Publications by authors named "Daisuke Hashimoto"

160 Publications

Recurrent atelectasis and brain infarction in a patient with anti-neutrophil antibody negative eosinophilic granulomatosis with polyangiitis: a case report.

BMC Rheumatol 2021 Sep 1;5(1):28. Epub 2021 Sep 1.

Department of Internal Medicine, Kochi Prefectural Hata-Kenmin Hospital, 3-1Yoshina, Yamanachou, Sukumo, 788-0785, Japan.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil antibody (ANCA)-associated necrotizing vasculitis, which predominantly affects small to medium vessels, and is associated with asthma and eosinophilia. EGPA has two different pathogenic aspects: eosinophilic granulomatous inflammation and ANCA-associated inflammation. A recent histological study of peripheral nerves showed that not only ANCA-associated inflammation but also eosinophil-associated vascular occlusion leads to ischemia. Endobronchial involvement is relatively common especially in the patients with granulomatosis with polyangiitis but rare in patients with EGPA. Central nervous system (CNS) involvement is also rare in patients with EGPA, the pathogenesis and relationship between these two rare conditions have not been elucidated.

Case Presentation: A 62-year-old woman was admitted with numbness, purpura, and eosinophilia. She had a 3-year-history of bronchial asthma. Chest computed tomography showed left lower lobe collapse, and brain magnetic resonance imaging indicated occipital lobe infarction. Skin biopsy findings led to the diagnosis of EGPA. ANCA test results were negative. All symptoms improved after initiating glucocorticoids. However, atelectasis and brain infarction relapsed with increasing eosinophil counts. Atelectasis quickly disappeared with increasing glucocorticoid dose, and glucocorticoid could be reduced to a maintenance dose after the initiation of mepolizumab.

Conclusion: Both atelectasis and brain infarction might develop not only via ANCA-associated inflammation but also via eosinophilic inflammation.
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http://dx.doi.org/10.1186/s41927-021-00200-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408937PMC
September 2021

Validation of the triple-checked criteria for drain management after pancreatectomy.

J Hepatobiliary Pancreat Sci 2021 Jul 30. Epub 2021 Jul 30.

Department of Surgery, Kansai Medical University, Hirakata, Japan.

Background: Drain management is important for the detection and treatment of clinically relevant postoperative pancreatic fistula (CR-POPF). We previously established the triple-checked criteria for drain removal: drain fluid amylase (DFA) <5000 U/L on postoperative day (POD) 1 and DFA <3000 U/L on POD 3, or C-reactive protein <15 mg/dL on POD 3. This study aimed to validate the efficacy of the triple-checked criteria.

Methods: In this study, 681 patients who underwent pancreatectomy were included. Drains were removed according to our previous criteria (sequentially checked criteria: DFA <5000 U/L on POD 1 and DFA <3000 U/L on POD 3) from 2012 to 2016 (control group) and the triple-checked criteria from 2017 to 2019 (intervention group).

Results: The control group included 406 patients, and the intervention group included 275 patients. Significantly more patients (n = 237, 86.2%) met the triple-checked criteria in the intervention group, relative to the sequentially checked criteria for early drain removal policy (n = 309, 76.1%; P = .001). Sensitivity, accuracy, and negative predictive value were significantly higher in the intervention group than in the control group (P < .001). The incidence of CR-POPF was not significantly different (11.1% vs 13.8%, P = .285).

Conclusions: The triple-checked criteria contributed to effective drain removal after pancreatectomy without increasing CR-POPF.
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http://dx.doi.org/10.1002/jhbp.1030DOI Listing
July 2021

Hepatic actinomycosis after total pancreatectomy: A case report.

Int J Surg Case Rep 2021 Aug 20;85:106212. Epub 2021 Jul 20.

Department of Surgery, Kansai Medical University, Osaka, Japan.

Introduction And Importance: Hepatic actinomycosis (HA) is a rare infection mimicking a malignancy. HA after total pancreatectomy for a pancreatic tumor has not been reported.

Case Presentation: A 70-year-old woman with a history of gastrectomy and sigmoidectomy for benign lesions, underwent a total pancreatectomy for a non-invasive, intraductal papillary mucinous carcinoma (IPMC). She required partial resection of the transverse colon due to insufficient blood flow and had an anastomotic failure. Four months later, she developed a fever and effusion from the upper abdominal midline incision. No bacteria were cultured from the effusion. Contrast-enhanced computed tomography demonstrated an 80-mm iso-vascular liver mass. A slightly high-signal intensity on T2-weighted magnetic resonance imaging was demonstrated. Positron emission tomography (PET) showed a standardized uptake value of 11.9 at the liver mass. The percutaneous liver biopsy did not establish a diagnosis. Because a malignancy could not be ruled out, an exploratory laparotomy was performed. A tissue sample revealed aggregates of branched filamentous microorganisms; actinomycosis was diagnosed. Oral amoxicillin for 4 months resolved the mass.

Clinical Discussion: This patient had several causative factors for HA, including multiple surgical procedures involving the gastrointestinal tract, reconstruction of the biliary tract, anastomotic failure of the transverse colon, and diabetes mellitus following total pancreatectomy. Based on the past treatment history for IPMC and PET findings mimicking a malignancy, a laparotomy was performed to biopsy the lesion. Typically, penicillin is recommended for >6 months.

Conclusion: A rare case of HA mimicking a malignancy after a total pancreatectomy for IPMC is presented.
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http://dx.doi.org/10.1016/j.ijscr.2021.106212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335620PMC
August 2021

A simple risk score for detecting radiological occult metastasis in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma.

J Hepatobiliary Pancreat Sci 2021 Jul 27. Epub 2021 Jul 27.

Department of Surgery, Kansai Medical University, Osaka, Japan.

Background: We advocated carbohydrate antigen (CA) 19-9 ≥ 150 U/mL and tumor size ≥30 mm as "high-risk markers" for predicting unresectability among patients with radiologically resectable (R) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). The main aim is to establish a risk scoring system for occult abdominal metastasis (OAM) in R/BR PDAC.

Methods: Predictors of OAM were investigated retrospectively in an experiment cohort from 2006 to 2018. The proposed risk scoring system was validated in another cohort from 2019 to 2020.

Results: Five hundred and thirteen eligible patients were divided into the experimental (405 patients; OAM, 22%) and validation cohorts (108 patients). Multivariate analysis identified tumor location of body/tail (odds ratio [OR] 4.45, P < .0001) and "high-risk markers" (OR 2.07, P = .011) as independent predictors of OAM. A scoring system consisting of body/tail (yes: 1, no: 0) and "high-risk markers" (yes: 1, no: 0) was constructed. In the validation cohort, when staging laparoscopy (SL) was performed for patients with scores 1/2, the eligibility for SL, sensitivity, and negative predictive value of OAM were 55%, 91%, and 96%, respectively.

Conclusions: Tumor location of body/tail and "high-risk markers" were independent predictors of OAM, composing our simple and reproducible risk scoring system.
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http://dx.doi.org/10.1002/jhbp.1026DOI Listing
July 2021

Nutritional impact of active hexose-correlated compound for patients with resectable or borderline-resectable pancreatic cancer treated with neoadjuvant therapy.

Surg Today 2021 Jun 4. Epub 2021 Jun 4.

Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-City, Osaka, 573-1010, Japan.

Active hexose-correlated compound (AHCC) is a standardized extract from cultured Lentinula edodes mycelia, used as a potent biological response modifier in cancer treatment. We evaluated the nutritional effect of AHCC, given during neoadjuvant therapy, to patients with pancreatic ductal adenocarcinoma (PDAC). Thirty patients with resectable or borderline-resectable PDAC received neoadjuvant therapy with gemcitabine plus S-1. We compared, retrospectively, the outcomes of 15 patients who received AHCC combined with neoadjuvant therapy with those of 15 patients who did not receive AHCC combined with neoadjuvant therapy. The median changes of the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) were significantly better in the AHCC group. The relative dose intensity of neoadjuvant therapy was also significantly higher in the AHCC group. Thus, AHCC may improve the nutritional status during neoadjuvant therapy of patients with pancreatic ductal adenocarcinoma. To validate these results and examine the long-term impact of AHCC, a prospective phase II study for PDAC is ongoing.
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http://dx.doi.org/10.1007/s00595-021-02308-3DOI Listing
June 2021

Conversion surgery in patients with pancreatic cancer and peritoneal metastasis.

J Gastrointest Oncol 2021 Apr;12(Suppl 1):S110-S117

Department of Surgery, Kansai Medical University, Hirakata, Japan.

Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies globally. We have previously explored the clinical efficacy of intraperitoneal (IP) paclitaxel therapy for patients with PDAC and peritoneal metastasis, which demonstrated favourable response and disease control rates. However, the real implications of conversion surgery after IP therapy remain unclear.

Methods: We conducted two multicenter clinical trials of IP therapy with paclitaxel in patients with PDAC and peritoneal metastasis. We focused on patients who underwent conversion surgery and investigated the long-term outcomes, particularly, initial recurrence patterns and long-term survival.

Results: Seventy-nine patients with PDAC and peritoneal metastasis were treated, and 33 (41.8%) patients received SP (intravenous IP paclitaxel with S-1) and 46 (58.3%) were administered GAP (intravenous gemcitabine + nab-paclitaxel combined with IP paclitaxel) combination therapy. Of the 79 patients, 16 (20.3%) underwent conversion surgery. The median time to surgery was 9.0 (range, 4.1-13.0) months after the initiation of chemotherapy. Finally, 13 (81.3%) patients underwent R0 resection. Evans grade was IIA in nine patients, IIB in four patients, III in two patients, and IV in one patient. The median overall survival time in patients who underwent conversion surgery was 32.5 (range, 13.5-66.9) months. Twelve (75.0%) patients were found to have experienced recurrence after conversion surgery. Especially, peritoneal recurrence was observed in 50% of patients as the initial recurrence pattern. The median recurrence-free survival time was 9.2 (range, 5.1-32.8) months, and three patients have survived without recurrence to date.

Conclusions: Our IP therapy displays promising clinical efficacy with acceptable tolerability in patients with PDAC and peritoneal metastasis. Although we could observe some super-responders in the cohort, further improvements in IP therapy are warranted.
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http://dx.doi.org/10.21037/jgo-20-243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100706PMC
April 2021

Does direct invasion of peripancreatic lymph nodes impact survival in patients with pancreatic ductal adenocarcinoma? A retrospective dual-center study.

Pancreatology 2021 Aug 19;21(5):884-891. Epub 2021 Mar 19.

Department of Surgery, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Background: Pancreatic ductal adenocarcinoma can directly invade the peripancreatic lymph nodes; however, the significance of direct lymph node invasion is controversial, and it is currently classified as lymph node metastasis. This study aimed to identify the impact of direct invasion of peripancreatic lymph nodes on survival in patients with pancreatic ductal adenocarcinoma.

Methods: A total of 411 patients with resectable/borderline resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection at two high-volume centers from 2006 to 2016 were evaluated retrospectively.

Results: Sixty (14.6%) patients had direct invasion of the peripancreatic lymph nodes without isolated lymph node metastasis (N-direct group), 189 (46.0%) had isolated lymph node metastasis (N-met group), and 162 (39.4%) had neither direct invasion nor isolated metastasis (N0 group). There was no significant difference in median overall survival between the N-direct group (35.0 months) and the N0 group (45.6 month) (p = 0.409), but survival was significantly longer in the N-direct compared with the N-met group (25.0 months) (p = 0.003). Similarly, median disease-free survival was similar in the N-direct (21.0 months) and N0 groups (22.7 months) (p = 0.151), but was significantly longer in the N-direct compared with the N-met group (14.0 months) (p < 0.001). Multivariate analysis identified resectability, adjuvant chemotherapy, and isolated lymph node metastasis as independent predictors of overall survival. However, direct lymph node invasion was not a predictor of survival.

Conclusion: Direct invasion of the peripancreatic lymph nodes had no effect on survival in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma, and should therefore not be classified as lymph node metastasis.
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http://dx.doi.org/10.1016/j.pan.2021.03.008DOI Listing
August 2021

Multicenter randomized phase II trial of prophylactic right-half dissection of superior mesenteric artery nerve plexus in pancreatoduodenectomy for pancreatic head cancer.

Ann Gastroenterol Surg 2021 Jan 15;5(1):111-118. Epub 2020 Sep 15.

Department of Surgery and Science Faculty of Medicine Academic Assembly University of Toyama Toyama Japan.

Aim: Right-half dissection of the superior mesenteric artery (SMA) nerve plexus in pancreatoduodenectomy for pancreatic cancer was initiated to accomplish R0 resection; however, subsequent refractory diarrhea was a major concern. This study aimed to evaluate the necessity of this technique.

Methods: From April 2014 to June 2018, 74 patients with pancreatic head cancer were randomly allocated to either Group A, in which right-half dissection of the SMA nerve plexus was performed (n = 37), or Group B, in which total preservation of the nerve plexus was performed (n = 37). Short-term, long-term, and survival outcomes were prospectively compared between the groups.

Results: The patient demographics, including the R0 resection rate, were not significantly different between the groups. Postoperative diarrhea occurred in 26 (70.3%) patients in Group A and 18 (48.6%) patients in Group B. There was a tendency for the development of severe diarrhea in Group A within 1 year postoperatively, and the frequency of diarrhea gradually decreased within 2 years, although that did not affect tolerance to adjuvant chemotherapy. There was no difference in either locoregional recurrence (27.0% vs 32.4%) or systemic recurrence (46.0% vs 46.0%). The median overall survival time in Groups A and B was 37.9 and 34.6 months, respectively ( = 0.77).

Conclusion: We did not demonstrate a clinical impact of right-half dissection of the SMA nerve plexus on locoregional recurrence or survival. Therefore, the prophylactic dissection of the SMA nerve plexus is unnecessary given that refractory diarrhea could be induced by this technique (UMIN000012241).
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http://dx.doi.org/10.1002/ags3.12399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832966PMC
January 2021

Correction to: Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient with type 2 diabetes.

Diabetol Int 2020 Oct 23;11(4):393. Epub 2020 Apr 23.

Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan.

[This corrects the article DOI: 10.1007/s13340-020-00434-w.].
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http://dx.doi.org/10.1007/s13340-020-00436-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538514PMC
October 2020

Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient with type 2 diabetes.

Diabetol Int 2020 Oct 8;11(4):388-392. Epub 2020 Apr 8.

Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan.

Repaglinide, an oral hypoglycemic agent, is a short-acting insulin secretagogue. We describe a case, in which an extremely low dose of repaglinide caused severe hypoglycemia and novel drug interactions are suggested. A 71-year-old man with type 2 diabetes was taken to the hospital due to consciousness disorder caused by severe hypoglycemia. He was taking repaglinide 0.25 mg once in the morning with nilotinib 400 mg/day and febuxostat 20 mg/day. Endogenous insulin secretion was not suppressed even in hypoglycemia. Detection of plasma repaglinide 10 h after administration in this case indicates delayed elimination of the agent, which might be derived from reduced hepatocyte uptake due to inhibitory effects of nilotinib on OATP1B1 and reduced oxidation of the agents by inhibitory effects of nilotinib, mainly on CYP3A4 activities, and of febuxostat on CYP2C8 activities. Repaglinide is eliminated by the liver, and is a short-acting insulin secretagogue with a good safety profile in patients with type 2 diabetes complicated by renal impairment, including elderly patients; however, its delayed elimination due to drug-drug interactions should be noted.
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http://dx.doi.org/10.1007/s13340-020-00434-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538475PMC
October 2020

Is there disparity between regions and facilities in surgical resident training in Japan? Insights from a national survey.

Surg Today 2020 Dec 2;50(12):1585-1593. Epub 2020 Jun 2.

Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: This study sought to assess the disparity between regions and facilities in surgical resident training in Japan via a national level needs-assessment.

Methods: A survey was sent to all 909 graduating residents of 2016. Residents trained in the six prefectures with a population of 7 million or more were included in the large prefecture (LP) group. Residents trained in the other 41 prefectures were included in the small prefecture (SP) group. Each group was further divided into a university hospital (UH) group and a non-university hospital (NUH) group.

Results: The response rate was 56.3% (n = 512). Excluding nine residents who did not report their prefectures and facilities, surveys from 503 residents were analyzed. The UH group received significantly more years of training. In the SP and UH groups, there were significantly fewer residents who had performed 150 procedures or more under general anesthesia in comparison to the LP and NUH groups, respectively. Self-assessed competencies for several procedures were significantly lower in the SP and UH groups.

Conclusion: Disparity in surgical resident training was found between regions and facilities in Japan. The surgical residency curriculum in Japan could be improved to address this problem.
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http://dx.doi.org/10.1007/s00595-020-02037-zDOI Listing
December 2020

Roles of Autophagy and Pancreatic Secretory Trypsin Inhibitor in Trypsinogen Activation in Acute Pancreatitis.

Pancreas 2020 04;49(4):493-497

Kaizuka City Hospital, Osaka, Japan.

The focus of the review is on roles of autophagy and pancreatic secretory trypsin inhibitor (PSTI), an endogenous trypsin inhibitor, in trypsinogen activation in acute pancreatitis. Acute pancreatitis is a disease in which tissues in and around the pancreas are autodigested by pancreatic digestive enzymes. This reaction is triggered by the intrapancreatic activation of trypsinogen. Autophagy causes trypsinogen and cathepsin B, a trypsinogen activator, to colocalize within the autolysosomes. Consequently, if the resultant trypsin activity exceeds the inhibitory activity of PSTI, the pancreatic digestive enzymes are activated, and they cause autodigestion of the acinar cells. Thus, autophagy and PSTI play important roles in the development and suppression of acute pancreatitis, respectively.
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http://dx.doi.org/10.1097/MPA.0000000000001519DOI Listing
April 2020

Clinicopathological features and menin expression of pancreatic neuroendocrine neoplasm associated with multiple endocrine neoplasia type 1.

J Hepatobiliary Pancreat Sci 2020 Dec 14;27(12):984-991. Epub 2020 May 14.

Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

Background/purpose: We examined therapeutic strategies for pancreatic neuroendocrine neoplasm (pNEN) associated with MEN1 (M-pNEN) by investigating clinicopathological features and menin expression.

Methods: Seventy-seven patients who underwent resection of pNEN at our department from January 2001 to December 2017 were retrospectively analyzed. Immunohistochemical analysis of menin was performed using resected specimens.

Results: Seven patients (9%) met the diagnostic criteria for MEN1. M-pNEN had more tumors (P < .01), a higher recurrence rate (P = .028), and higher residual pancreatic recurrence (P < .01) than sporadic pNEN (S-pNEN). There were no significant differences in tumor size, lymph node metastasis, or World Health Organization grade between the two groups. Reduced menin staining in the tumor nuclei was found in 86% of M-pNEN; whereas only 34% of S-pNEN showed decreased nuclear staining. The remainder (66%) showed strong nuclear staining similar to normal islet cells (P = .0071). Furthermore, four patients (57%) with MEN1 had many microadenomas with reduced nuclear menin staining. Overall survival of M-pNEN patients was significantly better than S-pNEN patients (P = .049).

Conclusion: M-pNEN patients tend to develop spatially and temporally multifocal pNENs. However, M-pNEN patient prognosis is good with repeated surgeries at recurrence. Therefore, minimal resection with strict follow-up is recommended rather than extensive pancreatic resections for consideration of recurrence in M-pNEN.
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http://dx.doi.org/10.1002/jhbp.739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818135PMC
December 2020

Are graduating residents sufficiently competent? Results of a national gap analysis survey of program directors and graduating residents in Japan.

Surg Today 2020 Sep 3;50(9):995-1001. Epub 2020 Mar 3.

Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: To evaluate the self-assessed competency of graduating residents (GRs) in Japan upon completion of their residency and to identify the gap between their competency and the competency expected by their program directors (PDs).

Method: A list of 31 essential surgical procedures was compiled according to the consensus of surgical educators from around the country. A survey with this list was sent to all 909 GRs and their 611 PDs in 2016. The GRs rated their competency to perform these procedures and the PDs were asked to evaluate the expected competency of their GRs using the Zwisch Scale.

Result: The response rate was 56.3% for the GRs and 76.8% for the PDs. Fewer than half of the GRs who responded felt confident performing ten (32%) of the surgical procedures evaluated. For most procedures, the GRs' self-reported competency was lower than the expectation reported by their PDs. This gap was more than 10% for 13 of the procedures.

Conclusion: More than half of the GRs in Japan lacked the confidence in their skill to perform one-third of the surgical procedures selected for evaluation in this study. These findings should be used to update the surgical education curriculum in Japan.
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http://dx.doi.org/10.1007/s00595-020-01981-0DOI Listing
September 2020

Efficacy of Staging Laparoscopy for Pancreatic Cancer.

Anticancer Res 2020 Feb;40(2):1023-1027

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Background/aim: Preoperative evaluation of resectability of pancreatic cancer (PC) is difficult, so that staging laparoscopy (SL) has come to be used for detecting occult metastases. We aimed to evaluate the prognostic impact of SL in comparison with exploratory laparotomy (EL) in unresectable PC.

Patients And Methods: Between 2010 and 2016, 57 patients with PC underwent SL after conventional tumor staging. Patient characteristics, operative findings and survival rates were compared between SL and EL group.

Results: Twenty patients (35%) were identified as having unresectable factors in SL group. In contrast, laparotomy showed unresectable factors in 8 patients who did not receive preoperative SL (EL group). The time between the surgery to the induction of chemotherapy was significantly shorter in the SL group (mean=6 days, range=2-17) than in the EL group (mean=10 days, range=6-15). There was no significant difference in overall survival between the two groups; however, EL was associated with shorter survival in the early postoperative period.

Conclusion: SL was associated with a shorter time interval to chemotherapy and lead to the prevention of unnecessary laparotomy.
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http://dx.doi.org/10.21873/anticanres.14037DOI Listing
February 2020

Training in the Japanese Society of Hepato-Biliary-Pancreatic Surgery board certification system for expert surgeons during 225 consecutive pancreaticoduodenectomies.

Ann Hepatobiliary Pancreat Surg 2019 May 31;23(2):145-154. Epub 2019 May 31.

Department of Gastroenterological Surgery, Omuta Tenryo Hospital, Omuta, Japan.

Backgrounds/aims: A board certification system has been established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) for certifying surgeons who can perform high-level hepato-biliary-pancreatic surgeries safely. The aim of this study was to compare operative outcomes after pancreaticoduodenectomy performed by trainees, board-certified instructors, and expert surgeons of JSHBPS to determine the efficacy of education of trainees and operative safety.

Methods: From 2009 to 2017, 225 consecutive patients underwent pancreaticoduodenectomy. Operations were performed by trainees, instructors, or JSHBPS experts. Clinical course and postoperative outcomes were retrospectively evaluated.

Results: Twenty-two surgeons performed pancreaticoduodenectomy and two became expert surgeons. First, data of all patients who underwent pancreaticoduodenectomy (n=225) were analyzed. Significantly shorter median operating time and less median operative bleeding were documented in the experts' group (428 min, 576 g, respectively) than in the trainees' (498.5 min, 818 g, respectively) and instructors' (557 min, 911 g, respectively) groups. Morbidity did not differ significantly between the three groups. Second, data of patients who underwent simple pancreaticoduodenectomy (n=130) were analyzed. Similarly, operating time was shorter and operative bleeding less in the experts' group. With increasing their experiences, intraoperative bleeding by 2 surgeons became the expert surgeons decreased.

Conclusions: Surgeons judged experts by the JSHBPS board certification system achieve significantly shorter operating time and less operative bleeding during pancreaticoduodenectomy. In addition, PD performed by trainees has an acceptable incidence of postoperative complications. This is the first report which indicated the efficacy of education toward being the JSHPBS board-certified expert surgeon.
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http://dx.doi.org/10.14701/ahbps.2019.23.2.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558129PMC
May 2019

A snapshot of surgical resident training in Japan: results of a national-level needs assessment survey.

Surg Today 2019 Oct 17;49(10):870-876. Epub 2019 May 17.

Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Purpose: To evaluate the status of surgical training in Japan through a national-level needs assessment.

Methods: A survey was sent to all 909 graduating residents (GRs) and their 611 program directors (PDs) for the year 2016. A working group of surgical educators from around the country was formed under the education committee of the Japan Surgical Society. The survey items were developed by consensus of this working group. The survey investigated the knowledge and problems of the current curriculum, and the status of the current residency training.

Results: The response rates were 56.3% of the GRs and 76.8% of the PDs. Among the participants, 47.6% of the GRs and 29.4% of the PDs believed that the residency curriculum did not match the clinical experience. Over 80% of the GRs and PDs agreed on the importance of training outside of the OR, whereas only 13% of the GRs had received such training regularly. Trainees also reported a lower satisfaction rate about the opportunity to train outside of the OR.

Conclusion: This national-level needs assessment of surgical training in Japan identified several gaps in the curriculum. These results provide valuable data to assist the ongoing efforts for surgical residency curriculum improvement.
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http://dx.doi.org/10.1007/s00595-019-01819-4DOI Listing
October 2019

Neuroendocrine Tumor of the Hilar Bile Duct.

Anticancer Res 2019 Feb;39(2):903-907

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Neuroendocrine tumors usually develop in the gastrointestinal tract, pancreas, and lung. Therefore, a neuroendocrine tumor of the bile duct is quite rare. We present a 59-year-old-male patient whose preoperative diagnosis was hilar cholangiocarcinoma. One month after embolization of the left branch and anterior branch of the portal vein, he underwent left hepatic trisegmentectomy and extrahepatic bile duct resection. Pathological examination revealed the neuroendocrine tumor in the submucosal layer of the hilar bile duct. Because there was no neuroendocrine tumor in other organs, the tumor was considered a primary neuroendocrine tumor of the hilar bile duct, rather than a liver metastasis from other organs. We also present a review of the English literature regarding neuroendocrine tumors of the bile duct.
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http://dx.doi.org/10.21873/anticanres.13192DOI Listing
February 2019

Carcinosarcoma of Vater's papilla: case report of a rare neoplasm and review of the literature.

Surg Case Rep 2019 Jan 31;5(1):13. Epub 2019 Jan 31.

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.

Background: Carcinosarcoma is a rare tumor that includes both carcinoma and sarcoma components. It develops commonly in the female reproductive tract, most often in the uterus. However, as there are a small number of similar cases in the English literature, we would like to present a rare case of a carcinosarcoma in Vater's papilla.

Case Presentation: A 76-year-old female patient was preoperatively diagnosed with a papillary adenocarcinoma in Vater's papilla by endoscopic biopsy. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy, and postoperative pathological examination diagnosed the carcinosarcoma. The patient received adjuvant chemotherapy with gemcitabine, but multiple liver metastases were found 3 months after the operation. Though chemotherapy with gemcitabine and cisplatin was introduced, she died owing to tumor progression 7 months after the operation.

Conclusion: Because carcinosarcoma of Vater's papilla is a rare disease, a suitable treatment strategy has been unclear. We also present a review of the English literature regarding carcinosarcoma of Vater's papilla.
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http://dx.doi.org/10.1186/s40792-019-0575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357208PMC
January 2019

Anticoagulant Therapy for Disseminated Intravascular Coagulation After Gastrointestinal Surgery.

Anticancer Res 2019 Jan;39(1):25-31

Department of Respiratory Medicine, Omuta Tenryo Hospital, Omuta, Japan.

Many studies about anticoagulant therapy for disseminated intravascular coagulation (DIC) confused gastrointestinal surgery-related DIC with DIC unrelated to a prior operation. Furthermore, the potentially increased risk of bleeding by anticoagulants complicates their use. We carried out a systematic review to describe the efficacy and safety of anticoagulant agents for DIC after gastrointestinal surgery. Several studies have indicated that gabexate mesylate improves DIC score without increasing bleeding events, and that antithrombin is associated with lower mortality of DIC after gastrointestinal surgery. Recombinant thrombomodulin has been the most frequently analyzed anticoagulant agent in this field. DIC score and survival rate were better in patients treated with recombinant thrombomodulin, without increasing bleeding events. In conclusion, anticoagulant therapy may be effective and safe in DIC after gastrointestinal surgery.
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http://dx.doi.org/10.21873/anticanres.13076DOI Listing
January 2019

Pancreatic cancer arising from the remnant pancreas after pancreatectomy: a multicenter retrospective study by the Kyushu Study Group of Clinical Cancer.

J Gastroenterol 2019 May 4;54(5):437-448. Epub 2018 Dec 4.

Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: After initial pancreatic resection, local recurrence of pancreatic cancer (PC) or new primary PC can develop in the remnant. There are limited data available regarding this so-called remnant PC. The aim of this retrospective study was to clarify the clinical features and establish a treatment strategy for remnant PC.

Methods: A multicenter retrospective study with the Kyushu Study Group of Clinical Cancer was carried out. Clinical data from 50 patients who developed remnant PC were analyzed. RAS mutation analysis of the initial tumor and of remnant PC was performed in 17 cases.

Results: The initial pancreatic resections were performed for 37 invasive ductal carcinomas, and for 13 other tumors. Thirty-seven patients underwent a second pancreatectomy for remnant PC (resected group), while thirteen patients were not operated (unresected group). The median overall survival times were 42.2 months in the resected group and 12.3 months in the unresected group (HR 0.374; 95% CI 0.17-0.83). In RAS mutation analysis, 14 cases had at least 1 missense variant of KRAS, HRAS, or NRAS in the initial pancreatic tumor and/or remnant PC. The same missense variants between the initial tumor and remnant PC were discovered only in KRAS of one patient, and in HRAS of one patient. No case had completely consistent missense variants between the initial tumor and remnant PC.

Conclusions: This study found that repeated pancreatectomy for remnant PC can prolong patient survival, and RAS mutation analysis indicated that many remnant PCs are developed from metachronous multifocal origins.
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http://dx.doi.org/10.1007/s00535-018-01535-9DOI Listing
May 2019

Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas.

Oncogene 2019 02 24;38(8):1211-1224. Epub 2018 Sep 24.

Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

The accumulation of prostaglandin E2 (PGE) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE, although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras; Ptf1a (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.
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http://dx.doi.org/10.1038/s41388-018-0510-yDOI Listing
February 2019

Serum Marker Score Based on Prognostic Nutrition Index, Carcinoembryonic Antigen, and Carbohydrate Antigen 19-9 Is Associated With Recurrence for Patients Undergoing Surgery for Pancreatic Ductal Adenocarcinoma.

Pancreas 2018 10;47(9):1130-1134

From the Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

Objectives: The prognostic value of the prognostic nutrition index (PNI) in pancreatic ductal adenocarcinoma (PDAC) is still controversial. This study aimed to assess the correlation between PNI and the outcome for PDAC patients and to generate a new score from PNI and serum markers.

Methods: This study investigated 151 patients who underwent pancreatic resection for PDAC between April 2002 and June 2012. Disease-free survival (DFS), overall survival, and clinicopathological parameters were analyzed according to the PNI value.

Results: The low PNI patients had poorer 5-year DFS rate than high-PNI patients (10.7% and 34.8%, respectively). Multivariate analyses revealed that independent risk factors for poor DFS were high carcinoembryonic antigen (hazard ratio [HR], 1.53; P = 0.038), high carbohydrate antigen 19-9 (HR, 1.67; P = 0.017), positive lymph node metastasis (HR, 1.98; P = 0.017), R1 or 2 resection (HR, 3.50; P < 0.001), and low PNI (HR, 0.37 [high/low]; P = 0.029]. Scoring based on the formula -0.49 × (PNI) + 0.41 × (carcinoembryonic antigen) + 0.67 × (carbohydrate antigen 19-9) was significantly associated with poor DFS (P < 0.001) and overall survival (P = 0.0019).

Conclusions: Low PNI and serum marker score are significantly associated with poor DFS.
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http://dx.doi.org/10.1097/MPA.0000000000001146DOI Listing
October 2018

Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma.

HPB (Oxford) 2018 10 11;20(10):939-948. Epub 2018 May 11.

Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan.

Background: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC).

Methods: The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort.

Results: Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055).

Conclusion: The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.
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http://dx.doi.org/10.1016/j.hpb.2018.03.018DOI Listing
October 2018

Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Oncotarget 2018 Apr 17;9(29):20795-20806. Epub 2018 Apr 17.

Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

Background: The methylation level of long interspersed nucleotide element-1 (LINE-1) is a good surrogate marker of the global DNA methylation level. The relationship between LINE-1 methylation level and prognosis in primary liver cancer (PLC) patients remains unclear.

Results: LINE-1 methylation levels were significantly lower in HCC and cHCC-CC tissues, but not in ICC tissues, than those in noncancerous liver parenchyma (HCC: < 0.0001; cHCC-CC: 0.001; and ICC: = 0.053). HCC cases with hypomethylated LINE-1 had significantly shorter relapse-free survival (RFS) (log-rank, = 0.008); however, this was not observed for the cHCC-CC or ICC cases. Multivariate Cox regression analysis revealed a significantly higher HCC recurrence rate in the group with hypomethylated LINE-1 (hazard ratio, 1.62; 95% confidence interval, 1.06-2.58; = 0.025).

Conclusions: The genome-wide DNA hypomethylation status estimated via LINE-1 methylation levels might be indicative of poor RFS in patients with HCC but not ICC or cHCC-CC.

Methods: We evaluated the level of LINE-1 methylation in 321 cases of curatively resected PLC {231 hepatocellular carcinoma (HCC), 19 combined hepatocellular and cholangiocarcinoma (cHCC-CC) and 71 intrahepatic cholangiocarcinoma (ICC)} via pyrosequencing of formalin-fixed paraffin-embedded (FFPE) tissues and examined its prognostic value.
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http://dx.doi.org/10.18632/oncotarget.25124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945516PMC
April 2018

Cystic gastric metastasis from pancreatic cancer.

Surg Case Rep 2018 Apr 10;4(1):31. Epub 2018 Apr 10.

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.

Gastrointestinal tract metastasis from pancreatic cancer is quite rare. We present the case of a 58-year-old male patient who underwent distal pancreatectomy for pancreatic body cancer 5 years prior. Four years after the initial operation, a 15-mm cystic submucosal tumor was found in the antrum of the stomach. Because the tumor had grown to 25 mm and the level of carcinoembryonic antigen in the cystic fluid derived by ultrasound-guided fine-needle aspiration biopsy was high, partial resection of the stomach was performed 5 years after the distal pancreatectomy. Pathological diagnosis was gastric metastasis of pancreatic cancer. The patient has been alive without recurrence for 13 months after the resection of the cystic tumor. We are not aware of any similar cases of cystic gastric metastasis from pancreatic cancer published in the English literature.
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http://dx.doi.org/10.1186/s40792-018-0443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891441PMC
April 2018

The predictors and oncological outcomes of repeat surgery for recurrence after hepatectomy for colorectal liver metastases.

Int J Clin Oncol 2018 Oct 4;23(5):908-916. Epub 2018 Apr 4.

Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

Purpose: Although recurrence after hepatectomy for colorectal liver metastases (CRLM) is common, the optimal treatment strategy remains unclear. The aims of this study were to clarify the impact of repeat surgery and identify the predictive factors for repeat surgery.

Methods: Among the 170 patients who underwent potentially curative surgery for CRLM, 113 developed recurrence. The predictive factors for the performance of repeat surgery were identified and a predictive model was constructed.

Results: The patterns of recurrence were as follows; single site [n = 100 (liver, n = 61; lung, n = 22; other, n = 17)], multiple site (n = 13). Repeat surgery was performed in 54 patients (47.8%) including re-hepatectomy (n = 25), radiofrequency ablation (n = 12), and resection of the extrahepatic recurrent disease (n = 17), and their overall survival (OS) was significantly better than that of those who could not (5-year OS 60.7 vs 19.5%, P < 0.0001). A multivariate analysis revealed that a primary N-negative status [relative risk (RR) 2.93, P = 0.017], indocyanine retention rate at 15 min ≤ 10% before hepatectomy (RR 2.49, P = 0.04), and carcinoembryonic antigen ≤ 5 ng/mL before hepatectomy (RR 2.96, P = 0.017) independently predicted the performance of repeat surgery. For patients who did not present any factors, the probability of repeat surgery was 19.6%. The addition of each subsequent factor increased the probability to 41.9, 67.8, and 84.0% (for 1, 2, and 3 factors, respectively).

Conclusions: Repeat surgery for not only intrahepatic but also extrahepatic recurrence is crucial for prolonging the survival of CRLM patients. The proposed model may help to predict the possibility of repeat surgery and provide optimal individualized treatment.
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http://dx.doi.org/10.1007/s10147-018-1273-8DOI Listing
October 2018

Number of acinar cells at the pancreatic stump predicts pancreatic fistula after pancreaticoduodenectomy.

Surg Today 2018 Aug 24;48(8):790-795. Epub 2018 Mar 24.

Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.

Purpose: To establish if the number of pancreatic acinar cells at the pancreatic cut end is a predictor of postoperative pancreatic fistula (POPF).

Methods: The number of acinar cells was assessed histologically in 121 consecutive patients who underwent pancreaticoduodenectomy (PD) between April, 2012 and July, 2016.

Results: POPF developed in 23 of the 121 patients. Univariate analysis revealed that male sex, long operating time, high volume of blood loss, soft remnant pancreas, large pancreatic duct, and the number of pancreatic acinar cells were significantly associated with POPF. Multivariate analysis revealed that male sex (p = 0.022) and the number of pancreatic acinar cells (p < 0.0001) were independently associated with POPF. In the receiver operating characteristic (ROC) curve analysis, the area under curve was 0.83895 when the cut off value of the number of pancreatic acinar cells to predict POPF was 890. Sensitivity and specificity of the number of pancreatic acinar cells were 82.6 and 77.6%, respectively.

Conclusions: A large number of pancreatic acinar cells at the cut end of the stump is predictive of POPF after PD. Although POPF is associated with multiple factors and the number of acinar cells is only one of these, our study is the first to confirm this common intuition of surgeons, which has not been assessed definitively before.
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http://dx.doi.org/10.1007/s00595-018-1656-5DOI Listing
August 2018

Idiosyncratic drug-induced liver injury: A short review.

Hepatol Commun 2017 08 28;1(6):494-500. Epub 2017 Jun 28.

Department of Gastroenterological Surgery, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan.

Idiosyncratic drug-induced liver injury (iDILI) is a rare adverse drug reaction that occasionally leads to acute liver failure or even death. An aging population that uses more drugs, a constant influx of newly developed drugs, and a growing risk from herbal and dietary supplements of uncertain quality can lead to an increase in iDILI. Antimicrobials, central nervous system agents, and herbal and dietary supplements are the most common causes of iDILI in developed countries. iDILI is still a diagnosis of exclusion, and thus careful history taking and thorough work-ups for competing etiologies, such as acute viral hepatitis, autoimmune hepatitis, and others, are essential. The pathogenesis of iDILI is not clear and includes a mix of host reactions, drug metabolites, and environmental factors. Immediate cessation of the suspected offending drug is key to preventing or minimizing progressive damage. No definitive therapies for iDILI are available, and the treatments remain largely supportive. ( 2017;1:494-500).
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http://dx.doi.org/10.1002/hep4.1064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678908PMC
August 2017
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