Publications by authors named "Shinji Uemoto"

797 Publications

An analysis of the outcomes in living donor liver transplantation for pediatric malignant hepatic tumors using nationwide survey data in Japan.

Transpl Int 2021 May 22. Epub 2021 May 22.

Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Malignant hepatic tumors (MHTs) in children are rare and account for approximately 5% of candidates for pediatric liver transplantation (LT) in Japan. We conducted a national survey of pediatric patients undergoing living donor LT for MHTs between October 1990 and April 2018. In total, 116 children underwent LT for MHTs during this study period: 100 hepatoblastomas (HBLs), 10 hepatocellular carcinomas (HCCs), and six other MHTs. The overall patient survival rate at 5 years was 81.3% for HBL, 60.0% for HCC, and 80.0% for other MHTs (P = 0.047). In patients with HBL, there was no significant difference in the 1- and 5-year patient survival rates between patients undergoing primary LT and those who received salvage LT for tumor recurrence (89.7%, 81.6% vs. 88.0%, 76%; P = 0.526). The 5-year overall survival rate after LT for HBL significantly improved from 63.2% in 1996-2008 to 89.8% in 2009-2018 (P = 0.018). The presence of lung metastasis before LT had no significant influence on the long-term survival (P = 0.742). Five patients with HCC died, including two who fell outside the Milan criteria. In conclusion, LT for pediatric MHTs, especially HBL, is a valuable treatment option for select patients.
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http://dx.doi.org/10.1111/tri.13924DOI Listing
May 2021

Outcomes of Pediatric Liver Transplantation in Japan: A Report from the Registry of the Japanese Liver Transplantation Society (JLTS).

Transplantation 2021 Jan 19. Epub 2021 Jan 19.

1. Transplantation Center, National Center for Child Health and Development, Tokyo, Japan 2. Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan 3. Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan 4. Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan 5. Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 6. Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan 7. Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, Fukuoka, Japan 8. Department of Hepato-Pancreatic-Biliary and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan 9. Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan 10. Shiga Medical University, Shiga, Japan 11. Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background: The Japanese Liver Transplantation Society (JLTS), a cooperative research consortium, was established in 1980 in order to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed factors that may affect the current outcomes of pediatric patients who undergo LT by evaluating one of the largest pediatric LT cohorts in the world.

Methods: Between November 1989 and December 2018, 3347 pediatric patients underwent LT in Japan. The survival outcomes of each donor and recipient variant were evaluated.

Results: The procedures performed during the study period included living donor LT (LDLT; n=3271), deceased donor LT (DDLT; n=69), and domino LT (n=7). There were 1510 male (45.1%) and 1837 female (54.9%) recipients with a median age of 1.7 years (range: 9 days to17.9 years). The graft survival rates at 1, 10, 20, and 30 years were 88.9%, 82.2%, 77.1%, and 75.4%, respectively. Donor age, donor BMI, blood type incompatibility, recipient age, etiology of liver disease, transplant type, center experience, and transplant era were found to be significant predictors of overall graft survival. LDLT is a major treatment modality for end-stage liver disease in children; DDLT and domino LT were applied as alternative treatments for LDLT in patients with specific pediatric liver diseases that are considered to have a poor prognosis following LDLT.

Conclusions: Satisfactory long-term pediatric patient survival outcomes were achieved in the JLTS series, and we should continue to promote the deceased donor organ transplantation program in Japan.
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http://dx.doi.org/10.1097/TP.0000000000003610DOI Listing
January 2021

Micro- and macro-borderless surgery using a newly developed high-resolution (4K) three-dimensional video system.

PLoS One 2021 12;16(5):e0250559. Epub 2021 May 12.

Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan.

Objective: Microsurgery using conventional optical microscopes or surgical loupes features a limited field of view and imposes a serious strain on surgeons especially during long surgeries. Here we advocate the micro- and macro-borderless surgery (MMBS) using a novel high-resolution (4K) three-dimensional (3D) video system. This study aimed to confirm the applicability of this concept in several surgical procedures.

Methods: We evaluated the possible use and efficacy of MMBS in the following experiments in porcine subjects. Experiment 1 (non-inferiority test) consisted of dissection and anastomosis of carotid artery, portal vein, proper hepatic artery, and pancreatoduodenectomy with surgical loupe versus MMBS. Experiment 2 (feasibility test) consisted of intra-abdominal and intra-thoracic smaller arteries anastomosed by MMBS as a pre-clinical setting. Experiment 3 (challenge on new surgery) consisted of orthotopic liver transplantation of the graft from a donor after circulatory death maintained by machine perfusion. Circulation of the cardiac sheet with a vascular bed in experiment 2 and liver graft during preservation in experiment 3 was evaluated with indocyanine green fluorescence imaging equipped with this system.

Results: Every procedure was completed by MMBS. The operator and assistants could share the same field of view in heads-up status. The focal depth was deep enough not to be disturbed by pulsing blood vessels or respiratory movement. The tissue circulation could be evaluated using fluorescence imaging of this system.

Conclusions: MMBS using the novel system is applicable to various surgeries and valuable for both fine surgical procedures and high-level surgical education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115828PMC
May 2021

Guidelines for Perioperative Care for Liver Transplantation: Enhanced Recovery After Surgery (ERAS) Society Recommendations.

Transplantation 2021 May 6. Epub 2021 May 6.

Department of Hepatobiliary and Liver Transplantation Surgery, AP-HP, Hôpital de la Pitié-Salpêtrière, F-75013 Paris, France; Université de Picardie-Jules Verne, UR UPJV 7518 SSPC, F-80000, Amiens, France. Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France. - Sorbonne Université, INSERM, UMR-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France. - Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Pitié-Salpêtrière, AP-HP, Paris, France. Department of Anesthesiology and Critical Care, A.O.U. Città della Salute e della Scienza di Torino Torino, Italy Division of Anesthesiology, Department of Anesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva, Switzerland. University of Montreal Hospital Research Center, Canada; Department of Anesthesiology and Department of Medicine, Division of Critical Care, University of Montreal Hospital Centre, Canada General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Torino, Corso Bramante 88-90, 10126, Torino, Italy. Department of Anaesthesiology (AMH, A-SJM, AK, JLJ), Service of Abdominal Surgery, CHU Liège, University of Liège, Domaine du Sart Tilman, Liège, Belgium Division of Abdominal Surgery and Transplantation, University of Liège Hospital (CHU ULiège), Liège, Belgium Anesthesiology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Digestive Organs Transplant Division, Gastroenterology Department, Sao Paulo University School of Medicine, Sao Paulo, Brazil HPB Surgery and Liver Transplantation Unit, CHUM St-Luc, University of Montreal, 1058 Saint-Denis, Montreal, QC, H2X 3J4, Canada Transplant Anesthesia and Critical Care Unit, University School of Medicine, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan Division of Transplantation, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland Department of General & Digestive Surgery, ISABIAL, Hospital General Universitario de Alicante, Spain Section Hepato-Pancreatico-Biliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Oregon Health & Science University, Department of Surgery, Division of Abdominal Organ Transplantation, United States Department of Anesthesiology and Critical Care, Gastroenterology Department, Sao Paulo University School of Medicine, Sao Paulo, Brazil Department of Critical Care, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands Department of Anesthesiology and Critical Care, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, UK Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Oregon Health & Science University, Department of Anesthesiology and Critical Care, United States Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne UNIL, Rue du Bugnon 46, 1011, Lausanne, Switzerland Department of Clinical Surgery, University of Edinburgh and Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, UK Department of Digestive, Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP Pitié-Salpêtriere, Sorbonne Université, Centre de Recherche de Saint-Antoine (CRSA), INSERM, UMRS-938, Paris, France.

Background: Enhanced Recovery After Surgery (ERAS) is a multimodal, evidence-based, program of care developed to minimize the response to surgical stress, associated with reduced perioperative morbidity and hospital stay. This study presents the specific ERAS Society recommendations for liver transplantation (LT) based on the best available evidence and on expert consensus.

Methods: PubMed and ClinicalTrials.gov were searched in April 2019 for published and ongoing RCTs on LT in the last 15 years. Studies were selected by 5 independent reviewers, and were eligible if focusing on each validated ERAS items in the area of adult LT. An e-Delphi method was used with an extended interdisciplinary panel of experts to validate the final recommendations.

Results: Forty-three articles were included in the systematic review. Consensus was reached among experts after the second round. Patients should be screened for malnutrition and treated whenever possible. Prophylactic nasogastric intubation and prophylactic abdominal drainage may be omitted, and early extubation should be considered. Early oral intake, mobilization and multimodal-balanced analgesia are recommended.

Conclusions: The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the e-Delphi method. Nevertheless, prospective studies need to confirm the clinical use of the suggested protocol.PROSPERO CRD4201913279.
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http://dx.doi.org/10.1097/TP.0000000000003808DOI Listing
May 2021

Laparoscopic Versus Open Liver Resection for Hepatocellular Carcinoma: A Case Controlled Study with Propensity Score Matching.

World J Surg 2021 Apr 21. Epub 2021 Apr 21.

Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan.

Background: Several studies have suggested that laparoscopic liver resection (LLR) is associated with fewer postoperative complications than open liver resection (OLR) for hepatocellular carcinoma (HCC). However, this issue remains controversial since the data may have been attributable to an imbalance in patients' background.

Methods: We retrospectively analyzed 290 hepatectomies for HCC undertaken between 2011 and 2019. Liver resection difficulty was based on the 3 levels of the Institut Mutualiste Montsouris classification. Resection ratio was calculated using computed tomography volumetry. Patient characteristics were compared between the LLR and OLR groups. Propensity score matching (PSM) was adopted to adjust the imbalance between the cohorts, and the incidence of postoperative complications was compared.

Results: The difficulty and resection ratio were significantly lower in LLR (n = 112) than in OLR (n = 178) (difficulty grade I/II/III: 84/10/18 vs. 43/39/96, p < 0.001; resection ratio: 11.4 ± 12.7 vs. 22.7 ± 17.2%, p < 0.001). The incidence of postoperative complications (Clavien-Dindo grade III or more) was lower in LLR (2.7% vs. 21.9%, p < 0.001), which was mainly attributable to fewer incidences of ascites and pleural effusion. PSM generated 68 well-matched patients in each group. The lower incidence of postoperative complications in LLR was also maintained in the PSM cohort (2.9% vs. 16.2%, p = 0.017). On multivariate analysis, LLR was the independent predictor of postoperative complications (OR 0.184, 95% CI 0.051-0.672, p = 0.010).

Conclusion: The present study demonstrated that a laparoscopic approach reduces the incidence of postoperative complications in liver resection for HCC.
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http://dx.doi.org/10.1007/s00268-021-06115-2DOI Listing
April 2021

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

J Hepatobiliary Pancreat Sci 2021 Mar 31. Epub 2021 Mar 31.

Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.

Background/purpose: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM.

Methods: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated.

Results: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals.

Conclusions: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.
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http://dx.doi.org/10.1002/jhbp.956DOI Listing
March 2021

Reply to: "Predicted Volume or Actual Weight for Graft Selection Policy in Living-donor Liver Transplantation".

Transplantation 2021 Apr;105(4):e44-e45

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

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http://dx.doi.org/10.1097/TP.0000000000003584DOI Listing
April 2021

On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity.

Redox Biol 2021 May 2;41:101926. Epub 2021 Mar 2.

Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au-S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance.
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http://dx.doi.org/10.1016/j.redox.2021.101926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010883PMC
May 2021

A subcentimeter duodenal neuroendocrine neoplasm with a liver metastasis upgraded to G3: a case report.

Surg Case Rep 2021 Mar 19;7(1):72. Epub 2021 Mar 19.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Although duodenal neuroendocrine neoplasms (DuNENs) usually have indolent phenotypes, some DuNENs exhibit aggressive clinical manifestations. Tumor size > 1 cm, lymph node metastasis, and high grade have been associated with poor prognosis. However, preoperative risk evaluation is often difficult, because Ki-67 index on biopsy is frequently underestimated due to the intratumor heterogeneity. Here, we present a case of a subcentimeter DuNEN with a low Ki-67 index on endoscopic biopsy, who developed lymph node metastasis and high-grade liver metastasis.

Case Presentation: The patient was a 52-year-old female who presented an epigastric pain. Esophagogastroduodenoscopy revealed a duodenal submucosal lesion with a size of 8 mm. The endoscopic biopsy showed DuNEN with a Ki-67 index of 3.3% (G2 categorized by the World Health Organization 2019 classification). We performed an open partial duodenectomy with adjacent lymph node dissection. Pathological examination of the resected specimens revealed a Ki-67 index of 13.5% (G2) in the "hot spot" and lymph node metastasis. A hepatic low-density area detected on preoperative contrast-enhanced computed tomography appeared to be a liver metastasis on postoperative gadoxetic acid-enhanced magnetic resonance imaging. Subsequently, we performed a laparoscopic partial hepatectomy. Pathological examination of the liver specimen showed a metastatic neuroendocrine tumor with a Ki-67 index of 27.5% (NET-G3). The patient has been alive for 14 months since the hepatectomy.

Conclusions: This case shows the possibility of high malignant potential of DuNEN even if the primary lesion is < 1 cm and has a low Ki-67 index on biopsy.
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http://dx.doi.org/10.1186/s40792-021-01155-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979845PMC
March 2021

Conditional Recurrence-Free Survival after Oncologic Extended Resection for Gallbladder Cancer: An International Multicenter Analysis.

Ann Surg Oncol 2021 May 5;28(5):2675-2682. Epub 2021 Mar 5.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC.

Patients And Methods: Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000-2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free.

Results: Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3-T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49-3.13, P < 0.001], 12-month recurrence-free (HR 3.42, 95% CI 1.88-6.23, P < 0.001), and 24-month recurrence-free (HR 2.71, 95% CI 1.11-6.62, P = 0.029). Of the 125 patients without these risk factors, only 2 had recurrence after 36 months.

Conclusion: C-RFS improves over time, and only T3-T4 disease remains a risk factor for recurrence at 24 months after OER for GBC. For all recurrence-free survivors after 36 months, the probability of recurrence is similar regardless of T category or disease stage.
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http://dx.doi.org/10.1245/s10434-021-09626-3DOI Listing
May 2021

Post-transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1,954 Transplants.

Liver Transpl 2021 Mar 2. Epub 2021 Mar 2.

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation/Pediatric Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1,954 LTs in 1,849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1,849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the "LT-PTLD score," that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions.
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http://dx.doi.org/10.1002/lt.26034DOI Listing
March 2021

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

Surg Today 2021 Mar 3. Epub 2021 Mar 3.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy.

Methods: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics.

Results: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489).

Conclusions: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.
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http://dx.doi.org/10.1007/s00595-021-02257-xDOI Listing
March 2021

Corticosteroid-associated osteonecrosis of the femoral head after orthotopic liver transplantation and the outcomes of subsequent total hip arthroplasty.

J Orthop Sci 2021 Feb 26. Epub 2021 Feb 26.

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Corticosteroids are essential for immunosuppression after orthotopic liver transplantation (OLT), but also have many side effects. Osteonecrosis of the femoral head (ONFH) is one of the most serious complications requiring prostheses. However, few studies have investigated ONFH after OLT. The purpose of this study is to survey the incidence of corticosteroid-induced ONFH after OLT and the outcomes of total hip arthroplasty (THA).

Methods: Between January 2001 and December 2010, a series of 926 patients underwent OLT at our Hospital. A retrospective analysis was performed on a total of 738 patients who survived at least 2 years after OLT. The incidence of symptomatic ONFH, the interval from OLT to the initial diagnosis of ONFH, and the cumulative dose of corticosteroids were analyzed. The side effects related to OLT, such as other osteonecrosis lesions, osteoporotic fractures, and infection, were monitored. For patients who underwent THA, radiological findings and Japanese Orthopaedic Association (JOA) scores were evaluated.

Results: ONFH occurred in 10 patients (13 hips) (6 men [7 hips], 4 women [6 hips]), with an incidence of 1.36%. The average age at OLT was 51.4 years (range, 31-61 years). The average interval from OLT to ONFH was 86.7 months (range, 22-155 months). The average cumulative dose of corticosteroids was 7274 mg (range, 1342-29,514 mg). Twenty patients suffered from side effects related to OLT. Seven patients (8 hips) underwent THA. No adverse events including infection arose during the perioperative process. One hip dislocated, and one femoral stem displayed a radiolucent line. The average JOA score improved from 45.4 (range, 25-76) preoperatively to 86.9 (range, 73-99) at final follow-up. No patients required revision surgery.

Conclusions: The incidence of symptomatic ONFH after OLT was 1.36%. Once the graft function becomes stable, THA can be a safe and effective treatment option for patients with ONFH after OLT.
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http://dx.doi.org/10.1016/j.jos.2020.12.014DOI Listing
February 2021

Pretransplant Body Composition Abnormality Has a Negative Impact Especially on Living Donor Liver Transplantation.

Transplantation 2021 Mar;105(3):e37-e38

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

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http://dx.doi.org/10.1097/TP.0000000000003562DOI Listing
March 2021

Gene expression profiles of liver cancer cell lines reveal two hepatocyte-like and fibroblast-like clusters.

PLoS One 2021 4;16(2):e0245939. Epub 2021 Feb 4.

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

Cancer cell lines are widely used in basic research to study cancer development, growth, invasion, or metastasis. They are also used for the development and screening of anticancer drugs. However, there are no clear criteria for choosing the most suitable cell lines among the wide variety of cancer cell lines commercially available for research, and the choice is often based on previously published reports. Here, we investigated the characteristics of liver cancer cell lines by analyzing the gene expression data available in the Cancer Cell Line Encyclopedia. Unsupervised clustering analysis of 28 liver cancer cell lines yielded two main clusters. One cluster showed a gene expression pattern similar to that of hepatocytes, and the other showed a pattern similar to that of fibroblasts. Analysis of hepatocellular carcinoma gene expression profiles available in The Cancer Genome Atlas showed that the gene expression patterns in most hepatoma tissues were similar to those in the hepatocyte-like cluster. With respect to liver cancer research, our findings may be useful for selecting an appropriate cell line for a specific study objective. Furthermore, our approach of utilizing a public database for comparing the properties of cell lines could be an attractive cell line selection strategy that can be applied to other fields of research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861371PMC
February 2021

Epithelial expression of Gata4 and Sox2 regulates specification of the squamous-columnar junction via MAPK/ERK signaling in mice.

Nat Commun 2021 01 25;12(1):560. Epub 2021 Jan 25.

Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.

The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
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http://dx.doi.org/10.1038/s41467-021-20906-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835245PMC
January 2021

Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy.

J Gastroenterol Hepatol 2021 Jan 15. Epub 2021 Jan 15.

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

Background And Aim: Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models.

Methods: We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later.

Results: Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated.

Conclusions: Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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http://dx.doi.org/10.1111/jgh.15406DOI Listing
January 2021

Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models.

Cell Mol Gastroenterol Hepatol 2021 12;11(5):1351-1367. Epub 2021 Jan 12.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; Organ Transplant Unit, Kyoto University Hospital, Kyoto, Japan.

Background & Aims: Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment.

Methods: ALF was induced in C5-knockout (KO, B10D2/oSn) mice and their wild-type (WT) counterparts (B10D2/nSn) through intraperitoneal lipopolysaccharide (LPS) and d-galactosamine (D-GalN) administration. Thereafter, monoclonal anti-C5 antibody (Ab) or control immunoglobulin was administered intravenously. Furthermore, a selective C5a-receptor (C5aR) antagonist was administered to WT mice to compare its efficacy with that of anti-C5-Ab-mediated total C5 inhibition. We clarified the therapeutic effect of delayed anti-C5-Ab administration after LPS/D-GalN challenge. We also assessed the efficacy of anti-C5-Ab in another ALF model, using concanavalin-A.

Results: Liver injury was evident 6 hours after LPS/D-GalN administration. C5-KO and anti-C5-Ab treatment significantly improved overall animal survival and significantly reduced serum transaminase and high-mobility group box-1 release with decreased histological tissue damage. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and less infiltration of CD11+/Ly6-G+ cells with lower cytokine/chemokine expression. Furthermore, C5-KO and anti-C5-Ab downregulated tumor necrosis factor-α production by macrophages before inducing marked liver injury. Moreover, single-stranded-DNA cells and caspase activation were reduced, indicating significant attenuation of apoptosis. Anti-C5-Ab treatment protected the liver more effectively than the C5aR antagonist, and its delayed doses were hepatoprotective. In addition, anti-C5-Ab treatment was effective against concanavalin-A-induced ALF.

Conclusions: C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022253PMC
January 2021

Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging.

Elife 2021 Jan 4;10. Epub 2021 Jan 4.

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

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1 tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1 and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1 cells in vivo, revealing the essential roles of Dclk1 cells in expansion of pancreatic neoplasia in all progressive stages.
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http://dx.doi.org/10.7554/eLife.55117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800378PMC
January 2021

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

Pancreatology 2021 Jan 1;21(1):263-268. Epub 2020 Dec 1.

Department of Surgery, Division of Hepato-biliary-pancreatic Surgery and Transplantation, Kyoto University, Japan.

Background: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy.

Methods: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis.

Results: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT.

Conclusion: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.
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http://dx.doi.org/10.1016/j.pan.2020.11.007DOI Listing
January 2021

Metronomic photodynamic therapy using an implantable LED device and orally administered 5-aminolevulinic acid.

Sci Rep 2020 12 16;10(1):22017. Epub 2020 Dec 16.

Department of Physiology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan.

Metronomic photodynamic therapy (mPDT) is a form of PDT that induces cancer cell death by intermittent continuous irradiation with a relatively weak power of light for a long duration (several days). We previously developed a wirelessly powered, fully implantable LED device and reported a significant anti-tumor effect of mPDT. Considering application in clinical practice, the method used for repeated administrations of photosensitizers required for mPDT should not have a high patient burden such as the burden of transvenous administration. Therefore, in this study, we selected 5-aminolevulinic acid (ALA), which can be administered orally, as a photosensitizer, and we studied the antitumor effects of mPDT. In mice with intradermal tumors that were orally administered ALA (200 mg/kg daily for 5 days), the tumor in each mouse was simultaneously irradiated (8 h/day for 5 days) using a wirelessly powered implantable green LED device (532 nm, 0.05 mW). Tumor growth in the mPDT-treated mice was suppressed by about half compared to that in untreated mice. The results showed that mPDT using the wirelessly powered implantable LED device exerted an antitumor effect even with the use of orally administered ALA, and this treatment scheme can reduce the burden of photosensitizer administration for a patient.
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http://dx.doi.org/10.1038/s41598-020-79067-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744509PMC
December 2020

Time-frequency analysis of serum with proton nuclear magnetic resonance for diagnosis of pancreatic cancer.

Sci Rep 2020 12 14;10(1):21941. Epub 2020 Dec 14.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Postgraduate School of Medicine, Kyoto University, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, Japan.

Although serum markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9) have been widely used in screening for pancreatic cancer (PC), their sensitivity and specificity are unsatisfactory. Recently, a novel tool of analyzing serum using the short-time Fourier transform (STFT) of free induction decays (FIDs) obtained by H-NMR has been introduced. We for the first time evaluated the utility of this technology as a diagnostic tool for PC. Serum was obtained from PC patients before starting any treatments. Samples taken from individuals with benign diseases or donors for liver transplantation were obtained as controls. Serum samples from both groups underwent H-NMR and STFT of FIDs. STFT data were analyzed by partial least squares discriminant analysis (PLS-DA) to clarify whether differences were apparent between groups. As a result, PLS-DA score plots indicated that STFT of FIDs enabled effective classification of groups with and without PC. Additionally, in a subgroup of PC, long-term survivors (≥ 2 years) could be discriminated from short-term survivors (< 2 years), regardless of pathologic stage or CEA or CA19-9 levels. In conclusion, STFT of FIDs obtained from H-NMR have a potential to be a diagnostic and prognostic tool of PC.
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http://dx.doi.org/10.1038/s41598-020-79087-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736857PMC
December 2020

Clinicopathological features and recurrence patterns of combined hepatocellular-cholangiocarcinoma.

World J Surg Oncol 2020 Dec 4;18(1):319. Epub 2020 Dec 4.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a primary liver carcinoma with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) components. We examined the clinicopathological characteristics and recurrence patterns of cHCC-CCA. Because of the rarity of cHCC-CCA, its etiology, clinicopathological features, and prognosis in comparison with other primary liver carcinoma remain unknown. Its recurrence pattern and sites in particular also need to be elucidated.

Methods: All patients who underwent hepatectomy for primary liver malignancies between 2005 and 2015 were retrospectively included in this study.

Results: Eight hundred and ninety-four hepatectomies were performed. Nineteen cases of cHCC-CCA (2.1%) in 16 patients were enrolled. Three patients underwent re-hepatectomy. The background of hepatitis viruses and tumor marker patterns of cHCC-CCA were similar to those of HCC and dissimilar to those of intrahepatic CCA (iCCA). Biliary invasion was common in cHCC-CCA and iCCA. The 5-year overall survival values of the cHCC-CCA, HCC, and iCCA patients were 44.7%, 56.6%, and 38.5%, respectively. The 5-year recurrence-free survival values of the cHCC-CCA, HCC, and iCCA patients were 12.2%, 28.7%, and 32.9%, respectively. The liver was the most common recurrence site. Unlike HCC, however, the lymph node was the second-most common recurrence site in both cHCC-CCA and iCCA. Pathological samples of the recurrent lesions were obtained in six patients, and four had cHCC-CCA recurrence pathologically.

Conclusion: cHCC-CCA had a mixture of characteristics of HCC and iCCA. Many cases of cHCC-CCA remained cHCC-CCA pathologically even after recurrence.
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http://dx.doi.org/10.1186/s12957-020-02099-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718660PMC
December 2020

Feasibility and mid- to long-term results of endovascular treatment for portal vein thrombosis after living-donor liver transplantation.

Diagn Interv Radiol 2021 Jan;27(1):65-71

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Japan.

Purpose: We aimed to evaluate mid- to long-term results of endovascular treatment for portal vein thrombosis (PVT) after living-donor liver transplantation (LDLT).

Methods: Thirty cases (14 males, 16 females; age range, 0.67-65 years) who underwent endovascular treatment including thrombolysis, angioplasty, stent placement, and/or collateral embolization for PVT after LDLT from 2001 to 2017 were retrospectively reviewed. Clinical and procedural data were collected and analyzed regarding the patency of the PVT site at the last follow-up date (PVT-free persistency) using Log-rank test. Results were considered statistically significant at P < 0.05.

Results: Median follow-up was 120 months. The technical success rate was 80% (n=24). Patency rates at 1 week and 1, 3, 6, 12, 36, and 60 months were 73%, 59%, 55%, 51%, 51%, 51%, and 51% for primary patency and 80%, 70%, 66%, 66%, 66%, 61%, and 61% for assisted patency after secondary endovascular treatment. PVT-free persistency rates regarding the subgroups were as follows: children under 12 years vs. adults, 50% vs. 68% (P = 0.42); acute vs. nonacute, 76% vs. 46% (P = 0.10); localized vs. extensive, 90% vs. 50% (P = 0.035); transileocolic approach vs. percutaneous-transhepatic approach, 71% vs. 54% (P = 0.39); and thrombolysis-based treatment vs. non-thrombolysis-based treatment, 71% vs. 44% (P = 0.12), respectively. Among technically successful cases, PVT-free persistency rate was 94% for those with hepatopetal flow in the peripheral portal vein vs. 17% for those without hepatopetal flow (P < 0.001). The only major complication occurring was pleural hemorrhage (n=1). Minor complications (i.e., fever) occurred in 18 patients (60%).

Conclusion: In conclusion, mid- to long-term portal patency following endovascular treatment was approximately 50%-60% in PVT patients after LDLT. PVT site patency over three months after the first endovascular treatment, localized PVT, and hepatopetal flow in the peripheral portal vein were identified as key prognostic factors for mid- to long-term portal patency.
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http://dx.doi.org/10.5152/dir.2020.19469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837713PMC
January 2021

Recent epidemiology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study.

BMC Cancer 2020 Nov 14;20(1):1104. Epub 2020 Nov 14.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, 54 Shogoin Kawaracho, Sakyo, Kyoto, Japan.

Background: The worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of these tumors using data from the national cancer registry started in 2016. This study examined the incidence and distribution of primary sites as well as rate of advanced disease from this population-based registry.

Methods: A retrospective, population-based study using data from the national cancer registry in Japan (NCR) was conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data were used to determine annual age-adjusted incidences.

Results: A total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was 0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1% of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs). Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC.

Conclusions: This is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan. These data will serve as an important first step to determining the exact etiology and trends for this pathology in Japan.
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http://dx.doi.org/10.1186/s12885-020-07581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666508PMC
November 2020

Liver Regeneration after Hepatectomy and Partial Liver Transplantation.

Int J Mol Sci 2020 Nov 9;21(21). Epub 2020 Nov 9.

Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
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http://dx.doi.org/10.3390/ijms21218414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665117PMC
November 2020

Foxp3+ Regulatory T Cells Inhibit CCl-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity.

Front Immunol 2020 15;11:584048. Epub 2020 Oct 15.

Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2 Ly-6C inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.
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http://dx.doi.org/10.3389/fimmu.2020.584048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593684PMC
June 2021

Pretransplantation splenomegaly frequently persists after liver transplantation and can manifest as hypersplenism and graft fibrosis - a retrospective study.

Transpl Int 2020 12 9;33(12):1807-1820. Epub 2020 Nov 9.

Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The risk factors and clinical impact of post-transplantation splenomegaly (SM) are poorly understood. We investigated the predictors and impacts of post-transplantation SM in 415 LT patients at Kyoto University Hospital from April 2006 to December 2015. First, the predictors and clinical consequences of SM three years post-transplantation were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years post-transplantation were compared between splenectomized and spleen-preserved recipients. There was no difference in indication for liver transplantation between these two groups. Third, survival outcomes were compared between splenectomized and spleen-preserved recipients. SM was determined as a SV/body surface area (BSA) higher than 152 ml/m . In the first analysis, preoperative SM occurred in 79.9% recipients and SM persisted three years post-transplantation in 72.6% recipients among them. Preoperative SV/BSA was the only independent predictor of three year post-transplantation SM, which was associated with lower platelet (PLT), white blood cell (WBC) counts and significant graft fibrosis (21.4% vs. 2.8%). In the second analysis, spleen-preservation was related to lower PLT, WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%) three years post-transplantation. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients. In conclusion, preoperative SM frequently persists more than three years post-transplantation and is associated with subclinical hypersplenism, graft fibrosis, graft loss, and even death.
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http://dx.doi.org/10.1111/tri.13761DOI Listing
December 2020