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Pancreatic Neoplasms: HELP
Articles by Kiyoshi Hasegawa
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Kiyoshi Hasegawa wrote the following 16 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer. 2018

Saito, Kei / Isayama, Hiroyuki / Sakamoto, Yoshihiro / Nakai, Yousuke / Ishigaki, Kazunaga / Tanaka, Mariko / Watadani, Takeyuki / Arita, Junichi / Takahara, Naminatsu / Mizuno, Suguru / Kogure, Hirofumi / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Hasegawa, Kiyoshi / Fukayama, Masashi / Kokudo, Norihiro / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. isayama-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan. isayama-tky@umin.ac.jp. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Med Oncol · Pubmed #29846849.

ABSTRACT: There has been a pressing need to develop optimal regimen for neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). The safety and efficacy of gemcitabine, S-1, and LV combination (GSL) therapy as NAC for borderline resectable (BR) and locally advanced (LA) PC was evaluated in this phase II study. Patients with pathologically proven BR or LA PC were enrolled and gemcitabine 1000 mg/m

2 Clinical Trial Adjuvant combination therapy with gemcitabine and autologous γδ T-cell transfer in patients with curatively resected pancreatic cancer. 2017

Aoki, Taku / Matsushita, Hirokazu / Hoshikawa, Mayumi / Hasegawa, Kiyoshi / Kokudo, Norihiro / Kakimi, Kazuhiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan; Second Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan. · Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan. · Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kakimi@m.u-tokyo.ac.jp. ·Cytotherapy · Pubmed #28188072.

ABSTRACT: BACKGROUND AIMS: The outcome for pancreatic cancer after surgery remains highly unsatisfactory, and development of more effective therapies is urgently needed. Therefore, we conducted a phase I clinical study of a novel combination of gemcitabine (GEM) and autologous γδ T-cell therapy for patients with curatively resected pancreatic cancer (University Hospital Medical Information Clinical Trials Registry identifier 000000931). METHODS: From July 2008 to December 2012, 56 consenting patients were recruited. After preliminary testing of γδ T-cell proliferative capacity, 28 patients were eligible to receive combined GEM plus γδ T-cell therapy. RESULTS: During treatment, most of the adverse events observed were due to GEM, including myelosuppression and gastrointestinal disorders. No severe adverse events were obviously related to the γδ T-cell therapy. To evaluate clinical efficacy, patients receiving combined therapy (Group A, n = 28) were compared with those receiving GEM alone (Group B, n = 20). No significant differences were observed between the two groups in recurrence-free survival or overall survival. However, we found that, relative to progressing patients, more γδ T-cells were detectable in the blood of recurrence-free patients after only two injections (P < .0388) and more so five injections (P < .0175). Patients with >15% peripheral γδ T-cells after two injections and >20% after five injections had a chance of a more favorable clinical outcome. Accumulation of γδ T cells was positively related to the quality of the infused products, with those having >80% γδ T cells being optimal. DISCUSSION: High quality of the γδ T-cell product is crucial to achieve a high percentage of γδ T cells in the blood and to achieve better clinical outcome.

3 Article Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous Neoplasms. 2020

Oyama, Hiroki / Tada, Minoru / Takagi, Kaoru / Tateishi, Keisuke / Hamada, Tsuyoshi / Nakai, Yousuke / Hakuta, Ryunosuke / Ijichi, Hideaki / Ishigaki, Kazunaga / Kanai, Sachiko / Kogure, Hirofumi / Mizuno, Suguru / Saito, Kei / Saito, Tomotaka / Sato, Tatsuya / Suzuki, Tatsunori / Takahara, Naminatsu / Morishita, Yasuyuki / Arita, Junichi / Hasegawa, Kiyoshi / Tanaka, Mariko / Fukayama, Masashi / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: mtada-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan. · Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Hepato-Pancreatico-Biliary Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Gastroenterology · Pubmed #31473224.

ABSTRACT: BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing. RESULTS: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC. CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.

4 Article Usefulness of indocyanine green-fluorescence imaging for real-time visualization of pancreas neuroendocrine tumor and cystic neoplasm. 2018

Shirata, Chikara / Kawaguchi, Yoshikuni / Kobayashi, Kosuke / Kobayashi, Yuta / Arita, Junichi / Akamatsu, Nobuhisa / Kaneko, Junichi / Sakamoto, Yoshihiro / Kokudo, Norihiro / Hasegawa, Kiyoshi. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·J Surg Oncol · Pubmed #30261107.

ABSTRACT: We evaluated the usefulness of fluorescence imaging using indocyanine green to identify pancreas tumors in 23 patients undergoing pancreas resection. This technique was useful in visualizing pancreas lesions during surgery, specifically, neuroendocrine tumors as fluorescence and cystic neoplasms as a fluorescence defect.

5 Article NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer. 2018

Hoshikawa, Mayumi / Aoki, Taku / Matsushita, Hirokazu / Karasaki, Takahiro / Hosoi, Akihiro / Odaira, Kosuke / Fujieda, Nao / Kobayashi, Yukari / Kambara, Kaori / Ohara, Osamu / Arita, Junichi / Hasegawa, Kiyoshi / Kakimi, Kazuhiro / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Second Department of Surgery, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan. · Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation Hub Program, RIKEN, Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan. · Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan. · Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; Medinet Co. Ltd., Yokohama, Kanagawa 222-0033, Japan. · Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba 294-0226, Japan. · Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation Hub Program, RIKEN, Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan. Electronic address: kakimi@m.u-tokyo.ac.jp. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan. ·Biochem Biophys Res Commun · Pubmed #29253566.

ABSTRACT: To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.

6 Article Vascular anatomy of the jejunal mesentery and complications associated with division of the first jejunal venous trunk during pancreaticoduodenectomy. 2018

Kobayashi, Yuta / Sakamoto, Yoshihiro / Arita, Junichi / Akamatsu, Nobuhisa / Kaneko, Junichi / Hasegawa, Kiyoshi / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. ·J Surg Oncol · Pubmed #29205361.

ABSTRACT: BACKGROUND: Little is known about the anatomy of the jejunal veins (JVs) flowing into the superior mesenteric vein (SMV), and whether they can be safely divided during pancreaticoduodenectomy. METHODS: Computed tomography was used to review the jejunal branches off the superior mesenteric artery (SMA) and into the SMV in 123 consecutive patients. The common trunk of the JVs (jejunal venous trunk, JVT) was classified as ventral or dorsal to the SMA. RESULTS: The first JVT involved multiple JVs in 108 (87.8%) cases. The first JVT diameter (≥7 or <7 mm) was significantly associated with the number of JVs (≥4 or <4; P < 0.05). Surgical outcomes were not significantly different between cases in which the first JVT was sacrificed (n = 32) or preserved (n = 91), except for operation time and portal venous resection frequency. One of the 32 cases (3.1%) with first JVT sacrifice showed severe congestion of the jejunal limb requiring emergency jejunal resection. CONCLUSIONS: The size and topology of the first JVT are associated with the number of JVs involved. This is important for understanding the resectional area of the mesojejunum and the pathogenesis of jejunal congestion.

7 Article Predictors of Postoperative Non-Chylous Massive Discharge after Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma. 2018

Ito, Kyoji / Kawaguchi, Yoshikuni / Sakamoto, Yoshihiro / Arita, Junichi / Hasegawa, Kiyoshi / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. ·Dig Surg · Pubmed #28817822.

ABSTRACT: BACKGROUND: Pancreaticoduodenectomy (PD) is performed for pancreatic ductal adenocarcinoma (PDA) located at the pancreas head/body. Non-chylous massive discharge after PD is frequently encountered and can cause a vicious cycle of complications associated with severe dehydration and protein loss. METHODS: From August 2008 to June 2015, 102 patients who underwent PD for PDA were retrospectively reviewed. High non-chylous discharge was defined as postoperative daily serous discharge exceeding 10 mL/kg. Predictive factors for high non-chylous discharge were assessed using multivariable analysis. RESULTS: Fifty-one patients (50%) developed high non-chylous discharge. Body mass index (BMI) and hemoglobin, total protein, and cholinesterase levels were significantly lower in the high-discharge group compared to the corresponding levels in the low-discharge group. The incidence of postoperative pancreatic fistula and delayed gastric emptying was significantly lower and higher in the high-discharge group than in the low-discharge group, respectively. Multivariable analysis revealed that BMI <22.0 kg/m2, hemoglobin <12.0 g/dL and intraoperative blood loss ≥800 mL were independent predictive factors for high non-chylous discharge. CONCLUSIONS: Preoperative low levels of BMI and hemoglobin and intraoperative high blood loss were independent predictive factors for high non-chylous discharge. Improvement of preoperative general and nutritional condition may reduce the incidence of high non-chylous discharge.

8 Article EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis. 2017

Tanaka, Mariko / Ishikawa, Shumpei / Ushiku, Tetsuo / Morikawa, Teppei / Isagawa, Takayuki / Yamagishi, Makoto / Yamamoto, Hiroyuki / Katoh, Hiroto / Takeshita, Kimiko / Arita, Junichi / Sakamoto, Yoshihiro / Hasegawa, Kiyoshi / Kokudo, Norihiro / Fukayama, Masashi. ·Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. · Department of Cardiovascular Medicine, Nagasaki University Hospital, Nagasaki, Japan. · Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Tokyo, Japan. · AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan. · Department of Hepatobiliary-pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · National Center for Global Health and Medicine, Tokyo, Japan. ·Oncotarget · Pubmed #29245923.

ABSTRACT: Glypican-1 (GPC1) protein in exosomes was recently identified as a biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analyses and

9 Article Intraductal papillary neoplasm originating from an anomalous bile duct. 2017

Maki, Harufumi / Aoki, Taku / Ishizawa, Takeaki / Tanaka, Mariko / Sakatani, Takashi / Beck, Yoshifumi / Hasegawa, Kiyoshi / Sakamoto, Yoshihiro / Kokudo, Norihiro. ·Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Pathology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. KOKUDO-2SU@h.u-tokyo.ac.jp. ·Clin J Gastroenterol · Pubmed #28213744.

ABSTRACT: An 82-year-old woman who had been suffering from repeated obstructive jaundice for 7 years was referred to our hospital. Although endoscopic aspiration of the mucin in the common bile duct had been temporally effective, origin of the mucin production had not been detectable. The patient thus had been forced to be on long-term follow-up without curative resection. Endoscopic retrograde cholangioscopy on admission revealed massive mucin in the common bile duct. In addition, an anomalous bile duct located proximal to the gallbladder was identified. Since the lumen of the anomalous duct was irregular and the rest of biliary tree was completely free of suspicious lesions, the anomalous duct was judged to be the primary site. Surgical resection of the segment 4 and 5 of the liver combined with the extrahepatic biliary tract was performed. Pathological diagnosis was compatible to intraductal papillary neoplasm with high-grade intraepithelial dysplasia of the anomalous bile duct. The patient has been free from the disease for 6.5 years after resection. This is the first case of intraductal papillary neoplasm derived from an anomalous bile duct, which was resected after long-term conservative treatment. The present case suggested the slow growing character of natural history of the neoplasm.

10 Article Safety and efficacy of cryopreserved homologous veins for venous reconstruction in pancreatoduodenectomy. 2017

Yamamoto, Masaki / Akamatsu, Nobuhisa / Aoki, Taku / Sakamoto, Yoshihiro / Tamura, Sumihito / Hasegawa, Kiyoshi / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. · Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: nakamats-tky@umin.ac.jp. · Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: kokudo-2su@h.u-tokyo.ac.jp. ·Surgery · Pubmed #27726914.

ABSTRACT: BACKGROUND: There are several techniques for reconstructing the portal vein-superior mesenteric vein during pancreatoduodenectomy. The aim of the present study was to present our results with portal vein-superior mesenteric vein reconstruction using cryopreserved homologous veins during pancreatoduodenectomy for patients with pancreatic head cancer. METHODS: Patients who underwent pancreatoduodenectomy for pancreatic head cancer were reviewed retrospectively. In patients with portal vein-superior mesenteric vein resection, the detailed method of reconstruction and clinical outcomes were reviewed. Clinical characteristics, patient survival, and portal vein-superior mesenteric vein patency were compared between those with and without homologous vein grafts. Factors affecting the patency of reconstructed veins were assessed by univariate analysis. RESULTS: Among 144 patients undergoing pancreatoduodenectomy, portal vein-superior mesenteric vein resection was performed in 36 patients (25%); 18 (50%) underwent reconstruction with homologous veins, and the other 18 (50%) underwent reconstruction without homologous veins. The extent of portal vein-superior mesenteric vein involvement, operative time, duration of clamping of portal vein-superior mesenteric vein, intraoperative blood loss, and length of the venous resection were greater (P ≤ .013 each) in those with homologous vein grafts. There was no significant difference in postoperative morbidity/mortality, patient survival, or portal vein-superior mesenteric vein patency. The 1- and 2-year overall patency of portal vein-superior mesenteric vein was 76% and 71%, respectively, while the 2-year patencies were 67% and 67% in those with homologous veins and 87% and 73% in those without homologous veins without difference between the groups. Circumferential resection and pathologic portal vein-superior mesenteric vein involvement were associated with the patency of the reconstructed vein (P = .002 and P = .028, resp). CONCLUSION: Use of homologous venous grafts for portal vein-superior mesenteric vein reconstruction are feasible alternatives during pancreatoduodenectomy for advanced pancreatic head cancer.

11 Article Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer. 2016

Yamamoto, Keisuke / Tateishi, Keisuke / Kudo, Yotaro / Hoshikawa, Mayumi / Tanaka, Mariko / Nakatsuka, Takuma / Fujiwara, Hiroaki / Miyabayashi, Koji / Takahashi, Ryota / Tanaka, Yasuo / Ijichi, Hideaki / Nakai, Yousuke / Isayama, Hiroyuki / Morishita, Yasuyuki / Aoki, Taku / Sakamoto, Yoshihiro / Hasegawa, Kiyoshi / Kokudo, Norihiro / Fukayama, Masashi / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. · Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. · Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. · Second Department of Surgery, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan. ·Oncotarget · Pubmed #27528027.

ABSTRACT: Inhibitors of bromodomain and extraterminal domain (BET) proteins, a family of chromatin reader proteins, have therapeutic efficacy against various malignancies. However, the detailed mechanisms underlying the anti-tumor effects in distinct tumor types remain elusive. Here, we show a novel antitumor mechanism of BET inhibition in pancreatic ductal adenocarcinoma (PDAC). We found that JQ1, a BET inhibitor, decreased desmoplastic stroma, a hallmark of PDAC, and suppressed the growth of patient-derived tumor xenografts (PDX) of PDACs. In vivo antitumor effects of JQ1 were not always associated with the JQ1 sensitivity of respective PDAC cells, and were rather dependent on the suppression of tumor-promoting activity in cancer-associated fibroblasts (CAFs). JQ1 inhibited Hedgehog and TGF-β pathways as potent regulators of CAF activation and suppressed the expression of α-SMA, extracellular matrix, cytokines, and growth factors in human primary CAFs. Consistently, conditioned media (CM) from CAFs promoted the proliferation of PDAC cells along with the activation of ERK, AKT, and STAT3 pathways, though these effects were suppressed when CM from JQ1-treated CAFs was used. Mechanistically, chromatin immunoprecipitation experiments revealed that JQ1 reduced TGF-β-dependent gene expression by disrupting the recruitment of the transcriptional machinery containing BET proteins. Finally, combination therapy with gemcitabine plus JQ1 showed greater efficacy than gemcitabine monotherapy against PDAC in vivo. Thus, our results reveal BET proteins as the critical regulators of CAF-activation and also provide evidence that stromal remodeling by epigenetic modulators can be a novel therapeutic option for PDAC.

12 Article Advantages and Disadvantages of Prophylactic Abdominal Drainage in Distal Pancreatectomy. 2016

Yamashita, Suguru / Ishizawa, Takeaki / Ichida, Akihiko / Kaneko, Junichi / Aoki, Taku / Sakamoto, Yoshihiro / Sugawara, Yasuhiko / Hasegawa, Kiyoshi / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. kokudo-2su@h.u-tokyo.ac.jp. ·World J Surg · Pubmed #26768889.

ABSTRACT: BACKGROUND: A method to completely prevent postoperative pancreatic fistula (PF) in distal pancreatectomy (DP) is lacking. Hence, prophylactic abdominal drains could be used to prevent PF from developing into life-threatening complications. METHODS: In 152 consecutive patients undergoing DP, three drains were placed routinely toward the pancreatic stump, supra-pancreatic space, and left subphrenic space. Abdominal drains were removed after surgery gradually based on amylase levels and positivity for bacterial infection in abdominal fluids. RESULTS: Postoperative symptomatic PF occurred in 57 of 152 patients (37.5 %). Prevalence of severe postoperative complications (Clavien-Dindo grade ≥ IIIa) was 16 %, with surgery-associated mortality observed in one patient (0.7 %). Prevalence of infection in drained abdominal fluids increased gradually and was >10 % on postoperative day (POD)-7. Severe postoperative complications led to longer postoperative hospital stays and higher treatment costs. Multivariate analyses revealed that a body mass index ≥ 25 kg/m(2), serum albumin level ≤ 3.8 g/dL, and white blood cell count at POD-3 ≥ 15,000/μL were independent predictors for development of severe postoperative complications. CONCLUSION: Use of prophylactic abdominal drains in DP seems to be effective for preventing PF from developing into fatal complications. However, definitive criteria should be established for enhancing safety and cost efficiency of DP through selective use and early removal of prophylactic drains.

13 Article Successful case of pancreaticoduodenectomy with resection of the hepatic arteries preserving a single aberrant hepatic artery for a pancreatic neuroendocrine tumor: report of a case. 2015

Ichida, Akihiko / Sakamoto, Yoshihiro / Akahane, Masaaki / Ishizawa, Takeaki / Kaneko, Junichi / Aoki, Taku / Hasegawa, Kiyoshi / Sugawara, Yasuhiko / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan, ichida-tky@umin.ac.jp. ·Surg Today · Pubmed #24477525.

ABSTRACT: A 65-year-old male with a pancreatic neuroendocrine tumor presenting with a duodenal ulcer was referred to our department. The tumor involved the common hepatic artery, gastroduodenal artery, left hepatic artery and the right posterior hepatic artery, but not the right anterior hepatic artery originating from the superior mesenteric artery. The hepatic arteries, except the aberrant right anterior hepatic artery, were embolized using coils 18 days before the surgery. The patient underwent pancreaticoduodenectomy with resection of the tumor-encased hepatic arteries, while preserving the aberrant artery. The patient was discharged uneventfully on postoperative day 13 with no ischemic complications. A histopathological examination revealed a grade 2 pancreatic neuroendocrine tumor according to the classification of the World Health Organization, and the surgical margin was negative. The patient developed hepatic metastases 16 months after surgery; hence, hepatic resection was performed. The present surgical strategy is applicable in patients with relatively low-grade pancreatic malignancies involving major hepatic arteries.

14 Article Subcellular localization of KL-6 mucin in intraductal papillary mucinous neoplasm of the pancreas. 2014

Inagaki, Yoshinori / Seyama, Yasuji / Hasegawa, Kiyoshi / Tang, Wei / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo. ·Drug Discov Ther · Pubmed #25047009.

ABSTRACT: This study aimed to clarify the expression profile of KL-6 mucin in intraductal papillary mucinous neoplasm (IPMN) and its relation to tumor malignancy. Expression of KL-6 mucin in 38 IPMNs (intraductal papillary mucinous adenoma (IPMA), 24 cases; minimally invasive intraductal papillary mucinous carcinoma (MI-IPMC), 8 cases; invasive carcinoma originating from IPMC (IC-IPMC), 6 cases) and 66 pancreatic ductal adenocarcinomas (PDACs) was evaluated immunohistochemically. IC-IPMCs and MI-IPMCs had positive staining of KL-6 mucin whereas 58% of IPMAs tested negative. Subcellular localization of KL-6 mucin varied among IPMNs whereas all of the PDAC had positive expression in the circumferential membrane and cytoplasm of cancer cells. IC-IPMCs and MI-IPMCs had a higher frequency of circumferential membrane and cytoplasmic localization of KL-6 mucin than did IPMAs. These results suggest that localization of KL-6 mucin could be used to predict the malignancy of IPMN.

15 Article Expression of KL-6/MUC1 in pancreatic ductal carcinoma and its potential relationship with β-catenin in tumor progression. 2011

Xu, Huanli / Inagaki, Yoshinori / Seyama, Yasuji / Hasegawa, Kiyoshi / Sugawara, Yasuhiko / Du, Guanhua / Wang, Fengshan / Tang, Wei / Kokudo, Norihiro. ·Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Japan. ·Life Sci · Pubmed #21466814.

ABSTRACT: AIM: The aim of this study was to evaluate the expression of Krebs yon den Lundgen-6/Mucin 1 (KL-6/MUC1) in pancreatic ductal carcinoma and its potential relationship with β-catenin in tumor progression. MAIN METHODS: The expressions of KL-6/MUC1 and β-catenin in 18 cases of pancreatic ductal carcinoma were detected by immunohistochemical staining. To determine the impact of KL-6/MUC1 down-regulation on pancreatic ductal carcinoma progression, siRNA targeting MUC1 was used to knockdown KL-6/MUC1 expression. The down-regulation of KL-6/MUC1 expression was confirmed by reverse transcription-polymerase chain reaction and immunofluorescence staining. E-cadherin and E-cadherin/β-catenin complex expressions were determined by immunoprecipitation. The expressions of KL-6/MUC1, β-catenin, cyclin D1 and c-myc were detected by Western blot. Cell proliferation, apoptosis and invasive abilities were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, Annexin V-FITC apoptosis detection kit and invasion assay. KEY FINDINGS: Positive KL-6/MUC1 staining was observed in the cancer tissues of all the 18 pancreatic ductal carcinoma cases (100.0%), and high nuclear β-catenin expression was seen in 12 cancers (66.7%). Reverse transcription-polymerase chain reaction and immunofluorescence staining showed that both KL-6/MUC1 mRNA and protein were effectively silenced by MUC1 siRNA. After KL-6/MUC1 knockdown, E-cadherin and E-cadherin/β-catenin complex expressions were increased, while the nuclear β-catenin, cyclin D1, and c-myc expressions were decreased. Down-regulation of KL-6/MUC1 also resulted in slower proliferation, increased apoptosis and decreased invasive ability. SIGNIFICANCE: This study indicated that KL-6/MUC1 played a complex role in regulating pancreatic ductal carcinoma cell proliferation, apoptosis, and invasion, and also supported the hypothesis that there is a functional link between KL-6/MUC1 expression and β-catenin subcellular localization.

16 Minor A R0 resection case of initially unresectable metastatic pancreatic cancer downstaged by FOLFIRINOX therapy. 2014

Sasaki, Takashi / Isayama, Hiroyuki / Aoki, Taku / Tanaka, Mariko / Hamada, Tsuyoshi / Nakai, Yousuke / Sakamoto, Yoshihiro / Hasegawa, Kiyoshi / Morikawa, Teppei / Fukayama, Masashi / Kokudo, Norihiro / Koike, Kazuhiko. ·Department of Gastroenterology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Department of Gastroenterology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan isayama-2im@h.u-tokyo.ac.jp Hepato-Biliary-Pancreatic Surgery Division Department of Surgery Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Department of Pathology and Diagnostic Pathology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Department of Gastroenterology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Hepato-Biliary-Pancreatic Surgery Division Department of Surgery Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Department of Pathology and Diagnostic Pathology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Hepato-Biliary-Pancreatic Surgery Division Department of Surgery Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan Department of Gastroenterology Graduate School of Medicine The University of Tokyo Bunkyo-ku, Tokyo, Japan. ·Pancreas · Pubmed #25010709.

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