipient mortality and biopsy-proven acute rejection episodes within 1 y after transplantation. Additionally, multivariate analysis showed that the only factors affecting recipient eGFR at postoperative d 7 were donor age, recipient age, and female sex (P Conclusions: The MAP score did not influence surgical complications or graft survival; therefore, it should not affect donor selection.. |
| 249. |
Hiroshi Noguchi, Yu Hisadome, Yu Sato, Takanori Mei, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Impact of the introduction of pure retroperitoneoscopic living-donor nephrectomy on perioperative donor outcomes: a propensity score matching comparison with hand-assisted laparoscopic living-donor nephrectomy, Asian Journal of Endoscopic Surgery, 10.1111/ases.12922, 14, 4
, 692-699, 2021.04, Abstract
Introduction: We previously reported that the outcomes of pure retroperitoneoscopic donor nephrectomy are superior to those of hand-assisted retroperitoneoscopic donor nephrectomy. Consequently, we introduced pure retroperitoneoscopic donor nephrectomy in our hospital. Here, we compared perioperative outcomes between hand-assisted intra-abdominal laparoscopic donor nephrectomy and pure retroperitoneoscopic donor nephrectomy.
Methods: We retrospectively reviewed data from 315 living-donor kidney transplantation procedures performed between October 2015 and December 2020 (213 involving hand-assisted intra-abdominal laparoscopic donor nephrectomy, October 2015 to June 2019; 102 involving pure retroperitoneoscopic donor nephrectomy, May 2019 to December 2020). After propensity score matching, 90 transplantations were included in each group (n = 180 overall).
Results: Donors in the pure retroperitoneoscopic donor nephrectomy group had longer warm ischemia times (P Conclusion: The introduction of pure retroperitoneoscopic donor nephrectomy was safe and effective. Moreover, it was less invasive and less harmful for donors, compared with hand-assisted intra-abdominal laparoscopic donor nephrectomy; recipient outcomes were equivalent.
Keywords: kidney transplantation; living-donor nephrectomy; retroperitoneoscopic surgery.. |
| 250. |
Yu Sato, Keizo Kaku, Yu Hisadome, Takanori Mei, Hiroshi Noguchi, Yasuhiro Okabe, Masafumi Nakamura, Impact of Recipient Age on Outcomes After Pancreas Transplantation, Transplantation Proceedings, 10.1016/j.transproceed.2021.04.013, 53, 6, 2046-2051, 2021.04, Background: Few reports have provided the ages of pancreas transplant recipients. The aim of this study was to determine whether recipient age affects survival of pancreatic grafts after transplantation.
Methods: We analyzed 73 patients who had undergone pancreas transplantation at our institution from August 2001 to March 2020 and assessed the effects of recipient age on pancreas graft survival within 5 years after pancreas transplantation.
Results: The cutoff value for recipient age established by receiver operating characteristic curve was 35 years. The pancreas graft survival rate of recipients aged 35 years or younger (1, 3, and 5 years: 72.9%, 41.7%, and 41.7%, respectively) was significantly lower than that of recipients aged over 35 years (1, 3, and 5 years: 93.2%, 88.4%, and 88.4%, respectively). Multivariate Cox hazard regression analysis showed that recipient age 35 years or younger (hazard ratio = 3.60; 95% confidence interval, 1.04-12.50; P = .044) and solitary pancreas transplantation (hazard ratio = 10.72; 95% confidence interval, 2.72-42.28; P < .001) were significant risk factors for pancreas graft loss within 5 years.
Conclusion: Our data suggest that younger recipient age is a risk factor for pancreas graft loss after transplantation.. |
| 251. |
Chikanori Tsutsumi, Kenoki Ohuchida, Koji Shindo, Taiki Moriyama, Shin Akagawa, Ryo Maeyama, Shuntaro Nagai, Kohei Nakata, Toshinaga Nabae, Nobuhiro Suehara, Kazuyoshi Nishihara, Akihiko Uchiyama, Toru Nakano, Masafumi Nakamura, High frequency of bone recurrence as an initial recurrence site after radical surgery in T1N3 gastric cancer: a propensity score matching analysis, Langenbecks Arch Surg, 10.1007/s00423-021-02231-8, 406, 7, 2305-2313, 2021.04, Purpose: T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence.
Methods: We retrospectively analyzed the outcomes of T1 GC and T2-4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients.
Results: After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2-4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2-4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months.
Conclusion: Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2-4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.. |
| 252. |
Shu Ichimiya, Hideya Onishi, Shinjiro Nagao, Satoko Koga, Kukiko Sakihama, Kazunori Nakayama, Akiko Fujimura, Yasuhiro Oyama, Akira Imaizumi, Yoshinao Oda, Masafumi Nakamura, GLI2 but not GLI1/GLI3 plays a central role in the induction of malignant phenotype of gallbladder cancer, Oncology Reports, 10.3892/or.2021.7947, 45, 3, 997-1010, 2021.04, Abstract
We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma‑associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle‑mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial‑mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2‑high expression patients had fewer numbers of CD3+ and CD8+ tumor‑infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD‑L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD‑L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.. |
| 253. |
Ryuichiro Kimura, Takao Ohtsuka, Makoto Kubo, Atsuko Kajihara, Atsushi Fujii, Yusuke Watanabe, Yasuhisa Mori, Naoki Ikenaga, Kohei Nakata, Koji Shindo, Kenoki Ohuchida, Masafumi Nakamura, FoundationOne® CDx gene profiling in Japanese pancreatic ductal adenocarcinoma patients: a single-institution experience , Surgery Today, 10.1007/s00595-020-02123-2
, 51, 4, 619-626, 2021.04, Abstract
Purpose: The aim of this study was to investigate the genetic mutation profiles of Japanese pancreatic ductal adenocarcinoma (PDAC) patients.
Methods: Next-generation sequencing was performed using FoundationOne® CDx on 17 PDAC patients who were treated by surgical resection at Kyushu University Hospital between February 2016 and January 2019. The tumor mutational burden and microsatellite instability status were also assessed.
Results: There were 16 patients (94%) with KRAS mutations, 13 (76%) with TP53 mutations, three (18%) with SMAD4 mutations, and one (6%) with a CDKN2A mutation. All patients had at least one pathogenic variant or a likely pathogenic variant. No patient had targeted therapies that matched with any clinical benefit according to FoundationOne® CDx. An unresectable PDAC patient with BRCA2-mutant disease was successfully treated by conversion surgery using platinum-based neoadjuvant chemotherapy.
Conclusions: Currently, FoundationOne® CDx might be difficult to use on PDAC patients, although further investigations with larger study populations are called for.
Keywords: FoundationOne; Gene profiling; Next-generation sequencing; Pancreatic cancer; Pancreatic ductal adenocarcinoma.
. |
| 254. |
Kohei Nakata, Takao Ohtsuka, Yoshihiro Miyasaka, Yusuke Watanabe, Noboru Ideno, Yasuhisa Mori, Naoki Ikenaga, Masafumi Nakamura, Evaluation of relationship between splenic artery and pancreatic parenchyma using three-dimensional computed tomography for laparoscopic distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-021-02101-3, 406, 6, 1885-1895, 2021.04, Abstract
Aim: Isolating the root of the splenic artery (SPA) is a challenging procedure in laparoscopic distal pancreatectomy (LDP). We investigated the usefulness of evaluation of the relationship between the SPA and pancreatic parenchyma using three-dimensional computed tomography (3D-CT).
Methods: In total, 104 patients were evaluated. The relationship between the SPA and pancreatic parenchyma was classified into two types: buried and non-buried. Video clips of 50 patients who underwent LDP requiring isolation of the SPA root were reviewed to determine whether the classification is related to difficulty of LDP.
Results: Of the 50 assessed patients who underwent LDP, the relationship between the SPA and pancreatic parenchyma was the buried type in 30 (60.0%) and non-buried type in 20 (40.0%). The buried type was associated with a significantly longer median operative time than the non-buried type (285.0 vs. 235.5 min, respectively; P
Conclusion: Preoperative 3D-CT around the pancreas is practical for predicting the difficulty of SPA isolation and determining the safety of the procedure.. |
| 255. |
Sokichi Matsumoto, Kohei Nakata, Akiko Sagara, Weiyu Guan, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.12894, 22, 2, 633-633, 2021.04, Abstract
Pancreatic stellate cells (PSCs) play a key role in desmoplastic stroma, which is a characteristic of pancreatic ductal adenocarcinoma (PDAC), and they also enhance the malignancy of pancreatic cancer cells. Our previous study reported chloroquine's mitigating effects on PSC activation; however, the drug is known to induce adverse effects in clinical practice. The present study aimed to reduce chloroquine doses and develop a useful pre-treatment that targets PSCs using nanoparticles. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as carriers and loaded with indocyanine green (Nano-ICG) or chloroquine (Nano-CQ). Tumor accumulation of Nano-ICG was evaluated using an in vivo imaging system. The effects of chloroquine, Nano-CQ and/or chemotherapy drug gemcitabine were investigated in an orthotopic xenograft mouse model. Nano-ICG selectively accumulated in pancreatic tumors and persisted therein for over 7 days after administration. Additionally, Nano-ICG accumulated in the peritoneal metastasized regions, but not in the liver, kidney and normal pancreatic tissues. Nano-CQ reduced the density of activated PSCs at lower chloroquine doses and significantly restrained tumor progression in combination with gemcitabine. In conclusion, the PLGA nanosystem successfully delivered the drug to pancreatic tumors. Nano-CQ efficiently reduced PSC activation and may be a promising novel pre-treatment strategy for PDAC.
Keywords: chloroquine; combination therapy; desmoplasia; nanoparticles; orthotopic xenograft; pancreatic cancer; pancreatic ductal adenocarcinoma; pre-treatment; stroma.. |
| 256. |
Nao Fujimori, Takashi Osoegawa, Akira Aso, Soichi Itaba, Yosuke Minoda, Masatoshi Murakami, Kazuhide Matsumoto, Katsuhito Teramatsu, Yu Takamatsu, Takehiro Takaoka, Takamasa Oono, Eikichi Ihara, Tomoharu Yoshizumi, Takao Ohtsuka, Masafumi Nakamura, Yoshihiro Ogawa, Efficacy of Early Endoscopic Ultrasound-Guided Transluminal Drainage for Postoperative Pancreatic Fistula, Canadian Journal Gastroenterology & Hepatology
, 10.1155/2021/6691705, 2021.04, Abstract
Background: Endoscopic ultrasound-guided transluminal drainage (EUS-TD) is generally performed 4 weeks after disease onset for evacuating pancreatic fluid collections. However, the optimal timing for conducting the procedure in those diagnosed with postoperative pancreatic fistula (POPF) has not been established. We aimed to elucidate the efficacy and safety of early EUS-TD procedures for treating POPF.
Methods: We retrospectively reviewed patients diagnosed with POPF who underwent EUS-TD in the Kyushu University Hospital between 2008 and 2019. Clinical features were comparatively analyzed between the two patient groups who underwent either early (≤15 days postoperatively) or late (>15 days postoperatively) EUS-TD. Factors prolonging hospital stay were also analyzed using Cox proportional hazard models.
Results: Thirty patients (median age, 64.5 years) were enrolled. The most common initial operation was distal pancreatectomy with splenectomy (60.0%). Median size of POPF was 69.5 (range, 38-145) mm, and median time interval between surgery and EUS-TD was 17.5 (range, 3-232) days. Totally, 47% patients underwent early EUS-TD. Rates of technical success, clinical success, and complications were 100%, 97%, and 6.9%, respectively. No recurrence of POPF occurred during a median follow-up period of 14 months. Clinical characteristics and outcomes were comparable between the early and late drainage patient groups, except for the rates of infection and nonencapsulation of POPF, which were significantly higher in the early drainage group. Performing simultaneous internal and external drainage (hazard ratio (HR): 0.31; 95% confidence interval (CI): 0.11-0.93, p=0.04) and conducting ≥2 treatment sessions (HR: 0.26; 95% CI: 0.08-0.84, p=0.02) were significantly associated with prolonged hospitalization after EUS-TD.
Conclusions: EUS-TD is a safe and effective method for managing POPF, regardless of when it is performed in the postoperative period. Once infected POPF occurs, clinicians should not hesitate to perform EUS-TD even within 15 days of the initial operation.. |
| 257. |
Mai Yamada, Makoto Kubo, Hidetaka Yamamoto, Nami Yamashita, Masaya Kai, Karen Zaguirre, Kazuhisa Kaneshiro, Akiko Shimazaki, Saori Hayashi, Hitomi Kawaji, Masaki Mori, Yoshinao Oda, Masafumi Nakamura, Effect of the 2013 ASCO-CAP HER2 Testing Guideline on the Management of IHC/HER2 2+ Invasive Breast Cancer, Anticancer Res, 10.21873/anticanres.15217, 41, 8, 4143-4149, 2021.04, Abstract
Background/aim: With advances in anti-HER2 treatment and improved prognoses of HER2-positive breast cancer, the American Society of Clinical Oncology and the American Society of Pathologists (ASCO/CAP) have revised the HER2 diagnostic guidelines several times. We examined how to respond clinically to the revisions of the interpretation of the immunohistochemistry (IHC) method.
Patients and methods: We re-evaluated 254 patients diagnosed as HER2 IHC equivocal, who underwent fluorescence in situ hybridization (FISH) before and after the IHC diagnostic criteria update in 2013.
Results: Twenty of 131 (15.3%) IHC equivocal cases by the ASCO/CAP 2007 guideline were IHC score 3+ and one of 20 (0.76%) was negative for FISH. Five of 123 (4.1%) IHC equivocal cases by the ASCO/CAP 2013 guideline were negative for IHC as per the 2007 guideline and four were positive for FISH.
Conclusion: After revision of the ASCO/CAP 2013 guideline, 3.3% of HER2-negative cases before the revision should have received anti-HER2 treatment.
Keywords: HER2 diagnosis; IHC/HER2 equivocal; revision of ASCO/CAP guideline.. |
| 258. |
Kenji Ueki, Akihiro Tsuchimoto, Yuta Matsukuma, Kaneyasu Nakagawa, Hiroaki Tsujikawa, Kosuke Masutani, Shigeru Tanaka, Keizo Kaku, Hiroshi Noguchi, Yasuhiro Okabe, Kohei Unagami, Yoichi Kakuta, Masayoshi Okumi, Masafumi Nakamura, Kazuhiko Tsuruya, Toshiaki Nakano, Kazunari Tanabe, Takanari Kitazono
, Development and validation of a risk score for the prediction of cardiovascular disease in living donor kidney transplant recipients, Nephrology, Dialysis, Transplantation, 10.1093/ndt/gfaa275 , 36, 2, 365-374, 2021.04, Abstract
Background: Cardiovascular disease (CVD) is a major cause of death in kidney transplant (KT) recipients. To improve their long-term survival, it is clinically important to estimate the risk of CVD after living donor KT via adequate pre-transplant CVD screening.
Methods: A derivation cohort containing 331 KT recipients underwent living donor KT at Kyushu University Hospital from January 2006 to December 2012. A prediction model was retrospectively developed and risk scores were investigated via a Cox proportional hazards regression model. The discrimination and calibration capacities of the prediction model were estimated via the c-statistic and the Hosmer-Lemeshow goodness of fit test. External validation was estimated via the same statistical methods by applying the model to a validation cohort of 300 KT recipients who underwent living donor KT at Tokyo Women's Medical University Hospital.
Results: In the derivation cohort, 28 patients (8.5%) had CVD events during the observation period. Recipient age, CVD history, diabetic nephropathy, dialysis vintage, serum albumin and proteinuria at 12 months after KT were significant predictors of CVD. A prediction model consisting of integer risk scores demonstrated good discrimination (c-statistic 0.88) and goodness of fit (Hosmer-Lemeshow test P = 0.18). In a validation cohort, the model demonstrated moderate discrimination (c-statistic 0.77) and goodness of fit (Hosmer-Lemeshow test P = 0.15), suggesting external validity.
Conclusions: The above-described simple model for predicting CVD after living donor KT was accurate and useful in clinical situations.
Keywords: dialysis vintage; external validation; nutritional status; proteinuria; risk score.
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| 259. |
Shu Ichimiya, Akiko Fujimura, Muneyuki Masuda, Shogo Masuda, Ryuji Yasumatsu, Masayo Umebayashi, Hiroto Tanaka, Norihiro Koya, Shinichiro Nakagawa, Poh Yin Yew, Sachiko Yoshimura, Hideya Onishi, Masafumi Nakamura, Yusuke Nakamura, Takashi Morisaki, Contribution of pre-existing neoantigen-specific T cells to a durable complete response after tumor-pulsed dendritic cell vaccine plus nivolumab therapy in a patient with metastatic salivary duct carcinoma, Immunological Investigations, 10.1080/08820139.2021.1973491., 5, 1-17, 2021.04, Abstract
Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.. |
| 260. |
Hitomi Kawaji, Makoto Kubo, Nami Yamashita, Hidetaka Yamamoto, Masaya Kai, Atsuko Kajihara, Mai Yamada, Kanako Kurata, Kazuhisa Kaneshiro, Yurina Harada, Saori Hayashi, Akiko Shimazaki, Hitomi Mori, Sayuri Akiyoshi, Eiji Oki, Yoshinao Oda, Eishi Baba, Masaki Mori, Masafumi Nakamura, Comprehensive molecular profiling broadens treatment options for breast cancer patients, Cancer Medicine, 10.1002/cam4.3619, 10, 2, 529-539, 2021.04, Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.
Keywords: ERBB2; breast cancer; next generation sequencing; precision oncology; tumor mutational burden.. |
| 261. |
Naoki Ikenaga, Takao Ohtsuka, Kohei Nakata, Yusuke Watanabe, Yasuhisa Mori, Masafumi Nakamura, Clinical significance of postoperative acute pancreatitis after pancreatoduodenectomy and distal pancreatectomy, Surgery, 10.1016/j.surg.2020.06.040, 169, 4, 732-737, 2021.04, Abstract
Background: The definition of postoperative acute pancreatitis as a specific complication of pancreatic surgery was proposed in 2016. Its presence and relevance have not been established, especially after a distal pancreatectomy.
Methods: Medical records of 319 patients who underwent pancreatoduodenectomy or distal pancreatectomy were analyzed. Postoperative acute pancreatitis was defined as an increase in serum amylase activity greater than the upper normal limit on postoperative day 1, according to Connor's definition of postoperative acute pancreatitis.
Results: Postoperative acute pancreatitis occurred in 63.4% of 153 of the patients undergoing pancreatoduodenectomy and 65.7% of the 166 undergoing distal pancreatectomies. Patients who developed postoperative acute pancreatitis after pancreatoduodenectomy experienced an increase in the rate of morbidity (22.7% vs 7.1%; P = .0137), including postoperative pancreatic fistula (18.6% vs 1.8%; P = .024), resulting in greater postoperative stays (21 days vs 17 days; P = .0008). Postoperative acute pancreatitis in association with an increased serum C-reactive protein ≥18.0 mg/dL (which we defined as a clinically relevant postoperative acute pancreatitis) more strongly indicated the occurrence of severe complications (P = .0032) and was an independent predictor of postoperative pancreatic fistula after pancreatoduodenectomy (odds ratio, 3.03; P = .0448). Patients who developed postoperative acute pancreatitis after distal pancreatectomy experienced similar postoperative courses regarding morbidity and the duration of postoperative stay.
Conclusion: The clinical relevance of postoperative acute pancreatitis differs after a pancreatoduodenectomy versus a distal pancreatectomy. The development of effective strategies for preventing postoperative acute pancreatitis might improve surgical outcomes after pancreatoduodenectomy.. |
| 262. |
Chika Iwamoto, Kenoki Ohuchida, Tomohiko Shinkawa, Sho Okuda, Yoshiki Otsubo, Takashi Okumura, Akiko Sagara, Kazuhiro Koikawa, Yohei Ando, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Takao Ohtsuka, Masatoshi Eto, Koichi Akashi, Masafumi Nakamura, Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression, Cancer Lett., 10.1016/j.canlet.2021.04.013, 1, 512, 15-27, 2021.04, Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.. |
| 263. |
Kinuko Nagayoshi, Shuntaro Nagai, Kyoko Hisano, Yusuke Mizuuchi, Hayato Fujita, Masafumi Nakamura, Atrophic change of the abdominal rectus muscle significantly influences the onset of parastomal hernias beyond existing risk factors after end colostomy, Hernia, 10.1007/s10029-020-02192-9, 25, 1, 141-148, 2021.04. |
| 264. |
Keigo Ozono, Hideya Onishi, Naoya Iwamoto, Katsuya Nakamura, Kei Miyoshi, Masafumi Nakamura, Yoshinao Oda, Tropomyosin-related Kinase B Is Potentially a Biomarker of Prognosis and Therapeutic Target for Malignant Thymic Epithelial Tumors, Anticancer Res, 10.21873/anticanres.15868, 42, 8, 3779-3787, 2022.04, ackground/aim: Thymic epithelial tumors (TETs) mainly consist of thymoma and thymic carcinoma. Complete surgical resection is vital for the successful management of these TETs, and adjuvant therapy such as systematic chemotherapy and/or radiotherapy plays important roles in the management of recurrent or metastasized disease. However, there is still a lack of a standard treatment after the failure of these adjuvant therapies. There is thus a need to develop molecular targeted therapies for advanced malignant TETs. In the present study, we evaluated the biological significance of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling for TETs.
Materials and methods: The expression of TrkB in 48 formalin-fixed, paraffin-embedded TET specimens (43 thymoma and 5 thymic carcinoma) collected by surgical resection was evaluated immunohistochemically. A thymic carcinoma cell line was evaluated for the role of BDNF/TrkB signaling pathway in an in vitro assay.
Results: High TrkB expression was related to significantly poor prognosis in patients with TETs. In vitro experiments showed that BDNF/TrkB signaling was involved in the proliferation of Ty-82 cells, but not their invasion and migration.
Conclusion: TrkB expression is a biomarker of the prognosis for TETs and the BDNF/TrkB signaling pathway is potentially a new therapeutic target for mTETs.
Keywords: BDNF; Thymic carcinoma; TrkB; therapeutic target; thymoma.. |
| 265. |
Hiroshi Noguchi, Yuta Matsukuma, Kaneyasu Nakagawa, Kenji Ueki, Akihiro Tsuchimoto, Toshiaki Nakano, Yu Sato, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Treatment of chronic active T cell-mediated rejection after kidney transplantation: A retrospective cohort study of 37 transplants, Nephrology, 10.1111/nep.14048, 27, 7, 632-638, 2022.04, Aim: Data on the treatment of chronic active T cell-mediated rejection (CA-TCMR) are scarce, and therapeutical strategies for CA-TCMR have not been established. We retrospectively evaluated the outcomes and effects of treatment on pathological and clinical findings in patients with CA-TCMR.
Methods: This study comprised 37 patients who underwent kidney transplantation at our institute who were diagnosed with CA-TCMR between January 2018 and December 2020. Patients were followed until October 2021.
Results: A total of 32 of the 37 patients were treated. During the observation period, two patients died (5%), and five patients developed allograft loss (13%). A univariate Cox proportional hazards model showed that indication biopsy, higher spot urine protein/creatinine ratio (UPCR) and Banff ci/ct scores were risk factors for allograft loss. Of the treated patients, 23 underwent follow-up biopsies. The Wilcoxon signed-rank test showed significant improvement in the Baff scores for "ti", "i-IFTA", "t" and "t-IFTA" after treatment. On pathology, 13 (57%) of the patients who underwent follow-up biopsy improved to "no evidence of rejection" or "borderline change." Assuming that improvement in pathology to "borderline change" or "no evidence of rejection" on follow-up biopsy indicates response to treatment, multivariate logistic analysis showed that lower UPCR was a predictive factor for response to treatment. No specific effect of treatment type was observed.
Conclusions: Our results indicate that treatment could improve the pathological findings in CA-TCMR.
Keywords: chronic active T cell-mediated rejection; kidney transplantation; treatment.. |
| 266. |
Go Wakabayashi, Daniel Cherqui, David A Geller, Mohammed Abu Hilal, Giammauro Berardi, Ruben Ciria, Yuta Abe 7, Takeshi Aoki, Horacio J Asbun, Albert C Y Chan, Rawisak Chanwat, Kuo-Hsin Chen, Yajin Chen, Tan To Cheung, David Fuks, Naoto Gotohda, Ho-Seong Han, Kiyoshi Hasegawa, Etsuro Hatano, Goro Honda, Osamu Itano, Yukio Iwashita , Hironori Kaneko, Yutaro Kato, Ji Hoon Kim, Rong Liu, Santiago López-Ben, Mamoru Morimoto, Kazuteru Monden, Fernando Rotellar, Yoshihiro Sakamoto, Atsushi Sugioka, Tomoharu Yoshiizumi, Keiichi Akahoshi, Felipe Alconchel, Shunichi Ariizumi, Andrea Benedetti Cacciaguerra, Manuel Durán 6, Alain Garcia Vazquez, Nicolas Golse, Yoshihiro Miyasaka, Yasuhisa Mori, Satoshi Ogiso, Chikara Shirata, Federico Tomassini, Takeshi Urade, Taiga Wakabayashi, Hitoe Nishino, Taizo Hibi, Norihiro Kokudo, Masayuki Ohtsuka, Daisuke Ban, Yuichi Nagakawa, Takao Ohtsuka, Minoru Tanabe, Masafumi Nakamura, Akihiko Tsuchida, Masakazu Yamamoto, The Tokyo 2020 terminology of liver anatomy and resections: Updates of the Brisbane 2000 system, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1091, 29, 1, 6-15, 2022.04, Background: The Brisbane 2000 Terminology for Liver Anatomy and Resections, based on Couinaud's segments, did not address how to identify segmental borders and anatomic territories of less than one segment. Smaller anatomic resections including segmentectomies and subsegmentectomies, have not been well defined. The advent of minimally invasive liver resection has enhanced the possibilities of more precise resection due to a magnified view and reduced bleeding, and minimally invasive anatomic liver resection (MIALR) is becoming popular gradually. Therefore, there is a need for updating the Brisbane 2000 system, including anatomic segmentectomy or less. An online "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was hosted on February 23, 2021.
Methods: The Steering Committee invited 34 international experts from around the world. The Expert Committee (EC) selected 12 questions and two future research topics in the terminology session. The EC created seven tentative definitions and five recommendations based on the experts' opinions and the literature review performed by the Research Committee. Two Delphi Rounds finalized those definitions and recommendations.
Results: This paper presents seven definitions and five recommendations regarding anatomic segmentectomy or less. In addition, two future research topics are discussed.
Conclusions: The PAM-HBP Surgery Consensus has presented the Tokyo 2020 Terminology for Liver Anatomy and Resections. The terminology has added definitions of liver anatomy and resections that were not defined in the Brisbane 2000 system.. |
| 267. |
Masaki Kaibori, Kengo Yoshii, Yuzo Umeda, Takahito Yagi, Takehiro Okabayashi, Kenta Sui, Akira Mori, Yuhei Hamaguchi, Kiyoshi Kajiyama, Daisuke Hokuto, Kazuteru Monden, Tomoharu Yoshizumi, Yoriko Nomura, Kan Toriguchi, Jong Man Kim, Gi Hong Choi, Je Ho Ryu, Yangseok Koh, Koo Jeong Kang, Young Kyoung You, Kwang-Sik Chun, Young Seok Han, Chan Woo Cho, Young Il Choi, Dong-Sik Kim, Jae Do Yang, Keita Mor, Atsushi Hiraok, Hiroki Yamaue, Masafumi Nakamura, Masakazu Yamamoto, Itaru Endo, Surgical Outcomes of Laparoscopic versus Open Hepatectomy for Left Hepatocellular Carcinoma: Propensity Score Analyses Using Retrospective Japanese and Korean Individual Patient Data, Liver Cancer, 10.1159/000527294, 12, 1, 32-43, 2022.04, Introduction: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC).
Methods: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups.
Results: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03-1.71; p = 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group.
Conclusions: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.
Keywords: Hepatocellular carcinoma; Laparoscopic left hepatectomy; Open left hepatectomy; Overall survival; Postoperative complications; Recurrence-free survival.. |
| 268. |
Tomohiko Shinkawa, Kenoki Ohuchida, Yuki Mochida, Kukiko Sakihama, Chika Iwamoto, Toshiya Abe, Noboru Ideno, Yusuke Mizuuchi, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses
, J Exp Clin Cancer Res, 10.1186/s13046-022-02301-9, 41, 89, 1-20, 2022.04, Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses.
Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared.
Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs.
Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.
Keywords: Cancer-associated fibroblast; Organoid; Statin; Stroma-targeting therapy; Subtype-based therapy; Tumor differentiation; Tumor microenvironment.. |
| 269. |
Shinichiro Kawatoko, Kenichi Kohashi, Takehiro Torisu, Taisuke Sasaki, Shinya Umekita, Eiji Oki, Masafumi Nakamura, Takanari Kitazono, Yoshinao Oda, Solid-type poorly differentiated adenocarcinoma of the stomach: A characteristic morphology reveals a distinctive immunoregulatory tumor microenvironment, Pathol Res Pract, 10.1016/j.prp.2022.154124., 15, 238, 154124, 2022.04, Abstract
Solid-type poorly differentiated adenocarcinoma (solid-type-PDA) of the stomach is a unique histological subtype of "tubular adenocarcinoma", but little is known about its clinicopathological features, molecular pathological characteristics and immunoregulatory tumor microenvironment. Herein, we examined the immunohistochemical expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) in 57 cases of solid-type-PDA and classified them as either MMR-deficient or -proficient (dMMR, N = 23; pMMR, N = 34), and additionally identified 18 dMMR-well-differentiated adenocarcinoma (WDA) and 34 pMMR-WDA as control groups. We analyzed and compared solid-type-PDA with WDA by evaluating the immunoexpressions of key immune pathway proteins (programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1)) and tumor-infiltrating lymphocytes (TILs) (CD8, Foxp3 and PD-1). The results reveled IDO1 was significantly more frequent in dMMR-solid-type-PDA than in dMMR-WDA (P = 0.0046). Moreover, dMMR-solid-type-PDA tended to have higher mean CD8+ and Foxp3+ TILs compared with dMMR-WDA [P = 0.0006 (CD8+) and P = 0.1061 (Foxp3+)], and IDO1-positive tended to be associated with a large number of CD8+, Foxp3+ or PD-1+ TILs in almost all tumor subtypes. PD-L1 was significantly observed in 44 % (15/34) of pMMR-solid-type-PDA compared with 18 % (6/34) of pMMR-WDA (P = 0.0344). Although they are molecularly and morphologically classified as the same chromosomal instability subtype, overall survival (OS) and disease-free-survival (DFS) in pMMR-solid-type-PDA were significantly worse than those in pMMR-WDA [P = 0.0216 (OS) and P = 0.0160 (DFS)]. Our study demonstrates that immunoexpressions of several immunoregulatory proteins and TILs are more prevalent in dMMR-solid-type-PDA, potentially a useful discovery for designing tumor treatments with immune checkpoint inhibitors or combination therapies with a PD-1/PD-L1-inhibitor and IDO1-inhibitor.
Keywords: IDO1; Mismatch repair; PD-L1; Solid-type poorly differentiated adenocarcinoma.. |
| 270. |
Saori Hayashi, Makoto Kubo, Sawako Matsuzaki, Masaya Kai, Takafumi Morisaki, Mai Yamada, Kazuhisa Kaneshiro, Yuka Takao, Akiko Shimazaki, Kinuko Nagayoshi, Yusuke Mizuuchi, Masafumi Nakamura, Significance of the Multi-gene Panel myRisk in Japan, Anticancer Research , org/10.21873/anticanres.15907, 42, 8, 4097-4102, 2022.04. |
| 271. |
Kukiko Sakihama, Yutaka Koga, Takeo Yamamoto, Yuki Shimada, Yutaka Yamada, Jun Kawata, Koji Shindo, Masafumi Nakamura, Yoshinao Oda, RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm, Virchows Archiv, 10.1007/s00428-022-03277-9, 480, 1, 1189-1199, 2022.04, Abstract
Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.
Keywords: KRAS; Mucinous cystic neoplasm; Pancreas; RNF43.. |
| 272. |
Tatsuya Manabe, Yusuke Mizuuchi, Yasuhiro Tsuru, Hiroshi Kitagawa, Takaaki Fujimoto, Yasuo Koga, Masafumi Nakamura, Hirokazu Noshiro, Retrospective analysis of risk factors for postoperative perineal hernia after endoscopic abdominoperineal excision for rectal cancer, BMC Surg, 10.1186/s12893-022-01538-7, 22, 1, 88, 2022.04, Background: In contrast to open-surgery abdominoperineal excision (APE) for rectal cancer, postoperative perineal hernia (PPH) is reported to increase after extralevator APE and endoscopic surgery. In this study, therefore, we aimed to determine the risk factors for PPH after endoscopic APE.
Methods: A total 73 patients who underwent endoscopic APE for rectal cancer were collected from January 2009 to March 2020, and the risk factors for PPH were analyzed retrospectively.
Results: Nineteen patients (26%) developed PPH after endoscopic APE, and the diagnosis of PPH was made at 9-393 days (median: 183 days) after initial surgery. Logistic regression analysis showed that absence of pelvic peritoneal closure alone increased the incidence of PPH significantly (odds ratio; 13.76, 95% confidence interval; 1.48-1884.84, p = 0.004).
Conclusions: This preliminary study showed that pelvic peritoneal closure could prevent PPH after endoscopic APE.
Keywords: Endoscopic abdominoperineal excision; Postoperative perineal hernia; Rectal cancer.. |
| 273. |
Yumiko Kinoshita, Rieko Izukura, Junji Kishimoto, Maki Kanaoka, Hayato Fujita, Koji Ando, Shuntaro Nagai, Sayuri Akiyoshi, Tetsuzo Tagawa, Makoto Kubo, Junichi Inokuchi, Kenoki Ohuchida, Eiji Oki, Kentaro Tanaka, Masatoshi Eto, Tomoharu Yoshizumi, Masafumi Nakamura, Akiko Chishaki, Reliability, validity, and responsiveness of the Japanese version of the EORTC QLQ-ELD14 in evaluating the health-related quality of life of elderly patients with cancer, J Cancer Res Clin Oncol, 10.1007/s00432-022-04414-2, 28, 1-16, 2022.04, Purpose: This study evaluated the reliability, validity, and responsiveness of the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-ELD14 and measured the health-related quality of life (HRQOL) of elderly Japanese patients with cancer aged ≥ 60 and ≥ 70 years.
Methods: The study recruited elderly Japanese patients with cancer aged ≥ 60 (≥ 70) years (n = 1803 [n = 1236]). The EORTC QLQ-ELD14 was evaluated for reliability, validity, responsiveness, and correlations of changes in score between the EORTC QLQ-ELD14 and the EORTC QLQ-C30 before and after the commencement of the COVID-19 pandemic.
Results: In both age groups, the proportion of missing items was low ( 0.2) after the commencement of the COVID-19 pandemic. The changes in score between the EORTC QLQ-ELD14 and the "global health status/QOL" and "summary score" of the EORTC QLQ-C30 had moderate-to-high negative correlations for all items, except two. Hypotheses to evaluate construct validity were accepted at 90%, while responsiveness was accepted at 80%.
Conclusion: The Japanese version of the EORTC QLQ-ELD14 questionnaire appears to have acceptable reliability, validity, and responsiveness to evaluate HRQOL in elderly Japanese people with cancer.
Keywords: Aged; COVID-19 pandemic; Japanese; Neoplasms; Quality of life; Validation study.. |
| 274. |
Masatoshi Murakami, Nao Fujimori, Akihisa Ohno, Kazuhide Matsumoto, Katsuhito Teramatsu, Yu Takamatsu, Ayumu Takeno, Takamasa Oono, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Kousei Ishigami, Yoshihiro Ogawa, Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study, Discover Oncology, 10.1007/s12672-021-00462-1, 13, 1, 2022.04, Abstract
Background/aims: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases.
Methods: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed.
Results: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion.
Conclusions: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.
Keywords: Neoadjuvant chemotherapy; Operability; Pancreatic cancer; Pancreatic neoplasms; Recurrence.. |
| 275. |
Shinichiro Ono, Tomohiko Adachi, Takao Ohtsuka, Ryuichiro Kimura, Kazuyoshi Nishihara, Yusuke Watanabe, Hiroaki Nagano, Yukio Tokumitsu, Atsushi Nanashima, Naoya Imamura, Hideo Baba, Akira Chikamoto, Masafumi Inomata, Teijiro Hirashita, Masayuki Furukawa, Tetsuya Idichi, Hiroyuki Shinchi, Yuichiro Maruyama, Masafumi Nakamura, Susumu Eguchi, Predictive factors for early recurrence after pancreaticoduodenectomy in patients with resectable pancreatic head cancer: A multicenter retrospective study, surgery, 10.1016/j.surg.2022.08.004, 172, 6, 1782-1790, 2022.04, Background: Patients diagnosed with resectable pancreatic ductal adenocarcinoma often experience early recurrence even after upfront R0 resection. This study aimed to define early recurrence and identify preoperative risk factors for early recurrence after upfront pancreaticoduodenectomy in patients with resectable pancreatic ductal adenocarcinoma of the pancreatic head.
Methods: This multicenter, retrospective study involved 500 patients who underwent pancreaticoduodenectomy resectable pancreatic ductal adenocarcinoma of the pancreatic head at 10 institutions between 2007 and 2016. Preoperative, intraoperative, and postoperative clinicopathological results were compared between early and non-early recurrence groups. Predictors of early recurrence were determined using statistical analyses.
Results: Log-rank tests revealed a significant difference (P Conclusion: The optimal period that defines the early recurrence for resectable pancreatic ductal adenocarcinoma of the pancreatic head is 6 months. Tumor size ≥20 mm, preoperative carbohydrate antigen 19-9 levels ≥120 U/mL, retroperitoneal invasion of the tumor, and the presence of diabetes mellitus are independently associated with early recurrence.. |
| 276. |
Kyoko Yamaguchi, Tomoyasu Yoshihiro, Hiroshi Ariyama, Mamoru Ito, Michitaka Nakano, Yuichiro Semba, Jumpei Nogami, Kenji Tsuchihashi, Takuji Yamauchi, Shohei Ueno, Taichi Isobe, Koji Shindo, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Yoshihiro Nagao, Tetsuo Ikeda, Makoto Hashizume, Hiroyuki Konomi, Takehiro Torisu, Takanari Kitazono, Tomohiro Kanayama, Hiroyuki Tomita, Yoshinao Oda, Hitoshi Kusaba, Takahiro Maeda, Koichi Akashi, Eishi Baba, Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model, Gastric Cancer, 10.1007/s10120-022-01307-8, 25, 5, 862-878, 2022.04, Background: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development.
Methods: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO).
Results: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area.
Conclusions: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
Keywords: CDH1; CXCR4; Gastric cancer; Matrix metalloproteinase; Signet ring carcinoma.. |
| 277. |
Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Testuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui, Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity, Biochem Biophys Res Commun, 10.1016/j.bbrc.2022.04.035, 2022.04. |
| 278. |
Yasuhiro Okabe, Hiroshi Noguchi, Yu Sato, Takanori Mei, Keizo Kaku, Kenji Ueki, Akihiro Tsuchimoto, Masafumi Nakamura, Outcomes of Everolimus Plus Standard-Dose Tacrolimus Immunosuppression in De Novo Kidney Transplant: A Retrospective, Single-Center Study of 225 Transplants, Experimental and Clinical Transplantation, 10.6002/ect.2022.0028, 20, 4, 362-369, 2022.04, Objectives: In this study, our aim was to compare the outcomes of everolimus versus mycophenolate mofetil plus standard-dose tacrolimus immunosuppression in patients who received de novo kidney transplant at our center in Fukuoka, Japan.
Materials and methods: In this retrospective, observational, single-center, inverse probability of treatment weighting analysis study, 225 recipients who underwent kidney transplant at our center between January 2013 and December 2018 were included. The variables considered were recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of end-stage renal disease, donor age/sex, and number of HLA mismatches.
Results: Our analyses included 85 transplant recipients in the everolimus group and 141 transplant recipients in the mycophenolate mofetil group (n = 226 overall). There were no significant differences between the groups at 1 year for incidence of patient death and allograft loss, biopsy-proven acute rejection, BK virus-associated nephropathy, surgical complications, delayed graft function, and posttransplant diabetes mellitus. Incidence of cytomegalovirus infection and estimated glomerular filtration rate were significantly lower in the everolimus group than in the mycophenolate mofetil group. Posttransplant triglyceride and low-density lipoprotein were higher in the everolimus group than in the mycophenolate mofetil group. Multivariate ordered logistic analysis showed that older donor age and an acute rejection episode, but not induction with everolimus or mean tacrolimus trough concentration throughoutthe firstpostoperative year,were significant risk factors for severity of interstitial fibrosis/tubular atrophy at the 1-year protocol biopsy (P = .004 and P Conclusions: Short-term outcomes with everolimus plus standard-dose tacrolimus in recipients of de novo kidney transplant were comparable to those with mycophenolate mofetil plus standard-dose tacrolimus.. |
| 279. |
Mamoru Morimoto, Kazuteru Monden, Taiga Wakabayashi, Naoto Gotohda, Yuta Abe, Goro Honda, Mohammed Abu Hilal, Takeshi Aoki, Horacio J Asbun, Giammauro Berardi, Albert C Y Chan, Rawisak Chanwat, Kuo-Hsin Chen, Yajin Chen, Daniel Cherqui, Tan To Cheung, Ruben Ciria, David Fuks, David A Geller, Ho-Seong Han, Kiyoshi Hasegawa, Etsuro Hatano, Osamu Itano, Yukio Iwashita, Hironori Kaneko, Yutaro Kato, Ji Hoon Kim, Rong Liu, Santiago López-Ben, Fernando Rotellar, Yoshihiro Sakamoto, Atsushi Sugioka, Tomoharu Yoshizumi, Keiichi Akahoshi, Felipe Alconchel, Shunichi Ariizumi, Andrea Benedetti Cacciaguerra, Manuel Durán, Alain García Vázquez, Nicolas Golse, Yoshihiro Miyasaka, Yasuhisa Mori, Satoshi Ogiso, Chikara Shirata, Federico Tomassini, Takeshi Urade, Hitoe Nishino, Filipe Kunzler, Shingo Kozono, Hiroaki Osakabe, Chie Takishita, Daisuke Ban, Taizo Hibi, Norihiro Kokudo, Masayuki Ohtsuka, Yuichi Nagakawa, Takao Ohtsuka, Minoru Tanabe, Masafumi Nakamura, Masakazu Yamamoto, Akihiko Tsuchida, Go Wakabayashi, Minimally invasive anatomic liver resection: Results of a survey of world experts, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1094, 29, 1, 33-40
, 2022.04, Abstract
Background: Although the number of minimally invasive liver resections (MILRs) has been steadily increasing in many institutions, minimally invasive anatomic liver resection (MIALR) remains a complicated procedure that has not been standardized. We present the results of a survey among expert liver surgeons as a benchmark for standardizing MIALR.
Method: We administered this survey to 34 expert liver surgeons who routinely perform MIALR. The survey contained questions on personal experience with liver resection, inflow/outflow control methods, and identification techniques of intersegmental/sectional planes (IPs).
Results: All 34 participants completed the survey; 24 experts (70%) had more than 11 years of experience with MILR, and over 80% of experts had performed over 100 open resections and MILRs each. Regarding the methods used for laparoscopic or robotic anatomic resection, the Glissonean approach (GA) was a more frequent procedure than the hilar approach (HA). Although hepatic veins were considered essential landmarks, the exposure methods varied. The top three techniques that the experts recommended for identifying IPs were creating a demarcation line, indocyanine green negative staining method, and intraoperative ultrasound.
Conclusion: Minimally invasive anatomic liver resection remains a challenging procedure; however, a certain degree of consensus exists among expert liver surgeons.
Keywords: Glissonean approach; hepatic vein; liver anatomy; minimally invasive anatomic liver resection; segmentectomy.. |
| 280. |
Yuichi Nagakawa, Kohei Nakata, Hitoe Nishino, Takao Ohtsuka, Daisuke Ban, Horacio J Asbun, Ugo Boggi, Jin He, Michael L Kendrick, Chinnusamy Palanivelu, Rong Liu, Shin-E Wang, Chung-Ngai Tang, Kyoichi Takaori, Mohammed Abu Hilal, Brian K P Goh, Goro Honda, Jin-Young Jang, Chang Moo Kang, David A Kooby, Yoshiharu Nakamura, Shailesh V Shrikhande, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Yusuke Watanabe, Shingo Kozono, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Aya Maekawa, Yoshiki Murase, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Chie Takishita, Hiroaki Osakabe, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International expert consensus on precision anatomy for minimally invasive pancreatoduodenectomy: PAM-HBP surgery project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1081, 29, 1, 124-135, 2022.04, Abstract
Background: The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD.
Methods: Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection.
Conclusions: MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.
Keywords: consensus; minimally invasive surgical procedures; pancreatoduodenectomy; robotic surgery; superior mesenteric artery.. |
| 281. |
Daisuke Ban, Hitoe Nishino, Takao Ohtsuka, Yuichi Nagakawa, Mohammed Abu Hilal, Horacio J Asbun, Ugo Boggi, Brian K P Goh, Jin He, Goro Honda, Jin-Young Jan, Chang Moo Kang, Michael L Kendrick, David A Kooby, Rong Liu, Yoshiharu Nakamura, Kohei Nakata, Chinnusamy Palanivelu, Shailesh V Shrikhande, Kyoichi Takaori, Chung-Ngai Tang, Shin-E Wan, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Shingo Kozono, Aya Maekawa, Yoshiki Murase, Yusuke Watanabe, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Hiroaki Osakabe, Chie Takishita, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International Expert Consensus on Precision Anatomy for minimally invasive distal pancreatectomy: PAM-HBP Surgery Project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1071, 29, 1, 161-173, 2022.04, Background: Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021).
Methods: Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts.. |
| 282. |
Hirona Taira, Hiroshi Noguchi, Kenji Ueki, Keizo Kaku, Akihiro Tsuchimoto, Yasuhiro Okabe, Yusuke Ohya, Masafumi Nakamura, Initiation of dialysis for kidney graft failure: a retrospective single-center cohort study, Therapeutic Apheresis and Dialysis, 10.1111/1744-9987.13756, 26, 4, 806-814
, 2022.04. |
| 283. |
Tsubasa Sakurai, Sachiko Kamakura, Junya Hayase, Akira Kohda, Masafumi Nakamura, Hideki Sumimoto, GPR125 (ADGRA3) is an autocleavable adhesion GPCR that traffics with Dlg1 to the basolateral membrane and regulates epithelial apicobasal polarity, J Biol Chem, 10.1016/j.jbc.2022.102475, 298, 10, 102475, 2022.04, he adhesion family of G protein-coupled receptors (GPCRs) is defined by an N-terminal large extracellular region that contains various adhesion-related domains and a highly-conserved GPCR-autoproteolysis-inducing (GAIN) domain, the latter of which is located immediately before a canonical seven-transmembrane domain. These receptors are expressed widely and involved in various functions including development, angiogenesis, synapse formation, and tumorigenesis. GPR125 (ADGRA3), an orphan adhesion GPCR, has been shown to modulate planar cell polarity in gastrulating zebrafish, but its biochemical properties and role in mammalian cells have remained largely unknown. Here, we show that human GPR125 likely undergoes cis-autoproteolysis when expressed in canine kidney epithelial MDCK cells and human embryonic kidney HEK293 cells. The cleavage appears to occur at an atypical GPCR proteolysis site within the GAIN domain during an early stage of receptor biosynthesis. The products, i.e., the N-terminal and C-terminal fragments, seem to remain associated after self-proteolysis, as observed in other adhesion GPCRs. Furthermore, in polarized MDCK cells, GPR125 is exclusively recruited to the basolateral domain of the plasma membrane. The recruitment likely requires the C-terminal PDZ-domain-binding motif of GPR125 and its interaction with the cell polarity protein Dlg1. Knockdown of GPR125 as well as that of Dlg1 results in formation of aberrant cysts with multiple lumens in Matrigel 3D culture of MDCK cells. Consistent with the multilumen phenotype, mitotic spindles are incorrectly oriented during cystogenesis in GPR125-KO MDCK cells. Thus, the basolateral protein GPR125, an autocleavable adhesion GPCR, appears to play a crucial role in apicobasal polarization in epithelial cells.
Keywords: ADGRA3; Dlg1; GAIN domain; GPR125; GPS motif; adhesion GPCR; autoproteolysis; cystogenesis; epithelial cell polarity; spindle orientation.. |
| 284. |
Saori Hayashi, Makoto Kubo, Kazuhisa Kaneshiro, Masaya Kai, Mai Yamada, Takafumi Morisaki, Yuka Takao, Akiko Shimazaki, Sawako Shikada, Masafumi Nakamura, Genetic medicine is accelerating in Japan, Breast cancer , 10.1007/s12282-022-01342-4, 29, 4, 659-665, 2022.04. |
| 285. |
Hiroshi Noguchi, Kei Nishiyama, Keizo Kaku, Yasuhiro Okabe, Masafumi Nakamura, Factors Associated With Height Among Pediatric Kidney Transplant Recipients Aged ≤ 16 Years: A Retrospective, Single-Center Cohort Study of 60 Transplants, Experimental and Clinical Transplantation, 10.6002/ect.2021.0311, 20, 1, 35-41, 2022.04, Objectives: The aim of this study was to describe the factors associated with growth before and after kidney transplant. Materials and Methods: We retrospectively reviewed 60 pediatric patients with end-stage kidney disease aged ?16 years who underwent kidney transplant at our facility between November 2001 and March 2018. Height standard deviation score and possible associated factors were also compared. Results: Among the 60 patients, median age was 11 years (interquartile range, 5.3-14 years), and 24 (40%) were female. All patients were alive during the observational period. The 2-, 5-, and 15-year graft survival rates were 96.7%, 94.4%, and 77.8%, respectively. Mean height standard deviation score for preoperative kidney transplant was -2.1 ± 1.5. Duration of dialysis (months) was associated with preoperative height standard deviation score (β = -0.020; standard error = 0.006; t = -3.23; P = .002). Higher ag
e and episode of rejection were significant factors for loss of catch-up growth (P < .001 and P = .023, respectively). In total, 26 patients (43.3%) and 19 patients (31.7%) had short stature preoperatively and at 2 years after kidney transplant, respectively. Although 23 patients (38.3%) presented with catch-up growth after kidney transplant, 14 (53.9%) remained with short stature even 2 years after kidney transplant. Height standard deviation score 2 years after kidney transplant was associated with age, preoperative height standard deviation score, and episodes of rejection (P = .032, P < .001, and P = .005, respectively).. |
| 286. |
Yusuke Watanabe, Kohei Nakata, Yasuhisa Mori, Noboru Ideno, Naoki Ikenaga, Takao Ohtsuka, Masafumi Nakamura, Extensive (subtotal) distal pancreatectomy for pancreatic ductal adenocarcinoma: a propensity score matched cohort study of short- and long-term outcomes compared with those of conventional distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-022-02453-4, 407, 4, 1479-1488, 2022.04, Abstract
Purpose: Extensive distal pancreatectomy (ExDP) can transect the pancreatic parenchyma more from the right side than conventional distal pancreatectomy (CDP) can. This study aimed to evaluate the short- and long-term outcomes of ExDP for pancreatic ductal adenocarcinoma (PDAC) of the pancreatic body, located adjacent to the portal vein (PV).
Methods: Medical records of 98 patients who underwent ExDP (n = 15) or CDP (n = 83) for PDAC were retrospectively reviewed. Short- and long-term outcomes of the two groups were compared. Propensity score matched analysis was additionally performed to minimize the impact of treatment allocation bias.
Results: In the total cohort, the CDP group had a significantly higher proportion of pancreatic tail lesions (P Conclusions: Surgical and oncological outcomes after ExDP for PDAC were acceptable and comparable to those after CDP. ExDP is a feasible procedure, and could be an option for the treatment of PDAC of the pancreatic body near PV.
Keywords: Distal pancreatectomy; Extensive distal pancreatectomy; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Subtotal distal pancreatectomy.. |
| 287. |
Naoto Gotohda, Daniel Cherqui, David A Geller, Mohammed Abu Hilal, Giammauro Berardi, Ruben Ciria, Yuta Abe, Takeshi Aoki, Horacio J Asbun, Albert C Y Chan, Rawisak Chanwat, Kuo-Hsin Chen, Yajin Chen, Tan To Cheung, David Fuks, Ho-Seong Han, Kiyoshi Hasegawa, Etsuro Hatano, Goro Honda, Osamu Itano, Yukio Iwashita, Hironori Kaneko, Yutaro Kato, Ji Hoon Kim, Rong Liu, Santiago López-Ben, Mamoru Morimoto, Kazuteru Monden, Fernando Rotellar, Yoshihiro Sakamoto, Atsushi Sugioka, Tomoharu Yoshiizumi, Keiichi Akahoshi, Felipe Alconchel, Shunichi Ariizumi, Andrea Benedetti Cacciaguerra, Manuel Durán, Alain Garcia Vazquez, Nicolas Golse, Yoshihiro Miyasaka, Yasuhisa Mori, Satoshi Ogiso, Chikara Shirata, Federico Tomassini, Takeshi Urade, Taiga Wakabayashi, Hitoe Nishino, Taizo Hibi, Norihiro Kokudo, Masayuki Ohtsuka, Daisuke Ban, Yuichi Nagakawa, Takao Ohtsuka, Minoru Tanabe, Masafumi Nakamura, Masakazu Yamamoto, Akihiko Tsuchida, Go Wakabayashi, Expert Consensus Guidelines: How to safely perform minimally invasive anatomic liver resection, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1079, 29, 1, 16-32, 2022.04, Background: The concept of minimally invasive anatomic liver resection (MIALR) is gaining popularity. However, specific technical skills need to be acquired to safely perform MIALR. The "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was developed as a special program during the 32nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS).
Methods: Thirty-four international experts gathered online for the consensus. A Research Committee performed a comprehensive literature review, classifying studies according to the Scottish Intercollegiate Guidelines Network method. Based on the literature review and experts' opinions, tentative recommendations were drafted and circulated among experts using online Delphi Rounds. Finally, formulated recommendations were presented online in the Expert Consensus Meeting of the JSHBPS on February 23rd, 2021. The final recommendations were validated and finalized by the 2nd Delphi Round in May 2021.
Results: Seven clinical questions were selected, and 22 recommendations were formulated. All recommendations reached more than 85% consensus among experts at the final Delphi Round.
Conclusions: The Expert Consensus Meeting for safely performing MIALR has presented a set of clinical guidelines based on available literature and experts' opinions. We expect these guidelines to have a favorable effect on the safe implementation and development of MIALR.
Keywords: anatomic landmark; anatomic liver resection; laparoscopic liver resection; minimally invasive liver surgery; non-anatomic liver resection.. |
| 288. |
Weiyu Guan, Kohei Nakata, Akiko Sagara, Chika Iwamoto, Sho Endo, Ryota Matsuda, Sokichi Matsumoto, Naoki Ikenaga, Koji Shindo, Taiki Moriyama, Hideya Onishi, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway, Pancreatology, 10.1016/j.pan.2021.09.012, 22, 1, 9-19, 2022.04, Abstract
Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation.
Methods: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models.
Results: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown.
Conclusions: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.
Keywords: Endoplasmic reticulum stress; Stromal remodeling; Tumor-stromal interaction; Tunicamycin.. |
| 289. |
Keizo Kaku, Yasuhiro Okabe, Yu Sato, Takanori Mei, Hiroshi Noguchi, Masafumi Nakamura, Efficacy of Linear Stapler With Polyglycolic Acid Felt for Preventing Graft Duodenal Perforation After Pancreas Transplant, Exp Clin Transplant, 10.6002/ect.2022.0126, 20, 6, 595-601, 2022.04, Objectives: Graft duodenal perforation is a serious complication in pancreas transplantation. The aim of this study was to evaluate whether using a reinforced linear stapler during bench surgery in pancreas transplant affects the risk of graft duodenal perforation.
Materials and methods: This retrospective study included 47 patients who underwent pancreas transplant at our institution from 2011 to 2020. A reinforced stapler with polyglycolic acid felt was used to dissect the graft duodenum during bench surgery in 16 of the 47 patients (reinforced group). A conventional linear stapler was used in the remaining 31 patients (conventional group). Demographic, perioperative, and postoperative parameters were compared between the reinforced group and the conventional group.
Results: Graft duodenal perforation occurred in 6 patients (19.4%) in the conventional group and in none of the patients in the reinforced group. Logistic regression analysis revealed no significant associations between donor- orrecipient-related factors and graft duodenal perforation. Among operative factors, use of a reinforced stapler was the only factor significantly associated with the risk of graft duodenal perforation (odds ratio = 0.12).
Conclusions: The use of a reinforced stapler during dissection of the duodenum in bench surgery for pancreas transplant was associated with a lower risk of graft duodenal perforation than use of a conventional stapler.. |
| 290. |
Yasuhisa Mori, Kohei Nakata, Noboru Ideno, Naoki Ikenaga, Yasuhiro Okabe, Masafumi Nakamura, Efficacy of Distal Pancreatectomy Combined With Modified DuVal Procedure in Patients With a High Risk of Postoperative Pancreatic Fistula, The American Surgeon, 10.1177/0003134821995088, 88, 6, 1244-1249, 2022.04, Abstract
Background: The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. The present study aimed to clarify the efficacy of our modified DuVal (mDuVal) pancreatojejunostomy following DP in patients with a high risk of POPF.
Methods: The medical records of 346 consecutive patients who underwent DP between 2006 and 2016 were retrospectively reviewed. Perioperative features were compared between 24 patients undergoing mDuVal (mDuVal group) and 322 patients undergoing standard DP (standard DP group).
Results: Preoperative American Society of Anesthesiologists physical status 1 was more frequent in the standard group than in the mDuVal group (P = .02). The start of a solid diet after operation was significantly earlier in the mDuVal group than in the standard DP group (P = .01), while there were no significant differences between the groups for clinically relevant POPF, amylase concentration in the drainage fluid on postoperative day 1 and days 3-5, time to drain removal, additional intervention for POPF, overall complications, or postoperative hospital stay.
Discussion: The mDuVal procedure could be an option for patients with a high risk of POPF to improve the outcomes after DP. Further investigation involving large study populations is necessary to clarify the efficacy of this procedure.
Keywords: pancreatectomy; pancreatic fistula; postoperative complications.. |
| 291. |
Keizo Kaku, Yasuhiro Okabe, Yu Sato, Yu Hisadome, Takanori Mei, Hiroshi Noguchi, Masafumi Nakamura, Effective Technique for Pancreas Transplantation by Iliac Vascular Transposition, Without Heparin-Based Anticoagulation Therapy, World J Surg, 10.1007/s00268-021-06232-y, 46, 1, 215-222, 2022.04, Background: To evaluate patients undergoing a new procedure, iliac vascular transposition, in pancreas transplantation regarding the risk of thrombosis and graft survival without heparin-based anticoagulation therapy.
Methods: Iliac vascular transposition (IVT) involves changing the positions of the external iliac artery and vein relative to each other. In this study, this technique was evaluated in patients undergoing the procedure compared with patients not undergoing the procedure (iliac vascular parallel (IVP) group).
Results: No patients received prophylactic heparin therapy. Two patients in the IVP group (n = 26) developed complete thrombosis and six developed partial thrombosis, compared with no patients with complete thrombosis and one with partial thrombosis in the IVT group (n = 29). The cumulative incidence of thrombosis was significantly higher in the IVP group (p Conclusions: IVT in pancreas transplantation is a simple technique that results in a lower thrombosis risk and better graft survival rates without heparin-based anticoagulation therapy.. |
| 292. |
Kazuhisa Kaneshiro, Makoto Kubo, Masahiko Taniguchi, Mai Yamada, Yoshihiko Sadakari, Masaya Kai, Chiyo Tsutsumi, Tatsuo Tsukamoto, Naohiro Yoshida, Masaya Tanaka, Toshiro Ogata, Masafumi Nakamura, Current Status and Problems of Breast Cancer Treatment with Schizophrenia, Clin Breast Cancer, 10.1016/j.clbc.2021.10.006, 22
, 4
, e399-e406
, 2022.04, Abstract
Background
Schizophrenia is a devastating mental disease that affects approximately 1% of the world's population. Breast cancer is the second most common type of cancer in the world that causes death in women. It is often unclear whether patients with schizophrenia receive recommended cancer treatment that met the guideline. This study characterized breast cancer treatment disruptions in schizophrenia patients and sought to identify and resolve correctable predictors of those disruptions.
Materials and methods
A retrospective cohort study was conducted on 55 primary breast cancer patients diagnosed with schizophrenia and treated for breast cancer. We evaluated the characteristics of the breast cancer patients with schizophrenia compared to those of 610 breast cancer patients without schizophrenia.
Results
Compared to the control group, the schizophrenia group had significantly advanced T and N factors and disease stage. Significantly fewer patients in the schizophrenia group than in the control group received chemotherapy (P < .0001) or recommended cancer treatment (P = .0004). Within the schizophrenia group, the patients in need of ADL support were significantly less likely to receive recommended cancer treatment.
Conclusion
Patients with schizophrenia are often diagnosed with breast cancer in advanced stages. In addition, patients with schizophrenia with reduced ADL are less likely to receive chemotherapy or recommended cancer treatment. It is highly recommended that patients with schizophrenia undergo breast cancer screening so that they can be diagnosed early and treated adequately.. |
| 293. |
Yusuke Mizuuchi, Yoshitaka Tanabe, Masafumi Sada, Koji Tamura, Kinuko Nagayoshi, Shuntaro Nagai, Yusuke Watanabe, Sadafumi Tamiya, Kohei Nakata, Kenoki Ohuchida, Toru Nakano, Masafumi Nakamura, Cross-sectional area of psoas muscle as a predictive marker of anastomotic failure in male rectal cancer patients: Japanese single institutional retrospective observational study, Annals of Coloproctology, 10.3393/ac.2022.00122.0017, 38, 5, 353-361, 2022.04, Purpose: Preoperative sarcopenia worsens postoperative outcomes in various cancer types including colorectal cancer. However, we often experienced postoperative anastomotic leakage in muscular male patients such as Judo players, especially in rectal cancer surgery with lower anastomosis. It is controversial whether the whole skeletal muscle mass impacts the potential for anastomotic failure in male rectal cancer patients. Thus, the purpose of this study was to clarify whether skeletal muscle mass impacts anastomotic leakage in rectal cancer in men.
Methods: We reviewed the medical charts of male patients suffering from rectal cancer who underwent colo-procto anastomosis below the peritoneal reflection without a protective diverting stoma. We measured the psoas muscle area and calculated the psoas muscle index.
Results: One hundred ninety-seven male rectal cancer patients were enrolled in this study. The psoas muscle index was significantly higher in patients with anastomotic leakage (P<0.001). Receiver operating characteristic curve determined the optimal cut-off value of the psoas muscle index for predicting anastomotic leakage as 812.67 cm2/m2 (sensitivity of 60% and specificity of 74.3%). Multivariate analysis revealed that high psoas muscle index (risk ratio [RR], 3.933; P<0.001; 95% confidence interval [CI], 1.917-8.070) and super low anastomosis (RR, 2.792; P=0.015; 95% CI, 1.221-6.384) were independent predictive factors of anastomotic leakage.
Conclusion: This study showed that male rectal cancer patients with a large psoas muscle mass who underwent lower anastomosis had a higher rate of postoperative anastomotic leakage.
Keywords: Anastomotic leak; Lower colo-anorectal anastomosis; Psoas muscle index; ROC curve; Rectal neoplasms.. |
| 294. |
Kohei Nakata, Hiroyuki Yamamoto, Hiroaki Miyata, Yoshihiro Kakeji, Yuko Kitagawa, Masafumi Nakamura, Comparison of outcomes between laparoscopic and open pancreaticoduodenectomy without radical lymphadenectomy: Results of coarsened exact matching analysis using national database systems, Asian J Endosc Surg, 10.1111/ases.12948, 15, 1, 15-21
, 2022.04, Abstract
Introduction: Laparoscopic pancreaticoduodenectomy has recently been covered under Japan's insurance system for patients not requiring lymph node dissection. Only high-volume hospitals that meet specific criteria are permitted to perform laparoscopic pancreaticoduodenectomy. Although open and laparoscopic pancreaticoduodenectomy outcomes with lymph node dissection have been described previously, procedures performed without lymph node dissection have not been compared using a nationwide database. This study aimed to review the results of laparoscopic pancreaticoduodenectomy and compare them to those of open pancreaticoduodenectomy (OPD) using records from a nationwide database.
Methods: We collected patient demographic and medical data of 2900 patients who underwent pancreaticoduodenectomy (laparoscopic, n = 162; open, n = 2738) without lymph node dissection between 2016 and 2018 from the National Clinical Database in Japan. Coarsened exact matching was used to match patients in the laparoscopic and open pancreaticoduodenectomy groups.
Results: In-hospital mortality was not observed in the laparoscopic pancreaticoduodenectomy group. The rate of conversion to an open procedure was 6.8% (11 cases). After 1:1 matching, we obtained 141 pairs of patients for comparison. The mortality rate was comparable in the laparoscopic and open pancreaticoduodenectomy groups (0.0% vs 0.7%, respectively; P = 1.00). The laparoscopic approach showed more favorable results in terms of median blood loss. Postoperative pancreatic fistula formation and complications were comparable between the two groups.
Conclusions: Our results indicate that laparoscopic pancreaticoduodenectomy could be introduced successfully, and the outcomes achieved by the institutions included in our study were comparable to those of open pancreaticoduodenectomy.
Keywords: laparoscopic pancreaticoduodenectomy; mortality; registries.. |
| 295. |
Naoki Ikenaga, Kohei Nakata, Nobuhiro Fujita, Toshiya Abe, Noboru Ideno, Kousei Ishigami, Masafumi Nakamura, Clinical significance of postpancreatectomy acute pancreatitis defined by the International Study Group for Pancreatic Surgery, Ann Gastroenterol Surg, 10.1002/ags3.12587, 6, 6, 842-850, 2022.04. |
| 296. |
Sho Okuda, Kenoki Ohuchida, Koji Shindo, Taiki Moriyama, Jun Kawata, Koji Tamura, Masafumi Sada, Kinuko Nagayoshi, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Clinical impact of remnant lymphatic invasion on the recurrence of esophageal squamous cell carcinoma after esophagectomy with neoadjuvant chemotherapy, Oncol Lett, 10.3892/ol.2022.13457, 24, 4, 337, 2022.04, For stage II and III esophageal squamous cell carcinoma (ESCC), neoadjuvant chemotherapy (NAC) followed by esophagectomy is recommended in the Japanese guidelines for the diagnosis and treatment of esophageal cancer. However, recurrence of ESCC is common regardless of the NAC regimen and surgical method, and NAC demonstrates limited efficacy against recurrence. Therefore, the present study was conducted to identify risk factors of recurrence of ESCC with surgery after NAC. The outcomes of 51 patients who underwent esophagectomy for ESCC after NAC from 2010 to 2017 at Kyushu University Hospital were retrospectively analyzed. A total of 52 patients with ESCC without NAC followed by esophagectomy from 2001 to 2017 were selected for comparison. Among patients who underwent NAC followed by surgery, only lymphatic invasion (LY; hazard ratio, 2.761; 95% CI, 1.86-6.43, P=0.018) was an independent factor significantly associated with 3-year recurrence-free survival in the multivariate analysis. In patients with pathologic lymph node metastasis (pN) and no LY after NAC, there was significantly less recurrence compared with patients with pN and LY (P=0.0085), whereas in patients without LY after NAC, the presence of pN was not significantly associated with recurrence (P=0.2401). There were significantly fewer LY (+) patients in the NAC (+) group (P=0.0158) compared with those in the NAC (-) group. The presence of LY was an independent risk factor for recurrence of ESCC after esophagectomy following NAC. Overall, adjuvant treatment after surgery may be required in cases with remnant LY after NAC.
Keywords: esophageal squamous cell carcinoma; lymphatic invasion; neoadjuvant chemotherapy; recurrence factor.. |
| 297. |
Katsuhito Teramatsu, Takamasa Oono, Koki Oyama, Nao Fujimori, Masatoshi Murakami, Sho Yasumori, Akihisa Ohno, Kazuhide Matsumoto, Ayumu Takeno, Kohei Nakata, Masafumi Nakamura, Yoshihiro Ogawa, Circulating CD8+CD122+ T cells as a prognostic indicator of pancreatic cancer, BMC cancer, 10.1186/s12885-022-10207-0, 22, 1, 1134, 2022.04, Purpose: The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer.
Methods: Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed.
Results: Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (Conclusion: Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.
Keywords: Benign pancreatic cysts; CD4+ T cells; CD8+CD122+ T cells; Metastatic pancreatic cancer; Resectable pancreatic cancer.. |
| 298. |
Akiko Shimazaki, Makoto Kubo, Kanako Kurata, Yuka Takao, Saori Hayashi, Yurina Harada, Hitomi Kawaji, Kazuhisa Kaneshiro, Mai Yamada, Masaya Kai, Masafumi Nakamura, CCND1 Copy Number Variation in Circulating Tumor DNA from Luminal B Breast Cancer Patients, Anticancer Res, 10.21873/anticanres.15904, 42, 8, 4071-4077, 2022.04. |
| 299. |
Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Daiji Sakata, Yoshihiro Izumi, Tetsuya Sakurai, Yuko Hattori, Eiji Oki, Naoto Kubota, Koshiro Nishimoto, Masafumi Oyama, Kazufumi Kunimura, Takuto Ohki, Takeshi Bamba, Hideaki Tahara, Michiie Sakamoto, Masafumi Nakamura, Makoto Suematsu, Yoshinori Fukui, Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells, Int Immunol, 10.1093/intimm/dxac002, 34, 5, 277-289, 2022.04, Abstract
The effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.
Keywords: DOCK2; SULT2B1b; cholesterol sulfate; immune evasion.. |
| 300. |
Yuki Nakafusa, Naoyoshi Nitta, Kazunari Ishii, Naoto Shirasu, Takahiro Iwamoto, Takayuki Nemoto, Masafumi Nakamura, Masafumi Goto, Hiroo Iwata, Masaru Taniguchi, Yohichi Yasunami, Acceptance of Murine Islet Allografts Without Immunosuppression in the Inguinal Subcutaneous White Adipose Tissue Pretreated with bFGF, diabetes, 10.2337/db21-0684, 71, 8, 1721-1734, 2022.04, Prevention of immune rejection without immunosuppression is the ultimate goal of transplant immunobiology. One way to achieve this in cellular transplantation, such as with islet transplantation, is to create a favorable local environment at the transplant site. In the present study, we found that streptozotocin (STZ)-induced diabetic C57BL/6 mice remained normoglycemic for more than one year after transplantation of BALB/c islets without immunosuppression when the inguinal subcutaneous white adipose tissue (ISWAT) was the site of transplantation and when the site was pretreated with basic fibroblast growth factor. Mechanistically, mesenchymal stem cells (MSCs) expanded in the ISWAT after the treatment was found to produce TGFβ and prevention of islet allograft rejection could be achieved by co-transplantation with syngeneic MSCs isolated from the ISWAT after the treatment, which was abolished by anti-TGFβ antibody treatment. Importantly, TGFβ-producing cells remained present at the site of co-transplantation for up to the end of observation period at 240 days after transplantation. These findings indicate that prevention of islet allograft rejection without immunosuppression is feasible with the use of syngeneic TGFβ-producing MSCs expanded in the ISWAT after the treatment with bFGF, providing a novel strategy for prevention of islet allograft rejection without immunosuppression.. |
| 301. |
Yoshihiro Mise, Shinya Hirakawa, Hisateru Tachimori, Yoshihiro Kakeji, Yuko Kitagawa, Shohei Komatsu, Atsushi Nanashima, Masafumi Nakamura, Itaru Endo, Akio Saiura, Volume- and quality-controlled certification system promotes centralization of complex hepato-pancreatic-biliary surgery, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1307, 30, 7, 851-862, 2023.04, Background: Centralization of complex surgeries has made little progress when it only considers the minimum number of surgical procedures. We aim to assess the impact of certification system of Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) on centralization and surgical quality of advanced hepato-pancreatic-biliary (HPB) surgery.
Methods: The National Clinical Database was used to review 20 111 patients who underwent pancreatoduodenectomy (PD) and 9666 who underwent advanced hepatectomy defined as hepatectomy of more than one section during 2019 and 2020. JSHPBS certifies hospitals based on the annual number of advanced HPB surgeries and the surgical quality. Minimum numbers of surgeries for board-certified A and B institutions are 50 and 30, respectively. Short-term outcomes were compared among institutions.
Results: In 2020, 69.4% (7007/10090) and 72.9% (3433/4710) of patients underwent PD and advanced hepatectomy at board-certified institutions. In-hospital mortality rates after PD was 0.9% at certified A institutions, 1.4% at B institutions, and 2.7% at non-certified institutions (p Conclusion: The volume- and quality-controlled certification system of JSHBPS reduces surgical mortality after advanced HPB surgeries.. |
| 302. |
Woo-Hyoung Kang, Shin Hwang, Masaki Kaibori, Jong Man Kim, Kyung Sik Kim, Tsuyoshi Kobayashi, Hiroto Kayashima, Yang Seok Koh, Keiichi Kubota, Akira Mori, Yutaka Takeda, Sung Su Yun, Kousuke Matsui, Kan Toriguchi, Hiroaki Nagano, Myung Hee Yoon, Yuji Soejima, Shunichi Ariizumi, Bum-Soo Kim, Yohan Park, Hee Chul Yu, Bong Wan Kim, Jung Bok Lee, Sang-Jae Park, Jin-Young Jang, Hiroki Yamaue, Masafumi Nakamura, Masakazu Yamamoto, Itaru Endo; Collaboration of Korean Association of Hepato-Biliary-Pancreatic Surgery; Japanese Society of Hepato-Biliary-Pancreatic Surgery, Validation of quantitative prognostic prediction using ADV score for resection of hepatocellular carcinoma: A Korea-Japan collaborative study with 9200 patients, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1319
Full text linksCite, 30, 8, 993-1005, 2023.04, ackground: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation.
Methods: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020.
Results: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p Conclusions: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence.. |
| 303. |
Keizo Kaku, Yasuhiro Okabe, Shinsuke Kubo, Yu Sato, Takanori Mei, Hiroshi Noguchi, Yoshito Tomimaru, Toshinori Ito, Takashi Kenmochi, Masafumi Nakamura, Utilization of the Pancreas From Donors With an Extremely High Pancreas Donor Risk Index: Report of the National Registry of Pancreas Transplantation, Transplant International, 10.3389/ti.2023.11132. eCollection 2023., 2023.04. |
| 304. |
Yuichi Nagakawa, Jin-Young Jang, Manabu Kawai, Song Cheol Kim, Yosuke Inoue, Ryusei Matsuyama, Jin Seok Heo, Masayuki Honda, Teiichi Sugiura, Masayuki Ohtsuka, Shugo Mizuno, Wooil Kwon, Kenichiro Uemura, Ho-Seong Han, Motokazu Sugimoto, Keiichi Okano, Masafumi Nakamura, Keita Wada, Yusuke Kumamoto, Hiroaki Osakae, Akihiko Tsuchida, Yoo-Seok Yoon, Joon Seong Park, Hiroki Yamaue, Itaru Endo, Surgical Outcomes of Pancreatectomy with Resection of the Portal Vein and/or Superior Mesenteric Vein and Jejunal Vein for Pancreatic Head Cancer A Multicenter Study, Ann Surg, 10.1097/SLA.0000000000005330, 277, 5, e1081-e1088, 2023.04, Objective:
The aim of this study was to investigate the safety and survival benefits of portal vein and/or superior mesenteric vein (PV/SMV) resection with jejunal vein resection (JVR) for pancreatic ductal adenocarcinoma (PDAC).
Summary Background Data:
Few studies have shown the surgical outcome and survival of pancreatic resection with JVR, and treatment strategies for patients with PDAC suspected of jejunal vein (JV) infiltration remain unclear.
Methods:
In total, 1260 patients who underwent pancreatectomy with PV/ SMV resection between 2013 and 2016 at 50 facilities were included; treatment outcomes were compared between the PV/SMV group (PV/ SMV resection without JVR; n = 824), PV/SMV-J1 V group (PV/SMV resection with first jejunal vein resection; n = 394), and PV/SMV-J2,3 V group (PV/SMV resection with second jejunal vein or later branch resection; n = 42).
Results:
Postoperative complications and mortality did not differ between the three groups. The postoperative complication rate associated with PV/ SMV reconstruction was 11.9% in PV/SMV group, 8.6% in PV/SMV-J1 V group, and 7.1% in PV/SMV-J2,3V group; there were no significant differences among the three groups. Overall survival did not differ between PV/SMV and PV/SMV-J1 V groups (median survival; 29.2 vs 30.9 months, P = 0.60). Although PV/SMV-J2,3 V group had significantly shorter survival than PV/SMV group who underwent upfront surgery (P = 0.05), no significant differences in overall survival of patients who received preoperative therapy. Multivariate survival analysis revealed that adjuvant therapy and R0 resection were independent prognostic factors in all groups.
Conclusion:
PV/SMV resection with JVR can be safely performed and may provide satisfactory overall survival with the pre-and postoperative adjuvant therapy.. |
| 305. |
Kinuko Nagayoshi, Yusuke Mizuuchi, Jinghui Zhang, Kyoko Hisano, Koji Tamura, Masafumi Sada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Strong impact of sarcopenic state defined by skeletal muscle mass index on postoperative complication of Crohn's disease patients, Surgery Open Science, 10.1016/j.sopen.2023.07.022, 6, 15, 54-59, 2023.04, Background: Malnutrition impacts the clinical course of Crohn's disease; however, there is little evidence of its influence on perioperative adverse events. We assessed whether nutritional indicators are associated with postoperative complications in surgical treatment of Crohn's disease.
Methods: 137 patients with Crohn's disease who underwent surgical treatment between January 2011 and December 2020 were included. Skeletal muscle index was calculated by a single CT slice. We analyzed the risk factors for adverse events.
Results: 37 % of patients had postoperative complications. Adverse events occurred more frequently in patients with high serum C-reactive protein, low serum albumin, prognostic nutritional index Conclusions: Skeletal muscle index is the most useful nutritional predictor of postoperative complications in Crohn's disease patients among other nutritional indices. We believe that these patients are at high risk of postoperative complications and need appropriate nutritional support in the perioperative period.
Keywords: Crohn's disease; Nutritional status; Postoperative complications; Sarcopenia; Skeletal muscle mass index.. |
| 306. |
Keizo Kaku, Yasuhiro Okabe, Shinsuke Kubo, Yu Sato, Takanori Mei, Hiroshi Noguchi, Yoshito Tomimaru, Toshinori Ito, Takashi Kenmochi, Masafumi Nakamura, Size-mismatched transplantation from large donors to small recipients is associated with pancreas graft thrombosis: A retrospective national observational study, Clinical Transplantation , 10.1111/ctr.15090, 37, 11, e15090, 2023.04, Introduction: Donor-recipient (D/R) size mismatch has been evaluated for a number of organs but not for pancreas transplantation.
Methods: We retrospectively evaluated 438 patients who had undergone pancreas transplantation. The D/R body surface area (BSA) ratio was calculated, and the relationship between the ratio and graft prognosis was evaluated. We divided the patients into two groups and evaluated graft survival. The incidence of pancreas graft thrombosis resulting in graft failure within 14 days and 1-year graft survival were compared using Kaplan-Meier curves, and the prognostic factors associated with graft thrombosis were identified by univariate and multivariate analyses.
Results: The mean/median donor and recipient BSAs were 1.63 m2 /1.65 m2 , and 1.57 m2 /1.55 m2 , respectively; the mean and median D/R BSAs were both 1.05. The receiver operating characteristic curve cutoff for the D/R BSA ratio was 1.09, and significant differences were identified between patients with ratios of ?1.09 (high group) versus <1.09 (low group). The incidence of graft thrombosis resulting in pancreas graft failure within 14 days was significantly higher in the high group than in the low group (p < .01). One-year overall and death-censored pancreas graft survival were significantly higher in the low group than in the high group (p < .01). Multivariate analysis identified recipient height, donor BSA, and donor hemoglobin A1c as significant independent factors for graft thrombosis. Cubic spline curve analysis indicated an increased risk of graft thrombosis with increasing D/R BSA ratio.
Conclusion: D/R size mismatch is associated with graft thrombosis after pancreas transplantation.. |
| 307. |
Shoichi Nakamura, Kenoki Ohuchida, Yoshiki Ohtsubo. Yutaka Yamada, Chikanori Tsutsumi, Sho Okuda, Kyoko Hisano, Yuki Mochida, Tomohiko Shinkawa, Chika Iwamoto, Nobuhiro Torata, Yusuke Mizuuchi, Koji Shindo, Kohei Nakata, Taiki Moriyama, Takehiro Torisu, Eishi Nagai, Takashi Morisaki, Takanari Kitazono, Yoshinao Oda, Masafumi Nakamura, Single-cell transcriptome analysis reveals functional changes in tumour-infiltrating B lymphocytes after chemotherapy in oesophageal squamous cell carcinoma, Clin Transl Med, 10.1002/ctm2.1181., 13, 1
, e1181, 2023.04, Background: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy.
Methods: Single-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS).
Results: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p
Conclusions: Our findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs.
Keywords: neoadjuvant chemotherapy; oesophageal squamous cell carcinoma; single-cell transcriptome; tumour immune microenvironment; tumour infiltrating B lymphocytes.. |
| 308. |
Naoki Ikenaga, Kohei Nakata, Toshiya Abe, Noboru Ideno, Nao Fujimori, Takamasa Oono, Nobuhiro Fujita, Kousei Ishigami, Masafumi Nakamura, Risks and benefits of pancreaticoduodenectomy in patients aged 80 years and over, Langenbecks Arch Surg, 10.1007/s00423-023-02843-2., 408, 108, 108, 2023.04, Purpose: The frequency of pancreaticoduodenectomy is increasing in oldest old patients owing to population aging. We aimed to clarify the clinical significance of pancreaticoduodenectomy in patients aged ≥ 80 years with multiple underlying diseases.
Methods: A total of 649 consecutive patients who underwent pancreaticoduodenectomy from April 2010 to March 2021 in our institute were divided into two groups according to their age: ≥ 80 years (51) and ≤ 79 years (598). We compared mortality and morbidity between the groups. The age-related prognosis was analyzed in 302 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma treatment.
Results: There were no significant differences in morbidity (Clavien-Dindo classification grade III or higher; P = 0.1300), mortality (P = 0.0786), or postoperative hospital stay (P = 0.5763) between the groups. Patients aged ≥ 80 years, who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, had shorter overall survival than those aged ≤ 79 years (median survival time, 16.7 months vs. 32.7 months; P = 0.0206). However, the overall survival of patients aged ≥ 80 years who received perioperative chemotherapy was comparable to that of patients aged ≤ 79 years (P = 0.9795). In the multivariate analysis, the absence of perioperative chemotherapy was identified as an independent prognostic factor, while age ≥ 80 years was not. Perioperative chemotherapy was the sole independent prognostic factor in patients aged ≥ 80 years who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.
Conclusions: Pancreaticoduodenectomy is safe for patients aged ≥ 80 years. The survival benefits of pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma aged ≥ 80 years might be limited to those who can receive perioperative chemotherapy.
Keywords: Adenocarcinoma; Aged; Chemotherapy; Pancreaticoduodenectomy; Survival analysis.. |
| 309. |
Michitaka Nakano, Ryosuke Taguchi, Yoshikane Kikushige, Taichi Isobe, Kohta Miyawaki, Shinichi Mizuno, Nobuhiro Tsuruta, Fumiyasu Hanamura, Kyoko Yamaguchi, Takuji Yamauchi, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Calvin J Kuo, Eishi Bab, Koichi Akashi, RHAMM marks proliferative subpopulation of human colorectal cancer stem cells, Cancer Sci, 10.1111/cas.15795, 114, 7, 2895-2906, 2023.04, The cancer stem cell (CSC) theory features typically rare self-renewing subpopulations that reconstitute the heterogeneous tumor. Identification of molecules that characterize the features of CSCs is a key imperative for further understanding tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids that are miniature forms of tumor tissues by reconstructing cellular diversity to identify specific markers to characterize CSCs in heterogeneous tumors. Here, we report that the receptor for hyaluronan-mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single-cell transcriptomics of organoids highlighted RHAMM-positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+CD44+ cells from the human colorectal cancer tissues showed highly proliferative characteristics with a self-renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoid formation in vitro and inhibited tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction.
Keywords: CD44; RHAMM; cancer stem cells; colorectal cancer; organoid.. |
| 310. |
Yusuke Mizuuchi, Yoshitaka Tanabe, Masafumi Sada, Koji Tamura, Kinuko Nagayoshi, Shuntaro Nagai, Yusuke Watanabe, Sadafumi Tamiya, Kenoki Ohuchida, Kohei Nakata, Toru Nakano, Masafumi Nakamura, Relationship between prognostic impact of N3 lymph node metastasis at the root of the feeding artery and location of colon cancer, Langenbecks Arch Surg, 10.1007/s00423-023-02778-8, 408, 1, 31, 2023.04, Purpose: To determine whether N3 nodal involvement predicts outcomes and whether its prognostic implications vary with tumor location in patients with Stage III colon cancer (CC).
Methods: We defined N3 as lymph node metastases near the bases of the major feeding arteries. We retrospectively examined recurrence rates and patterns by tumor location and sites of lymph node metastases in 57 patients with N3 CC who had undergone curative resections between January 2000 and March 2019. Survival analysis was performed to compare the prognoses of patients with and without N3 lymph node metastasis.
Results: Most N3 patients had large tumors (T ? 3); five had T2 disease. Recurrence occurred quickly in one patient with T2N3M0 disease. Multivariate survival analysis demonstrated that N3 lymph node metastasis is an independent predictor of poor prognosis in Stage III CC patients (P < 0.001). Categorizing N3 patients according to UICC-TNM staging system does not stratify risk of recurrence (P = 0.970). To investigate the impact of tumor location on recurrence risk, we classified N3 CC into two subtypes according to tumor location: metastasis at the base of the superior mesenteric artery in right-sided CC and inferior mesenteric artery in left-sided CC. The former was found to have a statistically significant poorer prognosis than the latter (P = 0.091).
Conclusion: N3 is a robust prognostic marker in CC patients. Recurrence risk varies by tumor location. N3 right-sided CCs with lymph node metastasis at the base of the superior mesenteric artery have poorer prognoses than do N3 left-sided CCs.
Keywords: Feeding artery; Inferior mesenteric artery; N3 colon cancer; Superior mesenteric artery; Tumor sidedness.. |
| 311. |
Naoya Iwamoto, Hideya Onishi, Shogo Masuda, Akira Imaizumi, Keita Sakanashi, Shinji Morisaki, Shinjiro Nagao, Satoko Koga, Keigo Ozono, Masayo Umebayashi, Takashi Morisaki, Masafumi Nakamura, PTPN3 inhibition contributes to the activation of the dendritic cell function to be a promising new immunotherapy target, J Cancer Res Clin Oncol, 10.1007/s00432-023-05250-8, 149, 16, 14619-14630, 2023.04, Abstract
Purpose: In a previous study, protein tyrosine phosphatase non-receptor type (PTPN) 3 was identified as an immune checkpoint molecule in lymphocytes, and its potential as a novel target for cancer immunotherapy was anticipated. However, evaluation of dendritic cell (DC) function as antigen-presenting cells is critical for the development of immunotherapy. In this study, we aimed to analyze the biological effect of PTPN3 on DCs induced from human peripheral blood monocytes obtained from healthy individuals.
Methods: We used short-interfering RNA to knock down PTP3 in DCs. For DC maturation, we added cancer cell lysate and tumor necrosis factor-α/interferon-α to immature DCs. In the cytotoxic assay, the target cancer cells were SBC5, unmatched with DCs from healthy human leukocyte antigen (HLA)-A24, or Sq-1, matched with DCs. Enzyme-linked immunosorbent assay was used to determine the amount of cytokines. To examine the intracellular signaling system, intracellular staining was used.
Results: PTPN3 knockdown significantly increased the number of DCs, expression of CD80 and chemokine receptor (CCR)7, and production of interleukin-12p40/p70 in mature DCs. In the HLA-A24-restricted DC and human lung squamous cell carcinoma cell cytotoxic assay, inhibition of PTPN3 expression in mature DCs induced cytotoxic T lymphocytes with increased production of INF-γ and granzyme B, and enhanced toxicity against cancer cells and migration to cancer. Furthermore, inhibition of PTPN3 expression activated the mitogen-activated protein kinase pathway in DCs.
Conclusion: Based on our findings, inhibition of PTPN3 expression could contribute to the development of novel cancer immunotherapies that activate not only lymphocytes but also DCs.
Keywords: Anticancer immunotherapy; Immune checkpoint; MAPK pathway; Mature dendritic cell; PTPN3.. |
| 312. |
Hyung Sun Kim, Woojin Kim, Itaru Endo, Jin-Young Jang, Hongbeom Kim, Ki Byung Song, Dae Wook Hwang, Chang Moo Kang, Ho Kyoung Hwang, Sang-Jae Park, Sung-Sik Han, Yoo-Seok Yoon, Jae Do Yang, Ryosuke Amano, Sadaaki Yamazoe, Hiroaki Yanagimoto, Tetsuo Ajiki, Masayuki Ohtsuka, Daisuke Suzuki, Dong-Shik Lee, Yuji Kitahata, Koji Amaya, Jun Sakata, Hyung Il Seo, Junichiro Yamauchi, Yasuhiro Yabushita, Takayuki Tanaka, Naoki Sakurai, Teijiro Hirashita, Akihiko Horiguchi, Michiaki Unno, Dong Do You, Yo-Ichi Yamashita, Shogo Kobayashi, Yusuke Kyoden, Takao Ide, Hiroaki Nagano, Masafumi Nakamura, Hiroki Yamaue, Masakazu Yamamoto, Joon Seong Park, Proposal of nomograms to predict clinical outcomes in patients with ampulla of Vater cancer based on the Korea-Japan collaborative study, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1229, 30, 3, 360-373, 2023.04, Background: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study.
Methods: A total of 2007 patients with AOV adenocarcinoma who received operative therapy between 2002 January and 2015 December in Korea and Japan were retrospectively assessed to develop a prediction model. Nomograms for 5-year OS and 3-year RFS were constructed by dividing the patients who received and who did not receive adjuvant therapy after surgery, respectively. Significant risk factors were identified by univariate and multivariate Cox analyses. Performance assessment of the four prediction models was conducted by the Harrell's concordance index (C-index) and calibration curves using bootstrapping.
Results: A total of 2007 and 1873 patients were collected for nomogram construction to predict 5-year OS and 3-year RFS. We developed four types of nomograms, including models for 5-year OS and 3-year RFS in patients who did not receive postoperative adjuvant therapy, and 5-year OS and 3-year RFS in patients who received postoperative adjuvant therapy. The C-indices of these nomograms were 0.795 (95% confidence interval [CI]: 0.766-0.823), 0.712 (95% CI: 0.674-0.750), 0.804 (95% CI: 0.7778-0.829), and 0.703 (95% CI: 0.669-0.737), respectively.
Conclusions: This predictive model could help clinicians to choose optimal treatment and precisely predict prognosis in AOV cancer patients.
Keywords: Ampulla of Vater cancer; multicenter study; nomogram; prognosis.. |
| 313. |
Yusuke Mizuuchi, Kinuko Nagayoshi, Masafumi Nakamura, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futami, Kinya Okamoto, Tsunekazu Mizushima, Hisashi Nagahara, Kazuhiro Watanabe, Koji Okabayashi, Kazutaka Yamada, Hiroki Ohge, Shinji Tanaka, Yoshiki Okita, Yu Sato, Hideki Ueno, Atsuo Maemoto, Michio Itabashi, Hideaki Kimura, Koya Hida, Yusuke Kinugasa, Kenichi Takahashi, Fumikazu Koyama, Tsunekazu Hanai, Kiyoshi Maeda, Toshihiro Noake, Yoshifumi Shimada, Takayuki Yamamoto, Junya Arakaki, Keiji Mastuda, Junji Okuda, Eiji Sunami, Yoshito Akagi, Kenji Kastumata, Kay Uehara, Takeshi Yamada, Shin Sasaki, Soichiro Ishihara, Yoichi Ajioka, Kenichi Sugihara; Study Group for Inflammatory Bowel Disease-Associated Intestinal Cancers of the Japanese Society for Cancer of the Colon and Rectum, Prognostic impact of tumour location in stage II/III ulcerative colitis-associated colon cancer: subgroup analysis of a nationwide multicentre retrospective study in Japan, Br J Surg, 10.3393/ac.2022.00122.0017., 38, 5, 353-361, 2023.04. |
| 314. |
Toshiya Abe, Kohei Nakata, So Nakamur, Noboru Ideno, Naoki Ikenaga, Nobuhiro Fujita, Kousei Ishigami, Kazuyoshi Nishihara, Masafumi Nakamura, Prognostic Impact of Preoperative Osteosarcopenia for Patients with Pancreatic Ductal Adenocarcinoma After Curative Resection, Ann Surg Oncol, 10.1245/s10434-023-13936-z, 30, 11, 6673-6679, 2023.04, Backgrounds: The clinical significance of preoperative osteosarcopenia in pancreatic ductal adenocarcinoma (PDAC) has not been fully studied. The purpose of this study was to evaluate the role of preoperative osteosarcopenia in predicting the survival of patients with PDAC.
Methods: We retrospectively analyzed 265 patients who underwent curative surgical resection for PDAC between 2012 and 2018 in two Japanese institutes. The skeletal muscle index at the L3 vertebrae and the bone mineral density at the Th11 vertebra were calculated for the evaluation of osteosarcopenia before surgery. The relationship between perioperative osteosarcopenia and clinicopathological factors and prognosis was analyzed.
Results: The median overall survival (OS) and disease-free survival (DFS) of patients with osteosarcopenia were significantly shorter than those of patients without osteosarcopenia (OS: 23 and 48 months, respectively, P Conclusions: Preoperative osteosarcopenia may be a useful prognostic factor in patients with PDAC who undergo surgical resection. Further studies are needed to assess whether perioperative, nutritional interventions and rehabilitation contribute to improving the prognosis of these patients.. |
| 315. |
Koji Tamura, Takashi Ueki, Hiromichi Nakayama, Yusuke Watanabe, Masafumi Sada, Kinuko Nagayoshi, Yusuke Mizuuchi, Kenoki Ohuchida, Hitoshi Ichimiya, Masafumi Nakamura, Preoperative prediction of malignancy and surgical treatment strategy in appendiceal tumors: multicenter review of 51 consecutive cases, Langenbecks Arch Surg , 10.1007/s00423-023-02807-6, 408, 1, 36, 2023.04, urpose: A diagnostic and treatment strategy for appendiceal tumors (ATs) has not been established. We aimed to evaluate our treatment strategy in ATs, including laparoscopic surgery (LS), and to identify preoperative malignancy predictors.
Methods: A total of 51 patients between 2011 and 2021 were retrospectively reviewed. Data, including tumor markers and imaging findings, were compared between carcinoma and non-carcinoma patients. Validity of planned operation was evaluated based on pathological diagnosis.
Results: Twenty-five patients were diagnosed with carcinoma, 13 with low-grade mucinous neoplasm, and 13 with other diseases. Symptoms were more commonly present in carcinoma patients than in non-carcinoma patients (68.0% vs. 23.1%, p = 0.001). Elevated CEA and CA19-9 were more frequently observed in carcinoma patients than in non-carcinoma patients (p Conclusion: Clinical symptoms, elevated tumor markers, and worrisome features of solid enhanced mass and tumor wall irregularity on imaging can be malignancy predictors. For management of ATs, LS is feasible and useful for diagnosis and treatment.
Keywords: Appendiceal carcinoma; Appendiceal tumor; LAMN; Laparoscopic surgery; Mucinous neoplasm.. |
| 316. |
Sho Okuda, Kenoki Ohuchida, Shoichi Nakamura, Chikanori Tsutsumi, Kyoko Hisano, Yuki Mochida, Jun Kawata, Yoshiki Ohtsubo, Tomohiko Shinkawa, Chika Iwamoto, Nobuhiro Torata, Yusuke Mizuuchi, Koji Shindo, Taiki Moriyama, Kohei Nakata, Takehiro Torisu, Takashi Morisaki, Takanari Kitazono, Yoshinao Oda, Masafumi Nakamura, Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma, iScience.
, 10.1016/j.isci.2023.106480., 26, 4, 106480, 2023.04. |
| 317. |
Fumihiro Terasaki, Shinya Hirakawa, Hisateru Tachimori, Teiichi Sugiura, Atsushi Nanashima, Shohei Komatsu, Hiroaki Miyata, Yoshihiro Kakeji, Yuko Kitagawa, Masafumi Nakamura, Itaru Endo, Morbidity after left trisectionectomy for hepato-biliary malignancies: An analysis of the National Clinical Database of Japan, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1358, 30, 12, 1304-1315, 2023.04, Background: The aim of this study was to analyze the nationwide surgical outcome of a left trisectionectomy (LT) and to identify the perioperative risk factors associated with its morbidity.
Methods: Cases of LT for hepato-biliary malignancies registered at the Japanese National Clinical Database between 2013 and 2019 were retrospectively reviewed. Statistical analyses were performed to identify the perioperative risk factors associated with a morbidity of Clavien-Dindo classification (CD) ≥III.
Results: Left trisectionectomy was performed on 473 and 238 cases of biliary and nonbiliary cancers, respectively. Morbidity of CD ≥III and V occurred in 45% and 5% of cases with biliary cancer, respectively, compared with 26% and 2% of cases with nonbiliary cancer, respectively. In multivariable analyses, biliary cancer was significantly associated with a morbidity of CD ≥III (odds ratio, 1.87; p = .018). In subgroup analyses for biliary cancer, classification of American Society of Anesthesiologists physical status (ASA-PS) 2, portal vein resection (PVR), and intraoperative blood loss ≥30 mL/kg were significantly associated with a morbidity of CD ≥III.
Conclusions: Biliary cancer induces severe morbidity after LT. The ASA-PS classification, PVR, and intraoperative blood loss indicate severe morbidity after LT for biliary cancer.
Keywords: Japan; National Clinical Database; biliary cancer; left trisectionectomy; morbidity.. |
| 318. |
Kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video), Surg Endosc, 10.1007/s00464-023-10438-7, 37, 11, 8901-8909, 2023.04, Background: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach.
Methods: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches.
Results: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903).
Conclusions: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.
Keywords: Approach; Distal pancreatectomy; Minimally invasive pancreatectomy.. |
| 319. |
Lin Na, Hideya Onishi, Shinji Morisaki, Shu Ichimiya, Yutaka Yamada, Shogo Masuda, Shinjiro Nagao, Satoko Koga, Kazunori Nakayama, Akira Imaizumi, Yoshinao Oda, Masafumi Nakamura, MAML3 Contributes to Induction of Malignant Phenotype of Gallbladder Cancer Through Morphogenesis Signalling Under Hypoxia, Anticancer Res, 10.21873/anticanres.16462, 43, 7, 2909-2922, 2023.04, Background/aim: Hedgehog (HH) signalling is a potential therapeutic target for gallbladder cancer (GBC), and Mastermind-like 3 (MAML3) is involved in the transcription of Smoothened (SMO), which is a key protein of HH signalling during hypoxia in the cancer microenvironment. MAML3 is a NOTCH signalling activator, and HH and NOTCH are involved in morphogenesis signalling. However, the association between MAML3-NOTCH and HH signalling and its role in regulating GBC cells remain unknown. This study aimed to determine whether NOTCH signalling affects tumour aggressiveness in GBC under hypoxic conditions and if MAML3 could be a new comprehensive therapeutic target that regulates morphogenesis signalling, HH, and NOTCH in GBC.
Materials and methods: We used three cell lines (NOZ, TYGBK1, and TGBC2TKB) and 58 resected specimens. These samples were subjected to cell proliferation, RNA interference, invasion, western blot, and immunohistochemical analyses.
Results: MAML3 expression was higher under hypoxic conditions than under normoxic conditions and was involved in the activation of HH and NOTCH signalling. It contributed to the proliferation, migration, and invasion of GBC cells through the NOTCH signalling pathway and enhanced gemcitabine sensitivity. Immunohistochemical analysis showed that MAML3 expression was related to lymphatic invasion, lymph node metastasis, stage category, and a poor prognosis.
Conclusion: MAML3 contributes to the induction of the malignant phenotype of GBC under hypoxia through the HH and NOTCH signalling pathways and may be a comprehensive therapeutic target of morphogenesis signalling in GBC.. |
| 320. |
Masatoshi Murakami, Nao Fujimori, Kohei Nakata, Masafumi Nakamura, Shinichi Hashimoto, Hiroshi Kurahara, Kazuyoshi Nishihara, Toshiya Abe, Shunpei Hashigo, Naotaka Kugiyama, Eisuke Ozawa, Kazuhisa Okamoto, Yusuke Ishida, Keiichi Okano, Ryo Takaki, Yutaka Shimamatsu, Tetsuhide Ito, Masami Miki, Noriko Oza, Daisuke Yamaguchi, Hirofumi Yamamoto , Hironobu Takedomi, Ken Kawabe, Tetsuro Akashi , Koichi Miyahara, Jiro Ohuchid, Yasuhiro Ogura, Yohei Nakashima, Toshiharu Ueki, Kousei Ishigami, Hironobu Umakoshi, Keijiro Ueda, Takamasa Oono, Yoshihiro Ogawa, Machine learning-based model for prediction and feature analysis of recurrence in pancreatic neuroendocrine tumors G1/G2, J Gastroenterol, 10.1007/s00535-023-01987-8, 58, 6, 586-597, 2023.04, Background: Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of tumors. Although the prognosis of resected PanNENs is generally considered to be good, a relatively high recurrence rate has been reported. Given the scarcity of large-scale reports about PanNEN recurrence due to their rarity, we aimed to identify the predictors for recurrence in patients with resected PanNENs to improve prognosis.
Methods: We established a multicenter database of 573 patients with PanNENs, who underwent resection between January 1987 and July 2020 at 22 Japanese centers, mainly in the Kyushu region. We evaluated the clinical characteristics of 371 patients with localized non-functioning pancreatic neuroendocrine tumors (G1/G2). We also constructed a machine learning-based prediction model to analyze the important features to determine recurrence.
Results: Fifty-two patients experienced recurrence (14.0%) during the follow-up period, with the median time of recurrence being 33.7 months. The random survival forest (RSF) model showed better predictive performance than the Cox proportional hazards regression model in terms of the Harrell's C-index (0.841 vs. 0.820). The Ki-67 index, residual tumor, WHO grade, tumor size, and lymph node metastasis were the top five predictors in the RSF model; tumor size above 20 mm was the watershed with increased recurrence probability, whereas the 5-year disease-free survival rate decreased linearly as the Ki-67 index increased.
Conclusions: Our study revealed the characteristics of resected PanNENs in real-world clinical practice. Machine learning techniques can be powerful analytical tools that provide new insights into the relationship between the Ki-67 index or tumor size and recurrence.
Keywords: Machine learning; Pancreatic neuroendocrine tumor; Prediction model; Random survival forest; Recurrence.. |
| 321. |
Shuang Fei, Kenoki Ohuchida, Shin Kibe, Zilong Yan, Chika Iwamoto, Tomohiko Shinkawa, Bo Zhang, Jun Kawata, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front, Gastric Cancer, 10.1007/s00432-022-04554-5., 149, 9, 5885-5899, 2023.04, Purpose: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism.
Methods: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro.
Results: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density.
Conclusion: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.
Keywords: Angiogenesis; Cancer-associated acinar-to-ductal metaplasia; Liver metastasis; Macrophages; Pancreatic cancer; Prognosis.. |
| 322. |
Masataka Hayashi, Naoki Ikenaga, Kohei Nakata, Haizhen Luo, PingShan Zhong, Satomi Date, Koki Oyama, Nobuhiro Higashijima, Akihiro Kubo, Chika Iwamoto, Nobuhiro Torata, Toshiya Abe, Yutaka Yamada, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis, Cancer Science, 10.1111/cas.15901 , 114, 9, 3666-3678, 2023.04, Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.
Keywords: Fusobacterium nucleatum; CXCL1; CXCR2; pancreatic cancer; tumor immune microenvironment.. |
| 323. |
Toru Nakamura, Ken-Ichi Okada, Masayuki Ohtsuka, Ryota Higuchi, Hidenori Takahashi, Kazuyuki Nagai, Michiaki Unno, Yoshiaki Murakami, Atsushi Oba, Moriaki Tomikawa, Atsushi Kato, Akihiko Horiguchi, Masafumi Nakamura, Shintaro Yagi, Sohei Satoi, Itaru Endo, Ryosuke Amano, Ippei Matsumoto, Yoichi M Ito, Takukazu Nagakawa, Satoshi Hirano, Insights from managing clinical issues in distal pancreatectomy with en bloc coeliac axis resection: experiences from 626 patients, Br J Surg, 10.1093/bjs/znad212, 110, 10, 1387-1394, 2023.04, Background: Distal pancreatectomy with en bloc coeliac axis resection (DP-CAR) for pancreatic body cancer has been reported increasingly. However, its large-scale outcomes remain undocumented. This study aimed to evaluate DP-CAR volume and mortality, preoperative arterial embolization for ischaemic gastropathy, the oncological benefit for resectable tumours close to the bifurcation of the splenic artery and coeliac artery using propensity score matching, and prognostic factors in DP-CAR.
Methods: In a multi-institutional analysis, 626 DP-CARs were analysed retrospectively and compared with 1325 distal pancreatectomies undertaken in the same interval.
Results: Ninety-day mortality was observed in 7 of 21 high-volume centres (1 or more DP-CARs per year) and 1 of 41 low-volume centres (OR 20.00, 95 per cent c.i. 2.26 to 177.26). The incidence of ischaemic gastropathy was 19.2 per cent in the embolization group and 7.9 per cent in the no-embolization group (OR 2.77, 1.48 to 5.19). Propensity score matching analysis showed that median overall survival was 33.5 (95 per cent c.i. 27.4 to 42.0) months in the DP-CAR and 37.9 (32.8 to 53.3) months in the DP group. Multivariable analysis identified age at least 67 years (HR 1.40, 95 per cent c.i. 1.12 to 1.75), preoperative tumour size 30 mm or more (HR 1.42, 1.12 to 1.80), and preoperative carbohydrate antigen 19-9 level over 37 units/ml (HR 1.43, 1.11 to 1.83) as adverse prognostic factors.
Conclusion: DP-CAR can be performed safely in centres for general pancreatic surgery regardless of DP-CAR volume, and preoperative embolization may not be required. This procedure has no oncological advantage for resectable tumour close to the bifurcation of the splenic artery, and should be performed after appropriate patient selection.. |
| 324. |
Kota Nakamura, Minako Nagai, Ippei Matsumoto, Sohei Satoi, Fuyuhiko Motoi, Manabu Kawai, Yasuo Hosouchi, Ryota Higuch, Shugo Mizuno, Takao Ohtsuka, Keiichi Akahoshi, Kenichi Hakamada, Michiaki Unno, Hiroki Yamaue, Masafumi Nakamura, Itaru Endo, Masayuki Sho, Impact of antithrombotic therapy on postpancreatectomy hemorrhage in 7116 patients: A project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1349, 30, 10, 1161-1171, 2023.04, Background: We previously reported an association between antithrombotic therapy and an increased risk of postpancreatectomy hemorrhage (PPH). To validate our findings, we conducted a large-scale multicenter retrospective study from 63 high-volume centers in Japan.
Methods: Between 2015 and 2018, 7116 patients who underwent pancreatectomy were enrolled. The antithrombotic group consisted of 920 patients (12.9%) who received preoperative antithrombotic agents including aspirin, clopidogrel, ticlopidine, prasugrel, warfarin, and direct oral anticoagulants.
Results: PPH occurred in 235 (3.3%) of the patients. The incidence of PPH and mortality were significantly higher in the antithrombotic group than in the control group (5.7 vs. 3.0% and 2.2 vs. 0.9%, respectively; both p Conclusions: This multicenter study demonstrated that a history of antithrombotic use was a significant risk factor for PPH and mortality. In particular, the resumption of antithrombotic therapy in the early postoperative period should be done with caution.
Keywords: antithrombotic; hemorrhage; pancreatectomy; postoperative; therapy.. |
| 325. |
Shinji Morisaki, Hideya Onishi, Takafumi Morisaki, Makoto Kubo, Masayo Umebayashi, Hiroto Tanaka, Norihiro Koya, Shinichiro Nakagawa, Kenta Tsujimura, Sachiko Yoshimura, Poh Yin Yew, Kazuma Kiyotani, Yusuke Nakamura, Masafumi Nakamura, Takanari Kitazono, Takashi Morisaki, Immunological analysis of hybrid neoantigen peptide encompassing class I/II neoepitope-pulsed dendritic cell vaccine, Front Immunol
, 10.3389/fimmu.2023.1223331, 14, 1223331, 2023.04, Neoantigens/ are tumor-specific antigens that evade central immune tolerance mechanisms in the thymus. Long-term tumor-specific cytotoxic T lymphocyte activity maintenance requires class II antigen-reactive CD4+ T cells. We had previously shown that intranodal vaccination with class I neoantigen peptide-pulsed dendritic cells (DCs) induced a robust immune response in a subset of patients with metastatic cancer. The present study aimed to perform a detailed ex vivo analysis of immune responses in four patients receiving an intranodal hybrid human leukocyte antigen class II neoantigen peptide encompassing a class I neoantigen epitope (hybrid neoantigen)-pulsed DC vaccine. After vaccination, strong T-cell reactions against the hybrid class II peptide and the class I-binding neoantigen peptide were observed in all four patients. We found that hybrid class II neoantigen peptide-pulsed DCs stimulated CD4+ T cells via direct antigen presentation and CD8+ T cells via cross-presentation. Further, we demonstrated that hybrid class II peptides encompassing multiple class I neoantigen epitope-pulsed DCs could present multiple class I peptides to CD8+ T cells via cross-presentation. Our findings provide insight into the mechanisms underlying hybrid neoantigen-pulsed DC vaccine therapy and suggest future neoantigen vaccine design.
Keywords: antigen presentation; dendritic cell; neoantigen; neoepitope; vaccine.. |
| 326. |
Mamoru Ito, Makoto Kubo, Hitomi Kawaji, Yoshiki Otsubo, Kanako Kurata, Hikaru Abutani, Mikita Suyama, Yoshinao Oda, Tomoharu Yoshizumi, Masafumi Nakamura, Eishi Baba, Homologous Recombination Repair Gene Alterations Are Associated with Tumor Mutational Burden and Survival of Immunotherapy, Cancers (Basel)
, 10.3390/cancers15235608, 15, 23, 5608, 2023.04, Background: Comprehensive genomic profiling (CGP) has become generally accepted practice in cancer care since CGP has become reimbursed by national healthcare insurance in Japan in 2019. However, its usefulness for cancer patients is insufficient for several reasons.
Methods: In an observational clinical study of FoundationOne® CDx, potential biomarkers were explored and the cause of testing failure was investigated. A total of 220 cancer patients were enrolled in the study during the period from 2018 to 2019 at Kyushu University Hospital.
Results: The primary tumor sites of the 220 cases were breast (115), colon (29), stomach (19), and pancreas (20). The present dataset suggested that homologous recombination repair (HRR) gene alterations were positively associated with tumor mutational burden-high (TMB-high) (p = 0.0099). A public dataset confirmed that patients with HRR gene alterations had a higher TMB and showed significantly longer survival of immunotherapy. In the present study, 18 cases failed sequencing. A lower percentage of tumor cell nuclei was the most common reason for testing failures (p = 0.037). Cases that received neoadjuvant chemotherapy before sampling tended to fail testing.
Conclusions: HRR gene alterations can be a potential biomarker predicting TMB-high and a good response to immunotherapy. For successful sequencing, samples with lower percentages of tumor cell nuclei and previous neoadjuvant chemotherapy should be avoided.
Keywords: ARID1A; comprehensive genomic profiling; homologous recombination repair gene; tumor mutational burden.. |
| 327. |
Toshio Ichiki, Yuichi Yamada, Takamichi Ito, Takeshi Nakahara, Yasuharu Nakashima, Masafumi Nakamura, Tomoharu Yoshizumi, Akira Shiose, Koichi Akashi, Yoshinao Oda, Histological and immunohistochemical prognostic factors of primary angiosarcoma, Virchows Arch
, 10.1007/s00428-023-03572-z, 483, 1, 59-69, 2023.04, Angiosarcoma is a malignant vascular endothelial neoplasm with various histological patterns. Despite its highly malignant potential, histological prognostic prediction has not been adopted for angiosarcoma. This study aimed to establish a method of predicting the prognosis of primary angiosarcoma. Formalin-fixed, paraffin-embedded samples from 104 primary angiosarcomas were prepared. All the cases were reviewed based on histological examinations with H&E staining. Because the French Fédération Nationale des Centres de Lutte Contre Le Cancer system (FNCLCC) is not adopted for angiosarcoma, we experimentally established a modified version of FNCLCC. Immunohistochemical staining for ERG, CD31, CD34, D2-40, HHV-8, p16, C-MYC, and p53 was performed. Fluorescence in situ hybridization (FISH) was performed for 31 cases to assay c-MYC gene amplification. Multivariate analysis revealed that age (> 70 years old) (p = 0.0011), non-cutaneous angiosarcoma (p = 0.0265), metastasis on diagnosis (p Keywords: Angiosarcoma; Histology; MYC; p16.. |
| 328. |
Nobuhiro Fujita, Yasuhiro Ushijima, Masahiro Itoyama, Daisuke Okamoto, Keisuke Ishimatsu, Noriaki Wada, Seiichiro Takao, Ryo Murayama, Nao Fujimori, Kohei Nakata, Masafumi Nakamura, Takeo Yamamoto, Yoshinao Oda, Kousei Ishigami, Extracellular volume fraction determined by dual-layer spectral detector CT: Possible role in predicting the efficacy of preoperative neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma, Eur J radiol
, 10.1016/j.ejrad.2023.110756, 162, 110756, 2023.04, Purpose: To clarify the relationship between extracellular volume (ECV) measured by dual-energy CT (DECT) and efficacy of preoperative neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC), as compared with single-energy CT (SECT).
Methods: We enrolled 67 patients with PDAC who underwent dynamic contrast-enhanced CT with a dual-energy CT system prior to NAC. Attenuation values were measured on unenhanced and the equilibrium-phase 120-kVp equivalent CT images for PDAC and the aorta. ΔHU-tumor, ΔHU-tumor/ΔHU-aorta, and SECT-ECV were calculated. Iodine densities of the tumor and aorta were measured in the equilibrium phase, and DECT-ECV of the tumor was calculated. Response to NAC was evaluated and the correlation between imaging parameters and response to NAC was statistically assessed.
Results: Tumor DECT-ECVs were significantly lower in the response group (n = 7) than in the non-response group (n = 60), with most significant difference (p = 0.0104). DECT-ECV showed highest diagnostic value with an Az value of 0.798. When using the optimal cut off value of DECT-ECV (Conclusion: PDAC with lower DECT-ECV can potentially show better response to NAC. DECT-ECV might be a useful biomarker for predicting response to NAC in patients with PDAC.
Keywords: Dual-energy CT; Extracellular volume; Neoadjuvant chemotherapy; Pancreatic ductal adenocarcinoma.. |
| 329. |
Takanori Mei, Hiroshi Noguchi, Ryutaro Kuraji, Shinsuke Kubo, Yu Sato,
Keizo Kaku, Yasuhiro Okabe, Hideya Onishi, Masafumi Nakamura
, Effects of periodontal pathogen-induced intestinal dysbiosis on transplant immunity in an allogenic skin graft model, Scientific Reports , 10.1038/s41598-023-27861-4, 13, 544, 2023.04, Periodontal disease can induce dysbiosis, a compositional and functional alteration in the microbiota. Dysbiosis induced by periodontal disease is known to cause systemic inflammation and may affect transplant immunity. Here, we examined the effects of periodontal disease-related intestinal dysbiosis on transplant immunity using a mouse model of allogenic skin graft in which the mice were orally administered the periodontal pathogen Porphyromonas gingivalis (Pg).
For 6 weeks, the Pg group orally received Pg while the control group orally received phosphate-buffered saline solution. After that, both groups received allogenic skin grafts. 16s rRNA analysis of feces revealed that oral administration of Pg significantly increased three short chain fatty acids (SCFAs) producing genera. SCFA (acetate and propionate) levels were significantly higher in the Pg group (p=0.040 and p=0.005). The ratio of regulatory T cells, which are positively correlated with SCFAs, to total CD4+ T cells in the peripheral blood and spleen was significantly greater (p=0.002 and p<0.001) in the Pg group by flowcytometry. Finally, oral administration of Pg significantly prolonged skin graft survival (p<0.001) and reduced pathological inflammation in transplanted skin grafts.
In conclusion, periodontal pathogen-induced intestinal dysbiosis may affect transplant immunity through increased levels of SCFAs and regulatory T cells.. |
| 330. |
Ryo Seishima, Koji Okabayashi, Hiroki Ikeuchi, Motoi Uchino, Kitaro Futam, Tatsuki Noguchi, Hiroki Ohge, Yasuhito Iseki, Kazuhiro Watanabe, Michio Itabashi, Kinya Okamoto, Yuji Toiyama, Takayuki Ogino, Masafumi Nakamura, Kazutaka Yamada, Toshifumi Wakai, Yu Sato, Hideaki Kimura, Kenichi Takahashi, Koya Hida, Yusuke Kinugasa, Fumio Ishida, Junji Okuda, Koji Daito, Fumikazu Koyama, Hideki Ueno, Takayuki Yamamoto, Seiichiro Yamamoto, Tsunekazu Hanai, Atsuo Maemoto, Junya Arakaki, Koji Komori, Yoshito Akagi, Dai Shida, Shigeki Yamaguchi, Keiji Matsuda, Kiyoshi Maeda, Toshihiro Noake, Riichiro Nezu, Shin Sasaki, Junichi Hasegawa, Eiji Sunami, Yukihide Kanemitsu, Kenji Katsumata, Kei Uehara, Tomomichi Kiyomatsu, Takeshi Suto, Shinsuke Kazama, Takeshi Yamada, Takenori Goi, Soichiro Ishihara, Yoichi Ajioka, Kenichi Sugihara, Effect of Biologics on the Risk of Advanced-Stage Inflammatory Bowel Disease-Associated Intestinal Cancer: A Nationwide Study, Am J Gastroenterol, 10.14309/ajg.0000000000002149, 118, 7
, 1248
-1255
, 2023.04, Introduction: The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set.
Methods: The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC.
Results: In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P Discussion: Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.. |
| 331. |
Eri Ataka, Yuta Matsukuma, Kenji Ueki, Akihiro Tsuchimoto, Yasuhiro Okabe, Kosuke Masutani, Masafumi Nakamura, Toshiaki Nakano, Takanari Kitazono, Cumulative smoking dose is associated with subclinical renal injury: a Pathological study in individuals without chronic kidney disease, Nephrol Dial Transplant
, 10.1093/ndt/gfad124, 38, 12, 2799-2808, 2023.04, Background
Epidemiological studies have identified smoking as an independent risk factor for development of chronic kidney disease. However, the early renal pathological lesions have not been clearly elucidated.
Methods
We investigated time-zero biopsy specimens from 547 living kidney donors and evaluated the relationships between smoking and renal histological changes, including arteriolar hyalinization, intimal thickening of small–medium arteries, global glomerulosclerosis, and interstitial fibrosis and tubular atrophy (IF/TA).
Results
A total of 199 subjects (36.4%) had smoking history, of whom 92 (16.8%) and 107 (19.6%) had 10% global glomerulosclerosis: the OR per 20 pack-year increase was 1.24 [0.96–1.59]. The ORs for smokers with Conclusions
Subclinical pathological injury caused by smoking is potentially associated with renal arteriolar hyalinization and glomerular ischaemia.. |
| 332. |
Woohyung Lee, Dae Wook Hwang, Ho-Seong Han, In Woong Han, Jin Seok Heo, Michiaki Unno, Masaharu Ishida, Hiroshi Tajima, Nobuyuki Nishizawa, Kohei Nakata, Yasuji Seyama, Yoshiya Isikawa, Ho Kyoung Hwang, Jin-Young Jang, Taeho Hong, Joon Seong Park, Hee Joon Kim, Chi-Young Jeong, Jeong-Ik Park, Ippei Matsumoto, Hiroki Yamaue, Manabu Kawai, Masayuki Ohtsuka,Shugo Mizuno, Mitsuhiro Asakuma, Yuji Soejima, Teijiro Hirashita, Masayuki Sho, Yutaka Takeda, Jeong-Ik Park, Yong Hoon Kim, Hwa Jung Kim, Hiroki Yamaue, Masakazu Yamamoto, Itaru Endo, Masafumi Nakamura, Yoo-Seok Yoon, Comparison of infectious complications after spleen preservation versus splenectomy during laparoscopic distal pancreatectomy for benign or low-grade malignant pancreatic tumors: A multicenter, propensity score-matched analysis, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1213, 30, 2, 252-262, 2023.04, Background
Previous studies reported contrasting results regarding the advantages of spleen preservation during laparoscopic distal pancreatectomy (LDP) for preventing infectious complications.
Methods
A total of 3,787 patients who underwent LDP for benign or low-grade malignant pancreatic disease in 92 centers across Korea and Japan were included in this retrospective study. Postoperative infectious complications and other complications were compared between LDP with splenectomy (LDPS) and LDP with spleen preservation (LSPDP) by propensity score matching (PSM) analysis.
Results
After PSM, the LSPDP group had a lower rate of overall infectious complications (P = 0.079) and a significantly lower rate of intraabdominal abscess (P = 0.014) compared with the LDPS group. Within the LSPDP group, the vessel preservation subgroup had a significantly higher rate of infectious complications (P = 0.002) compared with the vessel resection subgroup. Low-volume centers had a higher rate of intraabdominal abscess than did high-volume centers in the LSPDP group (P = 0.001) and the splenic vessel preservation subgroup (P = 0.043).
Conclusions
Spleen preservation in LDP for benign or borderline malignant pancreatic diseases was advantageous in lowering the risk of infectious complications, specifically intraabdominal abscess. However, the risk of intraabdominal abscess may differ according to the level of surgeon’s experience.. |
| 333. |
Kinuko Nagayoshi, Yusuke Mizuuchi, Koji Tamura, Masafumi Sada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Combination of robotic and transperineal techniques for total pelvic exenteration followed by a posterior-anterior approach to the supralevator space - a video vignette, Colorectal Dis, 10.1111/codi.16765, 25, 11, 2282-2283, 2023.04. |
| 334. |
Jun Kawata, Yutaka Koga, Shoko Noguchi, Yuki Shimada, Yutaka Yamada, Takeo Yamamoto, Koji Shindo, Masafumi Nakamura, Yoshinao Oda, Clinicopathological features and genetic alterations in mixed-type ampullary carcinoma, Mod Pathol
, 10.1016/j.modpat.2023.100181, 36, 8, 100181, 2023.04, Mixed-type ampullary carcinoma is a subtype that combines intestinal (I)- and pancreatobiliary (PB)-type lesions, but few studies have examined its clinicopathological features and genetic alterations. The differences in genetic alterations between mixed type and other subtypes, as well as the genetic differences between I and PB-type lesions in the mixed type, remain unclear. In this study, we compared the clinicopathological features and prognosis of 110 ampullary carcinomas, classified by Hematoxylin and eosin (HE) and immunohistochemical (IHC) staining as follows: 63 PB type, 35 I type, and 12 mixed type. Comparative analysis of genetic mutations by targeted sequencing of 24 genes was also performed in 3 I-type cases, 9 PB-type cases, and I and PB lesions of 6 mixed-type cases. The mixed subtype had a poorer prognosis than the other subtypes, and there was also similar tendency in the adjuvant group (n=22). A total of 49 genetic mutations were detected in all 18 lesions for which genetic alteration was analyzed. No genetic mutations specific to the mixed type were found, and it was not possible to determine genetically whether the mixed type had originally been I type or PB type. However, five of 6 cases had mutations common to both I and PB lesions, and additional mutations were found only in either I or PB lesions. In support of this, the mixed type more frequently exhibited genetic heterogeneity intratumorally than the other subtypes. Mixed-type tumors are histologically, immunohistochemically, and genetically heterogeneous, and this heterogeneity is associated with poor prognosis and may affect treatment resistance.. |
| 335. |
Hiroyuki Kato, Akihiko Horiguchi, Shin Ishihara, Masafumi Nakamura, Itaru Endo, Clinical significance of extrahepatic bile duct resection for T2 gallbladder cancer using data from the Japanese Biliary Tract Cancer Registry between 2014 and 2018, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1379, 30, 12, 1316-1323, 2023.04, Purpose: The present study aimed to determine whether concomitant extrahepatic bile duct resection (EHBDR) improves the prognosis of patients with T2 gallbladder cancer (GBC).
Methods: Between 2014 and 2018, 4947 patients with GBC were registered in the National Biliary Tract Cancer Registry in Japan. This included 3804 patients (76.9%) who underwent curative-intent surgical resection; 1609 of these patients had pT2 GBC with no distant metastasis. Of the 1609 patients with GBC, 520 underwent EHBDR and 1089 did not. We compared the patients' backgrounds and disease-specific survival rates between the groups.
Results: The frequency of lymph node metastasis was significantly higher in the EHBDR group than in the non-EHBDR group (38.2% vs. 20.7%, p Conclusions: The EHBDR may improve the prognosis of patients with T2 gall bladder cancer with lymph node metastases; however, its indication should be carefully determined because of the increased risk of postoperative complications.
Keywords: Biliary Tract Cancer Registry; T2 gallbladder cancer; extrahepatic bile duct resection.. |
| 336. |
Takuji Okusaka, Masafumi Nakamura, Masahiro Yoshida, Masayuki Kitano, Yoshinori Ito, Nobumasa Mizuno, Keiji Hanada, Masato Ozaka, Chigusa Morizane, Yoshifumi Takeyama; Committee for Revision of Clinical Guidelines for Pancreatic Cancer of the Japan Pancreas Society, Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis, Int J Clin Oncol
, 10.1007/s10147-023-02317-x, 28, 4, 493-511, 2023.04, Objectives: Clinical Practice Guidelines for Pancreatic Cancer was first published in 2006 by the Japan Pancreas Society, and revised in 2009, 2013, 2016, and 2019. In July 2022, Clinical Practice Guidelines for Pancreatic Cancer was newly revised in Japanese.
Methods: For this revision, we developed an entirely new guideline according to the Minds Manual for Guideline Development 2020, which includes the concepts of GRADE-Grading Recommendations Assessment, Development, and Evaluation, to enable a better understanding of the current guidelines. Patients and the public were actively involved in both the development and implementation of the guideline.
Results: The guideline includes algorithms for diagnosis, treatment, chemotherapy, and precision medicine of pancreatic cancer, and addresses 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive & palliative medical care. It includes 73 clinical questions and 112 statements. The statements correspond to the clinical questions, evidence levels, recommendation strengths, and agreement rates.
Conclusions: This guideline represents the most standard clinical and practical management guideline available until date in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2022 in Japanese, and is an attempt to disseminate the Japanese guideline worldwide to introduce the Japanese approach to the clinical management of pancreatic cancer.. |
| 337. |
Naoki Ikenaga, Kohei Nakata, Masataka Hayashi, So Nakamura, Toshiya Abe, Noboru Ideno, Masatoshi Murakami, Nao Fujimori, Nobuhiro Fujita, Takuro Isoda, Shingo Baba, Kousei Ishigami, Yoshinao Oda, Masafumi Nakamura, Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy, J Gastrointest Surg, 10.1007/s11605-023-05591-2, 27, 2, 337-346, 2023.04, urpose: To evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy.
Methods: Among 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery.
Results: Nineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level.
Conclusions: Post-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; Neoadjuvant; Pancreatic ductal adenocarcinoma; Recurrence; Standardized uptake value.. |
| 338. |
Shinjiro Nagao, Hideya Onishi, Makoto Kawamoto, Shogo Masuda, Lin Na, Shinji Morisaki, Naoya Iwamoto, Yutaka Yamada, Satoko Koga, Shu Ichimiya, Kazunori Nakayama, Akira Imaizumi, Kinichi Nakashima, Yoshinao Oda, Masafumi Nakamura, C4orf47 contributes to the dormancy of pancreatic cancer under hypoxic conditions, Journal of Cancer , 10.7150/jca.78993, 14, 2, 306-317, 2023.04, In our comprehensive analysis of pancreatic cancer pathology, we found that the C4orf47 molecule was upregulated in hypoxic environments. C4orf47 is reported to be a centrosome-associated protein, but its biological significance in cancer is completely unknown; therefore, we assessed its role in pancreatic cancer. We found that C4orf47 was a direct target of HIF-1α and is upregulated in hypoxic conditions, in which it suppressed the cell cycle and inhibits cell proliferation through up-regulation of the cell cycle repressors Fbxw-7, P27, and p57; and the down-regulation of the cell cycle promoters c-myc, cyclinD1, and cyclinC. Furthermore, C4orf47 induced epithelial-mesenchymal transition and enhanced their cell plasticity and invasiveness. In addition, the p-Erk/p-p38 ratio was significantly enhanced and down-regulated CD44 expression by C4orf47 suppression, suggesting that C4orf47 is involved in pancreatic cancer dormancy under hypoxic conditions. Furthermore, the potential of C4orf47 expression was a good prognostic biomarker for pancreatic cancer. These results contribute to the elucidation of the pathology of refractory pancreatic cancer and the development of novel therapeutic strategies.. |
| 339. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, ASO Visual Abstract: A Prospective, Multicenter, Phase II, Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Clinical Trial, 10.1245/s10434-022-12611-z, 30, 1, 205-206, 2023.04. |
| 340. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Masafumi Nakamura, ASO Author Reflections: Novel Evidence on Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Ann Surg Oncol, 10.1245/s10434-022-12584-z., 30, 1, 203-204, 2023.04. |
| 341. |
Kazuhide Matsumoto, Nao Fujimori, Yoshitaka Hata, Yosuke Minoda, Masatoshi Murakami, Katsuhito Teramatsu, Yu Takamatsu, Ayumu Taken, Takamasa Oono, Eikichi Ihara, Kohei Nakata, Masafumi Nakamura, Takeo Yamamoto, Yutaka Koga, Yoshinao Oda, Tetsuhide Ito, Yoshihiro Ogawa, Ampullary Neuroendocrine Neoplasm: Clinicopathological Characteristics and Novel Endoscopic Entity, Dig Dis, 10.1159/000525013, 41, 2, 316-324, 2023.04, Background: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN.
Methods: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN).
Results: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.
Keywords: Crater sign; Endoscopic papillectomy; Neuroendocrine neoplasms of the ampulla of Vater; Pancreatic neuroendocrine neoplasms.. |
| 342. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, A Prospective Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Ann Surg Oncol, 10.1245/s10434-022-12566-1
Abstract, 30, 1, 193-202, 2023.04, Background: Only two clinical trials have shown the effects of neoadjuvant treatment for borderline resectable pancreatic cancer with arterial involvement (BRPC-A). Here, we aimed to analyze the efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel (GnP) for BRPC-A.
Patients and methods: A prospective, single-arm, multicenter phase II trial was conducted. Patients who were radiologically and histologically diagnosed with BRPC-A were enrolled. A central review was conducted to confirm the presence of BRPC-A. Patients received two to four cycles of GnP before surgery. The primary endpoint of the study was the R0 resection rate. Overall survival (OS) was evaluated in an ancillary study.
Results: Thirty-five patients were enrolled, of whom 33 were subjected to central review and 28 were confirmed to have BRPC-A. All eligible patients with BRPC-A received neoadjuvant GnP. Nineteen patients underwent pancreatic resections. Postoperative complications of Clavien-Dindo IIIa or lower were observed in 11 patients. No treatment-related mortalities were observed. R0 resection was achieved in 17 patients (89%); the R0 resection rate was 61% in eligible patients. One patient underwent curative resection after termination of the treatment protocol, resulting in an overall R0 resection rate of 64%. The median overall survival (OS) and 2-year OS rate were 24.9 months [95% confidence interval (CI) 19.0 months to not estimatable] and 53.6%, respectively. OS in patients with BRPC-A who achieved overall R0 resection was significantly longer than that in the other patients (p = 0.0255).. |
| 343. |
Takehito Otsubo, Shinjiro Kobayashi, Keiji Sano, Takeyuki Misawa, Satoshi Katagiri, Hisashi Nakayama, Shuji Suzuki, Manabu Watanabe, Shunichi Ariizumi, Michiaki Unno, Minoru Tanabe, Hiroaki Nagano, Norihiro Kokudo, Satoshi Hirano, Masafumi Nakamura, Ken Shirabe, Yasuyuki Suzuki, Masahiro Yoshida, Yasutsugu Takada, Toshio Nakagohri, Akihiko Horiguchi, Hideki Ohdan, Susumu Eguchi, Masayuki Ohtsuka, Masayuki Sho, Toshiki Rikiyama, Etsuro Hatano, Akinobu Taketomi, Tsutomu Fujii, Hiroki Yamaue, Masaru Miyazaki, Masakazu Yamamoto, Tadahiro Takada, Itaru Endo
, A nationwide certification system to increase the safety of highly advanced hepatobiliary-pancreatic surgery, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1186, 30, 1, 60-71, 2023.04, Background: To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety.
Methods: We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary.
Results: Highly advanced HBPS was performed in 121 518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (P Conclusions: Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS.
Keywords: board certification system for expert surgeons; hepatobiliary-pancreatic surgery; mortality; surgical outcomes.. |
| 344. |
kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament(with video), Surgical Endoscopy, 10.1007/s00464-023-10065-2, 37, 6, 4982-4989, 2023.04. |
| 345. |
Toshifumi Kin, Yasuhiro Shimizu, Susumu Hijioka, Kazuo Hara, Akio Katanuma, Masafumi Nakamura, Reiko Yamada, Takao Itoi, Toshiharu Ueki, Atsushi Masamune, Seiko Hirono, Shinsuke Koshita, Keiji Hanada, Ken Kamata, Akio Yanagisawa, Yoshifumi Takeyama, A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm -Multicenter observational study in Japan, Pancreatology, 10.1016/j.pan.2023.05.010, 23, 5, 550-555, 2023.04, Background/objectives: The detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN.
Methods: This multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined.
Results: Two-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p Conclusions: EUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.
Keywords: CT; EUS; IPMN; Mural nodule.. |
| 346. |
Chikanori Tsutsumi, Kenoki Ohuchida, Naoki Katayama, Yutaka Yamada, Shoichi Nakamura, Sho Okuda, Yoshiki Otsubo, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Eishi Nagai, Takashi Morisaki, Yoshinao Oda, Masafumi Nakamura, Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer, Gastric Cancer, 10.1007/s10120-023-01456-4, 2024.04, Background
Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME.
Methods
Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients.
Results
The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, among the immunosuppressive cell types assessed, M-MDSCs were most significantly enriched in GC tissues relative to adjacent normal tissues. The M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis among the immunosuppressive cells. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P=0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3－ M-MDSCs and were more abundant in treatment-resistant than -responsive GC patie
nts.
Conclusions
The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.
. |
| 347. |
Satoshi Obata, Kouji Nagata, Shinya Suematsu, Kei Nishiyama, Yasuhiro Okabe, Takuya Kondo, Junnosuke Maniwa, Atsuhisa Fukuta, Naonori Kawakubo, Yusuke Yanagi, Junko Miyata, Toshiharu Matsuur, Shouichi Ohga, Masafumi Nakamura, Tatsuro Tajiri, The Effectiveness of Deflux® Treatment for Vesicoureteral Reflux Following Pediatric Renal Transplantation: A Single-Institution Challenging Experience, J Pediatr Surg., 10.1016/j.jpedsurg.2023.12.005., 59
, 4
, 616-620, 2024.04, Purpose: To validate the effectiveness of Deflux® treatment for vesicoureteral reflux (VUR) following pediatric renal transplantation (RT), based on our single-institution experience.
Method: A retrospective study was conducted using the medical records of pediatric patients who underwent Deflux® treatment for VUR after RT from April 2008 to March 2022.
Results: Sixty-eight pediatric patients underwent RT. VUR was subsequently detected in 22 (32 %) of these patients. Seven of the 22 patients (32 %) underwent Deflux® treatment to avoid renal dysfunction due to urinary infection (UTI). The median age at the time of RT was 4 years (range:2-12). All 7 patients had urinary UTIs before Deflux® treatment. The median estimated glomerular filtration rate (eGFR) before Deflux® treatment was 67 ml/min/1.73 m2 (range:42-138 ml/min/1.73 m2). After Deflux® treatment, VUR was downgraded in three cases (43 %). Four patients (57 %) experienced postoperative UTI, two of who underwent a second Deflux® treatment, one underwent submuscular tunnel reconstruction, and the other one experienced UTI without VUR after 1st Deflux® treatment but did not reoccur. All seven patients continued prophylactic medication after Deflux® treatment, without any history of recurrent UTIs during the observation period after treatment (median 37 months [range 7-86 months]). Furthermore, the eGFRs did not significantly decrease after Deflux® treatment (median eGFR 58 ml/min/1.73 m2 [range:33-99 ml/min/1.73 m2], p > 0.1).
Conclusion: Deflux® treatment for VUR after RT is technically challenging because the new ureteral orifice is ventrally anastomosed at the bladder. We believe our results indicate the possibility of reducing the frequency of UTIs and contributing to preservation of the renal function after RT.
Type of study: Retrospective Study.
Level of evidence: Level III.
Keywords: Deflux®; Renal function; Renal transplantation urinary tract infection; Vesicoureteral. |
| 348. |
Koji Tamura, Takaaki Fujimoto, Toru Shimizu, Kinuko Nagayoshi, Yusuke Mizuuchi, Koji Shindo, Kenoki Ohuchid, Masafumi Nakamura, Risk factors and clinical significance of subcutaneous emphysema after robot-assisted laparoscopic rectal surgery: a single-center experience, Journal of Robotic Surgery, 10.1007/s11701-023-01802-9, 18, 42, 2024.04, Subcutaneous emphysema (SE) is a complication of laparoscopic surgery, potentially resulting in severe respiratory failure. No reports to date have focused on SE during robot-assisted (RA) rectal surgery. We aimed to reveal the risk factors and clinical significance of SE after RA/laparoscopic rectal surgery. We retrospectively reviewed 221 consecutive patients who underwent RA/laparoscopic rectal surgery. The occurrence of SE was evaluated on postoperative radiographs. Laparoscopic surgery was performed in 120 patients and RA in 101. SE developed in 55 (24.9%) patients. Logistic regression analysis identified RA surgery (odds ratio [OR]: 4.89, 95% confidence interval [CI] 2.13-11.22, p Keywords: Postoperative complication; Rectal cancer; Robot-assisted surgery; Subcutaneous emphysema. |
| 349. |
Keiichi Akahoshi, Junichi Shindoh, Minoru Tanabe, Shuichi Watanabe, Hayato Takamizawa, Susumu Eguchi, Itaru Endo, Shoji Kubo, Akinobu Taketomi, Hiroaki Nagano, Masafumi Nakamura, Kiyoshi Hasegawa, Etsuro Hatano, Tomoharu Yoshizumi, Norihiro Kokudo, Questionnaire survey of Japanese board-certified expert hepatobiliary and pancreatic surgeons and instructors on the surgical indications for hepatocellular carcinoma, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1408, 31, 3, 143-151, 2024.04, Background: Recent advancements in systemic therapy for hepatocellular carcinoma (HCC) necessitate the establishment of resectability criteria for advanced HCC.
Methods: A questionnaire survey sought to clarify the perspectives of Japanese expert hepatobiliary surgeons regarding surgical indications for HCC. Thirty-one questions were used to determine when surgery is strongly recommended (resectable: R) or not recommended (unresectable: UR).
Results: A total of 351 responses were obtained. While 64.7% of the respondents considered solitary tumors as being R, irrespective of size, opinions diverged on the upper limit of the number of tumors/tumor size for R: (1) up to three nodules with no size limit (27.9%), (2) up to three nodules ≤5 cm in diameter each (21.4%) and (3) up to three nodules ≤3 cm in diameter each (19.4%). Vp1, Vp2, Vp3, and Vp4 were considered as being R by 90.9%, 70.7%, 39.0%, and 8.0% of respondents, respectively. Half of the respondents indicated they would consider resection even for cases with extrahepatic spread under limited conditions.
Conclusions: The current views of Japanese expert surgeons on the resectability criteria for HCC were clarified for the first time. The findings could serve as a basis for preparing expert consensus statements on the resectability criteria for HCC.
Keywords: hepatocellular carcinoma; oncological criteria; resectability; surgery; survey.. |
| 350. |
Takashi Taniguchi, Noboru Ideno, Tomoyuki Araki, Shun Miura, Masahiro Yamamoto, Tomoki Nakafusa, Nobuhiro Higashijima, Takeo Yamamoto, Koji Tamura, So Nakamura, Toshiya Abe, Naoki Ikenaga, Kohei Nakata, Kenoki Ohuchida, Yoshinao Oda, Takao Ohtsuka, Masafumi Nakamura, MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma, DEN Open, 10.1002/deo2.333, 4, 1, e333, 2024.04, Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC.
Methods: EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified.
Results: We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively.
Conclusions: We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.
Keywords: duodenal fluid; early detection; extracellular vesicle; microRNA; pancreatic ductal adenocarcinoma.. |
| 351. |
Rintaro Nagayama, Toshiharu Ueki, Yasuhiro Shimizu, Susumu Hijioka, Masafumi Nakamura, Masayuki Kitano, Kazuo Hara, Atsushi Masamune, Toshifumi Kin, Keiji Hanada, Shinsuke Koshita, Reiko Yamada, Mamoru Takenaka, Takao Itoi, Akio Yanagisawa, Takao Otuka, Seiko Hirono, Atsushi Kanno, Noboru Ideno, Takamichi Kuwahara, Akinori Shimizu, Ken Kamata, Yasutsugu Asai, Yoshifumi Takeyama, Is preoperative pancreatic juice cytology useful for determining therapeutic strategies for patients with intraductal papillary mucinous neoplasm of the pancreas?, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1394, 31, 3, 183-192, 2024.04, Background: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies.
Methods: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP).
Results: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD Conclusions: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery.
Keywords: endoscopic retrograde cholangiopancreatography; intraductal papillary mucinous neoplasms; pancreatic carcinoma; pancreatic juice cytology; pancreatic neoplasms.. |
| 352. |
Tess M E van Ramshorst, Jony van Hilst, Elisa Bannone, Alessandra Pulvirenti, Horacio J Asbun, Ugo Boggi, Olivier R Busch, Safi Dokmak, Bjørn Edwin, Melissa Hogg, Jin-Young Jang, Tobias Keck, Igor Khatkov, Gustavo Kohan, Norihiro Kokudo, David A Kooby, Masafumi Nakamura, John N Primrose, Ajith K Siriwardena, Christian Toso, Charles M Vollmer, Herbert J Zeh, Marc G Besselink, Mohammad Abu Hilal, International survey on opinions and use of robot-assisted and laparoscopic minimally invasive pancreatic surgery: 5-year follow up, HPB, 10.1016/j.hpb.2023.09.004, 26, 1, 63-72, 2024.04, Background: Evidence on the value of minimally invasive pancreatic surgery (MIPS) has been increasing but it is unclear how this has influenced the view of pancreatic surgeons on MIPS.
Methods: An anonymous survey was sent to members of eight international Hepato-Pancreato-Biliary Associations. Outcomes were compared with the 2016 international survey.
Results: Overall, 315 surgeons from 47 countries participated. The median volume of pancreatic resections per center was 70 (IQR 40-120). Most surgeons considered minimally invasive distal pancreatectomy (MIDP) superior to open (ODP) (94.6%) and open pancreatoduodenectomy (OPD) superior to minimally invasive (MIPD) (67.9%). Since 2016, there has been an increase in the number of surgeons performing both MIDP (79%-85.7%, p = 0.024) and MIPD (29%-45.7%, p Conclusion: This survey showed considerable changes of MIPS since 2016 with most surgeons considering MIDP superior to ODP and an increased use of robot-assisted MIPS. Surgeons prefer OPD and therefore the value of MIPD remains to be determined in randomized trials.
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved. |
| 353. |
Yutaka Yamada, Takeo Yamamoto, Chikanori Tsutsumi, Takashi Matsumoto, Shoko Noguchi, Yuki Shimada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Yoshinao Oda, Immature stroma and high infiltration of CD15+ cells are predictive markers of poor prognosis in different subsets of patients with pancreatic cancer, Cancer Sci, 10.1111/cas.16060, 115, 3, 1001-1013, 2024.04, Preoperative treatment is commonly carried out for borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the relationship between the combination of immune cells in the tumor microenvironment and their intratumoral heterogeneity along with their association with histological findings remains unclear, especially in patients receiving preoperative chemotherapy. We aimed to explore the therapeutic strategies for patients with PDAC with poor prognosis after receiving chemotherapy based on histological and immunological microenvironmental classifications. We investigated the correlation between the prognosis and histological immune microenvironmental factors of patients who initially underwent surgery (n = 100) and were receiving gemcitabine plus nab-paclitaxel (GEM + nabPTX) as preoperative chemotherapy (n = 103). Immune profiles were generated based on immune cell infiltration into the tumor, and their correlation with patient outcomes and histological features was analyzed. Tumor-infiltrating neutrophils (TINs) were identified as independent poor prognostic factors using multivariate analysis in both surgery-first and preoperative chemotherapy groups. The patients were further classified into four groups based on immune cell infiltration into the tumor. Patients with high CD15 infiltration into the tumor and immature stroma at the cancer margins showed the worst prognosis in the preoperative chemotherapy group. The analysis of mRNA expression and immunohistochemical features revealed that CXCR2, the receptor for CXCL8, was correlated with disease-free and overall survival. We inferred that patients with immature stroma at the margins and high infiltration of CD15+ neutrophils within the tumor showed the worst prognosis and they could particularly benefit from treatment with inhibitors targeting CXCR2 or CXCL8.
Keywords: neoadjuvant chemotherapy; neutrophils; pancreatic cancer; receptors, chemokine; tumor microenvironment.. |
| 354. |
Taiki Moriyama, Kenoki Ohuchida, Takao Ohtsuka, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Higher incidence of cholelithiasis with Roux-en-Y reconstruction compared with Billroth-I after laparoscopic distal gastrectomy for gastric cancer: a retrospective cohort study, Langenbecks Arch Surg, 10.1007/s00423-024-03267-2, 409, 1, 75, 2024.04, Purpose: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer.
Methods: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated.
Results: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis.
Conclusion: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.
Keywords: Billroth-I; Cholelithiasis; Distal gastrectomy; Gastric cancer; Laparoscopy; Roux-en-Y.. |
| 355. |
Naoki Ikenaga, Tadayoshi Hashimoto, Junki Mizusawa, Ryo Kitabayashi, Yusuke Sano, Haruhiko Fukuda, Kohei Nakata, Kazuto Shibuya, Yuji Kitahata, Minoru Takada, Keiko Kamei, Hiroshi Kurahara, Daisuke Ban, Shogo Kobayashi, Hiroaki Nagano, Hajime Imamura, Michiaki Unno, Amane Takahashi, Shintaro Yagi, Hiroshi Wada, Hirofumi Shirakawa, Naoto Yamamoto, Seiko Hirono, Naoto Gotohda, Etsuro Hatano, Masafumi Nakamura, Makoto Ueno; on behalf of the Hepatobiliary and Pancreatic Oncology Group in Japan Clinical Oncology Group, A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study), BMC cancer, 10.1186/s12885-024-11957-9, 24, 1, 231, 2024.04, Background: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP).
Methods: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP.
Discussion: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy.
Trial registration: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].
Keywords: Clinical trial; Laparoscopy; Minimally invasive surgical procedures; Pancreatectomy; Pancreatic neoplasm.. |
