Publications by authors named "Kiyoshi Hasegawa"

514 Publications

Evaluation of preoperative nutritional variables to predict postoperative complications after pancreaticoduodenectomy.

Nutrition 2019 3;67-68S:100006. Epub 2020 Feb 3.

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:

Objectives: Perioperative malnutrition reportedly increases postoperative morbidity and mortality rates after abdominal surgery, including pancreaticoduodenectomy (PD). However, few studies have focused on the association between preoperative nutritional variables and the incidence of postoperative complications. The present study aimed to evaluate preoperative nutritional parameters to predict the incidence of postoperative complications after PD.

Methods: A total of 140 consecutive patients underwent PD between May 2012 and April 2015. Preoperative nutritional variables included body mass index, total lymphocyte count, albumin, total cholesterol, cholinesterase, and transthyretin. The rates of Clavien-Dindo (C-D) grade ≥II complications were evaluated for each nutritional variable. Predictive factors for the incidence of C-D grade ≥II complications were evaluated by assessing pre- and intraoperative factors.

Results: Of the 140 patients, 108 were included in the study after excluding 32 patients with missing data on preoperative nutritional variables. A cholinesterase concentration of <250 IU/L (odds ratio: 2.82; 95% confidence interval, 1.12-7.80; P = 0.028) was the only independent predictive factor for the incidence of C-D grade ≥II postoperative complications.

Conclusions: Low cholinesterase concentrations were significantly associated with a higher incidence of postoperative morbidity in patients undergoing PD. Preoperative nutritional variables can be used as predictors of postoperative complications after PD.
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http://dx.doi.org/10.1016/j.nutx.2020.100006DOI Listing
February 2020

Understanding conditional cumulative incidence of complications following liver resection to optimize hospital stay.

HPB (Oxford) 2021 Jul 8. Epub 2021 Jul 8.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

Background: After liver resection, the in-hospital observation periods associated with minimal risks for complications and unplanned readmission remains unclear. This study aimed to assess changes in risks of complications over time.

Methods: Surgical complexity of liver resection was stratified into grades I (low complexity), II (intermediate), and III (high). The cumulative incidence rate and risk factors for complication ≥ Clavien-Dindo grade II (defined as treatment-requiring complications) were assessed.

Results: Of 581 patients, grade I, II, and III resections were performed in 81 (13.9%), 119 (20.5%), and 381 patients (65.6%). Complexity grades (I vs. III, hazard ratio [HR] 0.45, P = 0.007; II vs. III, HR 0.60, P = 0.011) and background liver status (HR 1.76, P = 0.004) were risk factors for treatment-requiring complications. The cumulative incidence rate of treatment-requiring complications was higher after grade III resection than grade I resection (38.1% vs. 16.1%, P < 0.001) or grade II resection (38.1% vs. 25.2%, P = 0.019). Without cirrhosis/chronic hepatitis, the cumulative incidence rate of treatment-requiring complications decreased to less than 10% on postoperative day (POD) 3 after grade I resection, POD 5 after grade II resection, and POD 10 after grade III resection.

Conclusion: Conditional complication risk analysis stratified by surgical complexity may be useful for optimizing in-hospital observation.
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http://dx.doi.org/10.1016/j.hpb.2021.06.419DOI Listing
July 2021

Rituximab Desensitization in Liver Transplant Recipients With Preformed Donor-specific HLA Antibodies: A Japanese Nationwide Survey.

Transplant Direct 2021 Aug 16;7(8):e729. Epub 2021 Jul 16.

Department of Gastroenterological Surgery, Institute of Gastroenterology, Tokyo Women's Medical University of Medicine, Tokyo, Japan.

Background: The significance of preformed donor-specific anti-HLA antibodies (DSAs) in liver transplant recipients is controversial. Moreover, there has been no established desensitization protocol for DSA-positive recipients.

Methods: A Japanese nationwide survey was performed to investigate the clinical practice among preformed DSA-positive patients with special reference to rituximab desensitization.

Results: There was a total of 47 cases, including 2 pediatric cases, in which rituximab (287 ± 159 mg [319 (50-916)/m]) was administered to desensitize preformed DSA. The decision for the indication of rituximab desensitization was based on a single-antigen assay in the majority of cases (83%, 39/47), and the most frequent protocol was rituximab monotherapy (n = 12) followed by quadruple treatment with rituximab tacrolimus, mycophenolate mofetil, and plasmapheresis (n = 11). The overall 1-, 3-, and 5-y graft and patient survival rates among adult patients were 85%, 83%, 83%, and 81%, 77%, 74%, respectively, while neither graft loss nor death was observed in the 2 pediatric cases. The 1-, 3-, and 12-mo cumulative incidence of antibody-mediated rejection (AMR) was 11%, 13%, and 13%, respectively. The incidence of AMR was significantly higher in the lower rituximab dose group than in the higher rituximab dose group (cutoff 300 mg/m, 4% versus 24%,  = 0.041). The rate of infusion-related adverse drug reactions (ADRs) was 4.4%, and all ADRs were mild and self-limiting. A total of 99 ADRs among 27 patients were reported, none of which were severe adverse events associated with rituximab.

Conclusions: The rituximab induction was well tolerated among DSA-positive liver transplant recipients with a satisfactory outcome. A rituximab dose >300 mg/m was observed to achieve less incidence of the development of AMR.
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http://dx.doi.org/10.1097/TXD.0000000000001180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288898PMC
August 2021

Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update.

Liver Cancer 2021 Jun 19;10(3):181-223. Epub 2021 May 19.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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http://dx.doi.org/10.1159/000514174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237791PMC
June 2021

Management of neuroendocrine liver metastasis: Searching for new prognostic factor and appraising repeat hepatectomy.

Hepatobiliary Surg Nutr 2021 Jun;10(3):410-412

Hepato-Biliary and Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.21037/hbsn-21-88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188123PMC
June 2021

Indications and waiting list priority for deceased donor liver transplantation in HIV/HCV co-infected hemophilic patients in Japan through contaminated blood product.

Hepatol Res 2021 Aug 26;51(8):909-914. Epub 2021 Jun 26.

Department of Digestive and General Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

HIV/HCV co-infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver in co-infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co-infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants-in-aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co-infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono-infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End-stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co-infected patients in Japan.
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http://dx.doi.org/10.1111/hepr.13686DOI Listing
August 2021

A safe sequential treatment approach for patients who have acute cholecystitis with severe inflammation: Transmural gallbladder drainage followed by laparoscopic cholecystectomy under the guidance of fluorescence imaging.

Asian J Endosc Surg 2021 May 30. Epub 2021 May 30.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.

Introduction: For patients who have acute severe cholecystitis, urgent/early biliary drainage followed by delayed/elective laparoscopic cholecystectomy is recommended according to the Tokyo Guidelines 2018. Percutaneous transhepatic gallbladder drainage is an established technique. Recently, transmural gallbladder drainage under the guidance of endoscopic ultrasonography (EUS-GBD) was reported as a safe alternative. During surgery, fluorescence imaging using indocyanine green (ICG) has been increasingly used for visualizing the bile ducts. Herein, we report a sequential treatment approach which ensures safety without impairing normal activities before cholecystectomy: EUS-GBD followed by laparoscopic cholecystectomy using ICG fluorescence imaging.

Materials And Surgical Technique: A 66-year-old man with acute cholecystitis underwent urgent EUS-GBD and had the drainage tube placement through the duodenum into the gallbladder. During 2.5 months of the waiting period, he had no clinical troubles. After insertion of a laparoscope, we found a structure between the gallbladder and the duodenum. We injected 0.025 mg/mL of ICG into the nasobiliary drainage tube (placed in the gallbladder through the duodenum) and confirmed that the structure was a fistula. After removing the tube, the fistula was divided using a surgical stapler under the guidance of fluorescence imaging. The cystic and common bile ducts were also clearly visualized as fluorescence.

Discussion: We reported a safe sequential treatment approach for the patient who required biliary drainage: EUS-GBD followed by laparoscopic cholecystectomy under the guidance of ICG fluorescence imaging. This sequential approach may improve patients' satisfaction with respect to quality of life during the waiting period and may ensure the safety of laparoscopic cholecystectomy.
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http://dx.doi.org/10.1111/ases.12955DOI Listing
May 2021

Impact of board certification system and adherence to the clinical practice guidelines for liver cancer on post-hepatectomy risk-adjusted mortality rate in Japan: A questionnaire survey of departments registered with the National Clinical Database.

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

The Japanese Society of Gastroenterological Surgery, Tokyo, Japan.

Background: It is unclear to what extent a board certification system and implementation of clinical guidelines improves the quality of hepatectomy.

Methods: A web-based questionnaire survey was administered to departments registered with the National Clinical Database (NCD) in Japan between 1 October 2014 and 31 January 2015. Quality indicators (QIs), including affiliations with academic societies, numbers of board-certified doctors affiliated with each institute, and adherence to clinical practice guidelines for hepatocellular carcinoma, were evaluated by calculating risk-adjusted odds ratios (AORs) for 90-day postoperative mortality of patients who had undergone hepatectomy in 2013 and 2014.

Results: Of 1255 departments that had registered at least one hepatectomy in NCD, 592 departments, performing 8601 hepatectomies in total, responded to the questionnaire. AORs were significantly lower in departments that were certified as training hospitals by the Japanese Society of Gastroenterological Society, Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS), and Japan Society of Hepatology than in non-certified departments. Affiliation of three or more JSHBPS-certified experts or instructors with an institution also contributed to low AORs. None of the QIs regarding implementation of guidelines significantly impacted on the AOR.

Conclusions: Quality indicator measurements may improve quality of post-hepatectomy outcomes in Japan.
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http://dx.doi.org/10.1002/jhbp.1000DOI Listing
May 2021

Impact of hepatitis C virus on survival in patients undergoing resection of intrahepatic cholangiocarcinoma: Report of a Japanese nationwide survey.

Hepatol Res 2021 Aug 16;51(8):890-901. Epub 2021 Jun 16.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Aim: We reviewed the data of a nationwide follow-up survey to determine the impact of hepatitis C virus (HCV) infection on the outcomes of hepatectomy for mass-forming (MF) type, and combined mass-forming and periductal infiltrating (MF + PI) type intrahepatic cholangiocarcinoma (ICC).

Methods: In total, 956 patients with ICC who underwent curative hepatic resection were included in this cohort study, and patients were classified according to virus status. Patients were classified according to virus status as follows: HCV-related ICC (n = 138, 14.4%), hepatitis B virus (HBV)-related ICC (n = 43, 4.5%) and non-virus-related ICC (n = 775, 81.1%). To control for variables, we used 1:1 propensity score-matching to compare outcomes after surgery between HCV-related (n = 102) and non-virus-related ICC cases (n = 102).

Results: We successfully matched HCV-related and non-virus-related ICC cases with similar liver function and tumor characteristics. Patients with HCV-related ICC had significantly shorter recurrence-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, p = 0.016) and overall survival (hazard ratio: 0.57, 95% confidence interval: 0.37-0.88, p = 0.011) than patients with non-virus-related ICC. Cox proportional hazard analysis showed that HCV-related ICC offered a worse prognosis than non-virus-related ICC.

Conclusions: HCV infection increases the risk of recurrence and worsens overall survival in patients after curative resection for MF and combined MF + PI type ICC.
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http://dx.doi.org/10.1111/hepr.13676DOI Listing
August 2021

Adjuvant chemotherapy can prolong recurrence-free survival but did not influence the type of recurrence or subsequent treatment in patients with colorectal liver metastases.

Surgery 2021 May 21. Epub 2021 May 21.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address:

Background: Although liver resection is the only potentially curative treatment for colorectal liver metastases, recurrence is frequent. We previously published the early results of a randomized controlled phase 3 trial showing that adjuvant therapy with uracil-tegafur and leucovorin significantly prolongs recurrence-free survival. This study sought to elucidate the impact of adjuvant chemotherapy on patient survival after an additional follow-up period, building upon the results of our previous study.

Methods: After resection for colorectal liver metastases, patients were randomly assigned in a 1:1 ratio to receive adjuvant uracil-tegafur and leucovorin or surgery alone. Patients assigned to the uracil-tegafur and leucovorin group received 5 cycles of uracil-tegafur and leucovorin within 8 weeks after surgery.

Results: Patients were assigned to an adjuvant uracil-tegafur and leucovorin (n = 90) or a surgery alone (n = 90) group; 3 patients were excluded because of protocol violations. After a median follow-up period of 7.36 years (95% confidence interval, 6.93-7.87), 60 (68.2%) patients in the uracil-tegafur and leucovorin group and 61 (68.5%) patients in the surgery alone group developed recurrences. The median recurrence-free survival was 1.45 years (95% confidence interval, 0.96-2.16) in the uracil-tegafur and leucovorin group and 0.70 years (95% confidence interval, 0.44-1.07) in the surgery alone group. The locations and treatments of the first recurrences did not differ between the groups, nor did the overall survival (hazard ratio, 0.86; 95% confidence interval, 0.54-1.38; P = .54). The overall survival was significantly longer in patients who underwent curative repeated resection than in patients who received non-surgical treatment (hazard ratio, 0.25; 95% confidence interval, 0.15-0.40; P < .0001).

Conclusion: Adjuvant uracil-tegafur and leucovorin significantly prolonged the recurrence-free survival but not the overall survival. The repeated resection was the most important factor influencing overall survival.
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http://dx.doi.org/10.1016/j.surg.2021.04.012DOI Listing
May 2021

Effect of Diameter and Number of Hepatocellular Carcinomas on Survival After Resection, Transarterial Chemoembolization, and Ablation.

Am J Gastroenterol 2021 Apr 21. Epub 2021 Apr 21.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Biostatistics, School of Public Health, the University of Tokyo, Tokyo, Japan; Department of Surgery, Division of General and Hepatobiliary Surgery, G.B. Rossi Hospital, University of Verona Medical School, Verona, Italy; School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Department of Surgery, San Gerardo Hospital, Monza, Italy; Hepatobiliary Surgery Unit, Foundation "Policlinico Universitario A. Gemelli" IRCCS, Catholic University of the Sacred Heart, Rome, Italy; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Diagnostic Radiology, Saitama Medical University International Medical Center, Saitama, Japan; Department of Gastroenterology, Musashino Red Cross Hospital, Tokyo, Japan; Departments of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan; Department of Pathology, Keio University School of Medicine, Tokyo, Japan; Department of Gastroenterology, The Juntendo University, Tokyo, Japan; Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan; Department of Clinical Laboratory Medicine, Kurume University Hospital, Fukuoka, Japan; Department of Radiology, Kobe University Graduate School of Medicine, Hyogo, Japan; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; General and Transplant Surgery Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka, Japan; National Center for Global Health and Medicine, Tokyo, Japan.

Introduction: Most studies predicting survival after resection, transarterial chemoembolization (TACE), and ablation analyzed diameter and number of hepatocellular carcinomas (HCCs) as dichotomous variables, resulting in an underestimation of risk variation. We aimed to develop and validate a new prognostic model for patients with HCC using largest diameter and number of HCCs as continuous variables.

Methods: The prognostic model was developed using data from patients undergoing resection, TACE, and ablation in 645 Japanese institutions. The model results were shown after balanced using the inverse probability of treatment-weighted analysis and were externally validated in an international multi-institution cohort.

Results: Of 77,268 patients, 43,904 patients, including 15,313 (34.9%) undergoing liver resection, 13,375 (30.5%) undergoing TACE, and 15,216 (34.7%) undergoing ablation, met the inclusion criteria. Our model (http://www.u-tokyo-hbp-transplant-surgery.jp/about/calculation.html) showed that the 5-year overall survival (OS) in patients with HCC undergoing these procedures decreased with progressive incremental increases in diameter and number of HCCs. For patients undergoing resection, the inverse probability of treatment-weighted-adjusted 5-year OS probabilities were 10%-20% higher compared with patients undergoing TACE for 1-6 HCC lesions <10 cm and were also 10%-20% higher compared with patients undergoing ablation when the HCC diameter was 2-3 cm. For patients undergoing resection and TACE, the model performed well in the external cohort.

Discussion: Our novel prognostic model performed well in predicting OS after resection and TACE for HCC and demonstrated that resection may have a survival benefit over TACE and ablation based on the diameter and number of HCCs.
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http://dx.doi.org/10.14309/ajg.0000000000001256DOI Listing
April 2021

Correlation Between Portal Pressure and Indocyanine Green Retention Rate is Unaffected by the Cause of Cirrhosis: A Prospective Study.

World J Surg 2021 Aug 23;45(8):2546-2555. Epub 2021 Apr 23.

Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.

Background: Accurate estimation of the hepatic functional reserve before liver resection is important to avoid post-hepatectomy liver failure (PHLF). The aim of the present study was to evaluate the association of indocyanine green retention test with portal pressure by the cause of cirrhosis (non-viral vs. viral) and assessed postoperative outcomes including incidence of PHLF in patients with viral and non-viral cirrhosis.

Methods: The cohort includes 50 consecutive patients with liver cirrhosis scheduled for liver resection for primary liver tumors at the Lausanne University Hospital between 2009 and 2018.

Results: There were 31 patients with non-viral liver cirrhosis (Non-virus group) and 19 with viral liver cirrhosis (virus group). The indocyanine green retention rate at 15 min (ICG-R15) (p = 0.276), Hepatic Venous Portal Gradient (HVPG; p = 0.301), and postoperative outcomes did not differ between the non-virus group and viral group. ICG-R15 and HVPG showed a significant linear correlation in all patients (Spearman's rank correlation coefficient, ρ = 0.599, p < 0.001), the non-virus group (ρ = 0.555, p = 0.026), and the virus group (ρ = 0.534, p = 0.007). A receiver operating characteristic curve analysis showed that ICG-R15 was a predictor for presence of portal hypertension (PH; HVPG ≥ 12 mmHg) (area under the curve [AUC] = 0.780). The cut-off value of ICG-R15 for predicting the presence of PH was 16.0% with 72.3% of sensitivity and 79.0% of specificity.

Conclusions: The ICG-R15 level was associated with portal pressure in both patients with non-virus cirrhosis and patients with virus cirrhosis and predicts the incidence of PH with relatively good discriminatory ability. CLINICAL TRIAL NUMBER: https://clinicalTrials.gov(ID:NCT00827723) LOCAL ETHICS COMMITTEE NUMBER: CER-VD 251.08.
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http://dx.doi.org/10.1007/s00268-021-06111-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236033PMC
August 2021

Accuracy of Modern Clinical Risk Score Including RAS Status Changes Based on Whether Patients Received Perioperative Chemotherapy for Colorectal Liver Metastases.

World J Surg 2021 07 20;45(7):2176-2184. Epub 2021 Apr 20.

Department of Hepato-Biliary-Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Ariake, Tokyo, 113-8421, Japan.

Background: A modified Fong clinical score (m-Fong CS) that includes the RAS mutation status has recently been proposed and offered an improved survival stratification of patients who undergo surgery and systemic chemotherapy for colorectal liver metastases (CLM). The aim of this study is to assess whether a CS that includes RAS status is influenced by whether patients receive perioperative chemotherapy.

Methods: We created a new CS using multivariate analysis of data of patients who underwent hepatectomy for CLM for the first time between 2010 and 2016 at a single hospital (n = 341, 79% received perioperative chemotherapy). The resulting CS and m-Fong CS were then validated in the patient cohort at three other hospitals (n = 309). Furthermore, the applicability of the two CS in the total cohort (n = 650) was tested according to whether the patients received perioperative chemotherapy.

Results: The new CS comprised mutant RAS status, ≥4 CLMs, and a CA19-9 level ≥100 U/mL (1 point per factor). Both the new CS and m-Fong CS failed to stratify the survival of the 309 patients in the validation cohort, including those who did not receive perioperative chemotherapy (29%). Both of the CS accurately stratified the survival of patients who underwent perioperative chemotherapy but not of those who underwent surgery alone.

Conclusion: A CS that includes the RAS mutation status can stratify the survival of patients who undergo hepatectomy combined with perioperative chemotherapy, but it has limited value for patients who undergo surgery alone.
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http://dx.doi.org/10.1007/s00268-021-05976-xDOI Listing
July 2021

The efficacy of rituximab treatment for antibody-mediated rejection in liver transplantation: A retrospective Japanese nationwide study.

Hepatol Res 2021 Apr 5. Epub 2021 Apr 5.

Department of Gastroenterological Surgery, Institute of Gastroenterology, Tokyo Women's Medical University of Medicine, Tokyo, Japan.

Aim: Antibody-mediated rejection (AMR) has been consistently elucidated in liver transplantation (LT); however, the treatment for AMR, including rituximab, has not been indicated as a strongly recommended therapeutic protocol.

Methods: This study was conducted as the Japanese multicenter retrospective study to accumulate data on the use of rituximab for AMR among patients undergoing LT between August 2001 and December 2016. Thirteen patients (five children and eight adults) were enrolled.

Results: The types of AMR in the pediatric cases were chronic AMR in four cases and indeterminate AMR in one case. Among the pediatric cases, rituximab treatment only showed therapeutic efficacy in two patients with chronic AMR. Among the adult patients, five patients had chronic AMR, and three had acute AMR. Although two patients with chronic AMR died due to graft failure, liver function tests revealed improvement after rituximab treatment in the other patients. Two of the three patients with acute AMR died due to graft failure; rituximab treatment showed no therapeutic efficacy in these cases. Although bacterial infections occurred within 3 months after rituximab administration in three patients, rituximab treatment could be safely administered without any direct adverse effects.

Conclusions: The indication of rituximab therapy as an additional treatment for mild acute AMR and chronic AMR may be feasible; however, a prospective randomized control study is needed to evaluate the therapeutic efficacy of rituximab treatment for AMR.
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http://dx.doi.org/10.1111/hepr.13643DOI Listing
April 2021

Prognosis of primary sclerosing cholangitis according to age of onset.

J Hepatobiliary Pancreat Sci 2021 Apr 2. Epub 2021 Apr 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Liver failure and biliary tract cancer (BTC) are major life-threatening events in the clinical course of primary sclerosing cholangitis (PSC). Although these are competing events, they are typically evaluated as a composite prognostic endpoint. In Japan, the clinical characteristics and prognosis of PSC reportedly differ according to age of onset. We compared the prognosis of younger- versus older-onset PSC by competing risk analysis.

Methods: This was a retrospective analysis of 144 patients with PSC who were followed up for a median of 6.7 years. The patients were divided into two groups according to a cutoff age of onset of 44 years. We compared the prognosis of younger-onset PSC (n = 91) and older-onset PSC (n = 53) by competing risk analysis, incorporating mortality related and that unrelated to BTC as competing events.

Results: There was no difference in BTC-related mortality between patients with younger-onset and those with older-onset PSC (subdistribution hazard ratio [SHR], 0.89; 95% confidence interval [CI], 0.17-4.56, P = .888). The cumulative incidence of mortality due to other causes, including liver transplantation and liver failure, was non-significantly higher in patients with older-onset PSC (SHR, 1.58; 95% CI, 0.88-2.84; P = .129).

Conclusions: Although we did not find a significant difference in prognosis by onset age, patients with older-onset PSC had worse liver-transplantation-free survival than those with younger-onset PSC. A large cohort study is needed to evaluate the clinical outcomes of older- and younger-onset PSC.
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http://dx.doi.org/10.1002/jhbp.952DOI Listing
April 2021

Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E.

Hepatol Res 2021 May 6;51(5):538-547. Epub 2021 Apr 6.

Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan.

Aim: Studies regarding changes in antibodies to hepatitis E virus (HEV) after HEV infection in organ transplant patients are limited. This study aimed to clarify HEV infection trends in organ transplant patients who contracted HEV using data from a previous Japanese nationwide survey.

Methods: This study was undertaken from 2012 to 2019. Among 4518 liver, heart, and kidney transplant patients, anti-HEV immunoglobulin G (IgG) antibodies were positive in 164; data were collected from 106 of these patients, who consented to participate in the study. In total, 32 liver transplant patients, seven heart transplant patients, and 67 kidney transplant patients from 16 institutions in Japan were examined for IgG, IgM, and IgM antibodies to HEV and the presence of HEV RNA in the serum. The χ -test was used to determine the relationship between the early and late postinfection groups in patients with anti-HEV IgG positive-to-negative conversion rates. The Mann-Whitney U-test was used to compare clinical factors.

Results: Anti-HEV IgG positive-to-negative conversion occurred in 25 (23.6%) of 106 organ transplant patients. Of eight patients with hepatitis E who tested positive for HEV RNA, one (14.0%) had anti-HEV IgG positive-to-negative conversion. Twenty-four (24.5%) of 98 patients negative for HEV RNA had anti-HEV IgG positive-to-negative conversion.

Conclusions: This study revealed, for the first time, the changes in HEV antibodies in organ transplant patients. Loss of anti-HEV IgG could often occur unexpectedly in organ transplant patients with previous HEV infection.
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http://dx.doi.org/10.1111/hepr.13637DOI Listing
May 2021

Open and/or laparoscopic one-stage resections of primary colorectal cancer and synchronous liver metastases: An observational study.

Medicine (Baltimore) 2021 Mar;100(11):e25205

Department of Surgical Oncology.

Abstract: One-stage resections of primary colorectal cancer and liver metastases have been reported to be feasible and safe. Minimally invasive approaches have become more common for both colorectal and hepatic surgeries. This study aimed to investigate outcomes of these combined surgical procedures among different approaches.We retrospectively analyzed patients diagnosed as having primary colorectal cancer with synchronous liver metastases and who underwent 1-stage primary resection and hepatectomy with curative intent in our hospital. According to the surgical approach for the primary tumor and hepatic lesions, namely open laparotomy (Op) or laparoscopic approach (Lap), patients were classified into Op-Op, Lap-Op (laparoscopic colorectal resection plus open hepatectomy), and Lap-Lap groups, respectively. Clinicopathological factors were reviewed, and short- and long-term outcomes were compared among the groups.The Op-Op, Lap-Op, and Lap-Lap groups comprised 36, 18, and 17 patients, respectively. The superior/posterior hepatic segments were more frequently resected via an open approach. There was no laparoscopic major hepatectomy. The median volume of intraoperative blood loss was smaller in the Lap-Lap and Lap-Op groups (290 and 270 mL) than in the Op-Op group (575 mL, P = .008). The hospital stay after surgery was shorter in the Lap-Lap and Lap-Op groups (median: 17 days and 15 days, vs 19 days for the Op-Op group, P = .033). The postoperative complication rates and survivals were similar among the groups.Application of laparoscopy to 1-stage resections of primary colorectal cancer and liver metastases may offer advantages of enhanced recovery from surgical treatment, given appropriate patient selection.
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http://dx.doi.org/10.1097/MD.0000000000025205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982201PMC
March 2021

A new rapid diagnostic system with ambient mass spectrometry and machine learning for colorectal liver metastasis.

BMC Cancer 2021 Mar 10;21(1):262. Epub 2021 Mar 10.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Probe electrospray ionization-mass spectrometry (PESI-MS) can rapidly visualize mass spectra of small, surgically obtained tissue samples, and is a promising novel diagnostic tool when combined with machine learning which discriminates malignant spectrum patterns from others. The present study was performed to evaluate the utility of this device for rapid diagnosis of colorectal liver metastasis (CRLM).

Methods: A prospectively planned study using retrospectively obtained tissues was performed. In total, 103 CRLM samples and 80 non-cancer liver tissues cut from surgically extracted specimens were analyzed using PESI-MS. Mass spectra obtained by PESI-MS were classified into cancer or non-cancer groups by using logistic regression, a kind of machine learning. Next, to identify the exact molecules responsible for the difference between CRLM and non-cancerous tissues, we performed liquid chromatography-electrospray ionization-MS (LC-ESI-MS), which visualizes sample molecular composition in more detail.

Results: This diagnostic system distinguished CRLM from non-cancer liver parenchyma with an accuracy rate of 99.5%. The area under the receiver operating characteristic curve reached 0.9999. LC-ESI-MS analysis showed higher ion intensities of phosphatidylcholine and phosphatidylethanolamine in CRLM than in non-cancer liver parenchyma (P < 0.01, respectively). The proportion of phospholipids categorized as monounsaturated fatty acids was higher in CRLM (37.2%) than in non-cancer liver parenchyma (10.7%; P < 0.01).

Conclusion: The combination of PESI-MS and machine learning distinguished CRLM from non-cancer tissue with high accuracy. Phospholipids categorized as monounsaturated fatty acids contributed to the difference between CRLM and normal parenchyma and might also be a useful diagnostic biomarker and therapeutic target for CRLM.
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http://dx.doi.org/10.1186/s12885-021-08001-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945316PMC
March 2021

ABO Blood Group and Risk of Pancreatic Carcinogenesis in Intraductal Papillary Mucinous Neoplasms.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):1020-1028. Epub 2021 Mar 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: ABO blood group has been associated with risks of various malignancies, including pancreatic cancer. No study has evaluated the association of ABO blood group with incidence of pancreatic carcinogenesis during follow-up of patients with intraductal papillary mucinous neoplasms (IPMN).

Methods: Among 3,164 patients diagnosed with pancreatic cysts at the University of Tokyo (Tokyo, Japan) from 1994 through 2019, we identified 1,815 patients with IPMN with available data on ABO blood group. We studied the association of ABO blood group with incidence of pancreatic carcinoma, overall and by carcinoma types [IPMN-derived carcinoma or concomitant pancreatic ductal adenocarcinoma (PDAC)]. Utilizing competing-risks proportional hazards models, we estimated subdistribution hazard ratios (SHR) for incidence of pancreatic carcinoma with adjustment for potential confounders, including cyst characteristics.

Results: During 11,518 person-years of follow-up, we identified 97 patients diagnosed with pancreatic carcinoma (53 with IPMN-derived carcinoma and 44 with concomitant PDAC). Compared with patients with blood group O, patients with blood groups A, B, and AB had multivariable SHRs (95% confidence intervals) for pancreatic carcinoma of 2.25 (1.25-4.07; = 0.007), 2.09 (1.08-4.05; = 0.028), and 1.17 (0.43-3.19; = 0.76), respectively. We observed no differential association of ABO blood group with pancreatic carcinoma incidence by carcinoma types.

Conclusions: In this large long-term study, patients with IPMN with blood group A or B appeared to be at higher risk of pancreatic carcinoma compared with those with blood group O.

Impact: ABO blood group can be a biomarker for pancreatic cancer risk among patients with IPMNs.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1581DOI Listing
May 2021

Donor age (≥45 years) and reduced immunosuppression are associated with the recurrent primary sclerosing cholangitis after liver transplantation - a multicenter retrospective study.

Transpl Int 2021 05 16;34(5):916-929. Epub 2021 Mar 16.

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

The present study investigated the possible risk factors, including relationship/HLA matching between donor and recipient, and immunosuppressive therapies on the recurrence of primary sclerosing cholangitis (PSC) after liver transplantation (LT). Subjects were 197 recipients of LT for PSC, among whom 180 surviving more than 1 year after LT were further analyzed for risk factors of recurrence. The 5- and 10-year patient- and graft survival rates were 83% and 68%, and 71% and 62%, respectively. The overall PSC recurrence rate was 25% with a 5- and 10-year graft survival rate of 34% and 18%, which was significantly lower than the survival rate of those without recurrence (P < 0.001). Univariate analysis identified the following as risk factors for recurrence: donor age (P < 0.001), cyclosporine use (P = 0.012), mono or no immunosuppressive agent (P < 0.001), postoperative biliary complication (P < 0.001), and active intestinal bowel disease after LT (P < 0.001). Among these factors, donor age ≥45 years [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.21-2.69; P = 0.003] and mono or no immunosuppressive agent 1-year after LT (HR, 2.38; 95% CI, 1.23-3.45; P = 0.011) were identified as independent risk factors in the final multivariate Cox regression model. The results were similar in sub-analysis for ABO-identical/compatible adult living donor LT cases.
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http://dx.doi.org/10.1111/tri.13852DOI Listing
May 2021

Proposal of a novel H category-based classification of colorectal liver metastases based on a Japanese nationwide survey.

J Hepatobiliary Pancreat Sci 2021 Apr 16;28(4):317-326. Epub 2021 Mar 16.

Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Japan.

Background: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM ≥5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm.

Methods: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (≤ 5 vs >5 cm) and lesion number (1, 2-4, and ≥5).

Results: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size ≤5 cm; lesions other than nH1 or nH3; and ≥5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable.

Conclusion: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability.
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http://dx.doi.org/10.1002/jhbp.920DOI Listing
April 2021

Impact of Abdominal Incision Type on Postoperative Pain and Quality of Life Following Hepatectomy.

World J Surg 2021 06 17;45(6):1887-1896. Epub 2021 Feb 17.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: The aim of this prospective study was to analyze the impact of abdominal incision type on postoperative pain and quality of life (QOL) in hepatectomy.

Methods: In patients undergoing hepatectomy by open, hybrid, or pure laparoscopic approaches, we classified abdominal incisions as: pure laparoscopic (LAP), midline (MID), J-shaped (J), and J-shaped incision plus thoracotomy (TRC). Postoperative pain was measured on postoperative day (POD) 3, 7, 30, and 90 using a visual analog scale (VAS). QOL was evaluated using the short-form-36 questionnaire preoperatively and on POD 30 and 90.

Results: We categorized 165 patients into LAP (n = 9, 5%), MID (n = 21, 13%), J (n = 95, 58%), and TRC (n = 40, 24%) groups. Median VAS scores on PODs 3/7/30/90 were: LAP, 27.5/7.5/10/10; MID, 30/10/15/5; J, 50/27.5/20/10, and TRC, 50/30/30/19. The J and TRC groups had significantly higher VAS scores vs. MID on PODs 3 and 7; the LAP and MID groups did not differ significantly. No significant positive correlations were observed between incision length and postoperative VAS, when we stratified patients into two groups according to the presence or absence of a transverse incision. Physical QOL summary scores did not return to preoperative levels even on POD 90, in patients with an additional transverse incision. Mental QOL summary scores worsened with postoperative complications rather than with abdominal incision type.

Conclusions: Transverse incisions, rather than incision length, led to worse midline incision pain and poorer QOL recovery post-hepatectomy. A hybrid approach may be a considerable option when pure laparoscopic hepatectomy is technically difficult.

Trial Registration: This study was registered in the UMIN Clinical Trials Registry (registration number: UMIN000017467; http://www.umin.ac.jp/ctr/index.htm ).
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http://dx.doi.org/10.1007/s00268-021-05992-xDOI Listing
June 2021

[Application of Fluorescence Imaging to Liver Cancer Surgery].

Gan To Kagaku Ryoho 2021 Feb;48(2):181-185

Division of Hepato-Biliary-Pancreatic Surgery, Dept. of Surgery, Graduate School of Medicine, The University of Tokyo.

In hepatobiliary surgery, intraoperative fluorescence imaging can be used for real-time identification of the extrahepatic bile ducts (fluorescence cholangiography), liver cancers, and hepatic segmental boundaries, based on biliary excretion as well as fluorescence property of indocyanine green(ICG). These techniques have mainly been developed in Japan and currently become used worldwide, with the advancement and spread of near-infrared imaging systems for open and laparoscopic surgery. It can be expected that novel photodynamic therapy for liver cancers is developed by applying accumulation of biliary excreted agents like ICG in the cancer tissues not only to intraoperative imaging but also to active treatments.
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February 2021

An aberrant right hepatic artery arising from the gastroduodenal artery: a pitfall encountered during pancreaticoduodenectomy.

Surg Today 2021 Feb 11. Epub 2021 Feb 11.

Department of Visceral Surgery, University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.

Purpose: Among the variations of the right hepatic artery (RHA), the identification of an aberrant RHA arising from the gastroduodenal artery (GDA) is vital for avoiding damage to the RHA during surgery, since ligation of the GDA is necessary during pancreaticoduodenectomy (PD). However, this variation is not frequently reported. The purpose of this study was to focus on an aberrant RHA arising from the GDA, which was not noted in the classifications reported by Michels and Hiatt.

Methods: A total of 574 patients undergoing a PD between Jan 2001 and Dec 2015 at a tertiary care hospital in Switzerland (n = 366) and between Jan 2009 and May 2015 at a hospital in Japan (n = 208) were included in the analysis. Of these, preoperative CT angiography or/and MRI angiography findings were available for 532 patients. We retrospectively analyzed the hepatic artery variations, patient demographics, and surgical outcomes.

Results: Among the 532 patients who received a PD, an RHA originating from the GDA was observed in 19 cases (3.5%). Eleven patients (2.1%) had both an aberrant RHA and an aberrant left hepatic artery (LHA) (Hiatt Type 4). Six patients (1.2%) had a replaced CHA arising from the SMA (Hiatt Type 5). We could, therefore, correctly identify the aberration in all cases.

Conclusions: We observed rarely reported but important aberrant RHA variations arising from the GDA. To prevent injury during PD in patients with this type of aberrant RHA, intensive preparations using CT and/or MRI imaging before surgery and intraoperative liver Doppler ultrasonography are considered to be essential.
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http://dx.doi.org/10.1007/s00595-021-02242-4DOI Listing
February 2021

Landmarks and techniques to perform minimally invasive liver surgery: A systematic review with a focus on hepatic outflow.

J Hepatobiliary Pancreat Sci 2021 Jan 21. Epub 2021 Jan 21.

Center for Advanced Treatment of Hepatobiliary and Pancreatic Diseases, Ageo Central General Hospital, Saitama, Japan.

Purpose: In this systematic review, we aimed to clarify the useful anatomic structures and assess available surgical techniques and strategies required to safely perform minimally invasive anatomic liver resection (MIALR), with a particular focus on the hepatic veins (HVs).

Methods: A systematic review was conducted using MEDLINE/PubMed for English articles and Ichushi databases for Japanese articles through September 2020. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN).

Results: A total of 3372 studies were obtained, and 59 were selected and reviewed. Due to the limited number of published comparative studies and case series, the degree of evidence from our review was low. Thirty-two articles examined the anatomic landmarks and crucial structures for approaching HVs. Regarding the direction of HV exposure, 32 articles focused on the techniques and advantages of exposing HVs from either the root or the periphery. Ten articles focused on the techniques to perform a segmentectomy 8 in particularly difficult cases of MIALR. In seven articles, bleeding control from HVs was also discussed.

Conclusions: This review may help experts reach a consensus regarding the best approach to the management of hepatic veins during MIALR.
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http://dx.doi.org/10.1002/jhbp.898DOI Listing
January 2021

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis.

Cell Death Dis 2021 01 19;12(1):99. Epub 2021 Jan 19.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

While the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9a) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9a and wild-type livers, more apoptotic hepatocytes were detected in the G9a liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9a liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.
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http://dx.doi.org/10.1038/s41419-020-03381-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815717PMC
January 2021

Axin2 Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma.

Gastroenterology 2021 May 16;160(6):2133-2148.e6. Epub 2021 Jan 16.

Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.

Background & Aims: Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer.

Methods: We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-Cre mice.

Results: Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19 luminal surface BECs showed gradual replacement by CK19 cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2 PBG cells, but not CK19 luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor.

Conclusion: A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.
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http://dx.doi.org/10.1053/j.gastro.2021.01.028DOI Listing
May 2021

Advancement of Biomaterial-Based Postoperative Adhesion Barriers.

Macromol Biosci 2021 03 19;21(3):e2000395. Epub 2021 Jan 19.

Center for Disease Biology and Integrative Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials' efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.
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http://dx.doi.org/10.1002/mabi.202000395DOI Listing
March 2021

Identification of Glisson's Capsule Invasion During Hepatectomy for Colorectal Liver Metastasis by Contrast-Enhanced Ultrasonography Using Perflubutane.

World J Surg 2021 Apr 3;45(4):1168-1177. Epub 2021 Jan 3.

Department of Surgery, Graduate School of Medicine, Hepato-Biliary-Pancreatic Surgery Division, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Glisson invasion by CLM is associated with a risk of margin-positive resection, leading to poor long-term outcomes after hepatectomy. This study was performed to evaluate the efficacy of intraoperative ultrasonography (IOUS) for the diagnosis of Glisson's capsule invasion by colorectal liver metastasis (CLM).

Methods: This prospective study involved 50 consecutive patients undergoing hepatectomy for CLM. Preoperatively, all patients had undergone gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). During hepatectomy, a contrast agent (perflubutane) was intravenously injected and Glisson invasion was estimated based on three characteristic findings: a tumor thrombus, peripheral dilatation, and border irregularity/caliber change. The diagnostic abilities of the preoperative and intraoperative imaging studies were evaluated based on pathological examinations of resected specimens.

Results: Among 187 CLMs resected, pathological examinations proved Glisson invasion in 24 tumors (13%). IOUS revealed a tumor thrombus in 3 tumors (1.6%), peripheral dilatation in 4 (2.1%), and border irregularity and/or caliber change in 24 (12.8%). The sensitivity and specificity of IOUS with any of the above three findings for diagnosis of Glisson invasion was 79% and 96%, respectively, while preoperative EOB-MRI detected Glisson invasion in only four tumors (sensitivity/specificity, 17%/100%). The cutoff value of caliber change for diagnosis of Glisson invasion was set at 140% by receiver operating characteristic analysis. The R0 resection rates were not significantly different between patients with (82%) and without (85%) Glisson invasion.

Conclusions: Identification of characteristic findings (tumor thrombus, peripheral dilatation, and border irregularity/caliber change) by contrast-enhanced IOUS is useful for the prediction of Glisson invasion by CLM.
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http://dx.doi.org/10.1007/s00268-020-05883-7DOI Listing
April 2021
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