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Abstract: Background: Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. Methods: Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. Results: The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. Conclusions: A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules. [Copyright &y& Elsevier]

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare but severe complication after liver transplantation. In contrast to other thrombotic microangiopathies, treatment for TA-TMA has yet to be clarified. A 52-year-old male patient with liver cirrhosis due to hepatitis C underwent split liver transplantation from a deceased donor. His clinical course was without complication until 4 days after transplantation, when he experienced impaired consciousness, hemolytic anemia with fragmented erythrocytes, and marked thrombocytopenia. TA-TMA was diagnosed, and recombinant thrombomodulin was administered for 4 days. The patient's clinical symptoms and laboratory data rapidly improved. He has been followed up for 6 months and has not shown any complications. The pathogenesis of TA-TMA is endothelial damage in the vasculature. Recombinant thrombomodulin, an endothelial cell–protecting agent, is a promising new therapeutic choice for TA-TMA after liver transplantation. [ABSTRACT FROM AUTHOR]

The article describes the case of a 22-year-old woman who presented with abdominal bloating and derranged liver function test five months post-partum. Veno-occlusive disease was discovered through laparoscopic liver biopsy and computed tomography revealed ascites and occlusion of the hepatic vein. The patient underwent duct-to-duct right hepaticohapaticostomy and she received tacrolumus, mycophenolate and steroid immunosuppresion.

Background Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-γ-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. Methods Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. Results The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration ≥300 ng/mL, DCP concentration ≥300 mAU/mL, tumor number ≥4, tumor size ≥5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP ≥300 mAU/mL ( P = .03) and duration from last treatment to LDLT <3 months ( P = .01) were independent predictors of RFS. Conclusions DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC. [ABSTRACT FROM AUTHOR]

Background: Portal vein embolization (PVE) followed by major hepatectomy is a common treatment strategy for patients with perihilar cholangiocarcinoma (PHCC); however, the long-term dynamics of the liver remnant volume (LRV) remain unclear. Here, we report the dynamics of the LRV in patients who underwent hepatectomy following PVE., Methods: A total of 39 patients with PHCC who underwent right hemihepatectomy or left trisectionectomy with extrahepatic bile duct resection between 2004 and 2021 were enrolled in this study [PVE (n = 27) and non-PVE (n = 12]). Long-term remnant liver dynamics were analyzed in propensity score-matched pairs (n = 10/group)., Results: The LRV/future liver remnant volume (FLRV) at 1 week to 1 month after hepatectomy were smaller in the PVE group than in the non-PVE group (1.53 vs. 1.69, p = .044 and 1.52 vs 1.99, p = .003, respectively). In the non-PVE group, the LRV/FLRV ratio plateaued 1-3 months postoperatively, whereas progressive hypertrophy occurred in the PVE group, and the LRV/FLRV ratio became equal in both groups at 1 year after hepatectomy (1.96 vs. 1.97; p = .799). Multivariate analysis revealed that FLRV/total liver volume (TLV) ≤ 0.43 was the only independent predictor of LRV/FLRV ≥1.9 at 1 year after hepatectomy (odds ratio:5.345, 95% confidence interval:1.210-23.615; p = .027)., Conclusion: Although the long-term LRV was nearly equal in both groups, short-term LRV hypertrophy was lower in the PVE group than in the non-PVE group., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Background: In Japan, there has never been a national analysis of pediatric deceased donor liver transplantation (pDDLT) based on donor and recipient factors. We constructed a Japanese nationwide database and assessed outcomes of pDDLT focusing on the pediatric prioritization system introduced in 2018., Methods: We collected data on pDDLTs (<18 years) performed between 1999 and 2021 from the Japan Organ Transplant Network and Japanese Liver Transplantation Society, identified risk factors for graft survival and compared the characteristics and graft survival in pDDLTs conducted before and after the introduction of the pediatric prioritization system., Results: Overall, 112 cases of pDDLT were included, with a 1-year graft survival rate of 86.6%. Four poor prognostic factors were identified: recipient intensive care unit stay, model for end-stage liver disease/pediatric end-stage liver disease score, donor cause of death, and donor total bilirubin. After the introduction of the system, allografts from pediatric donors were more reliably allocated to pediatric recipients and the annual number of pDDLTs increased. The 1-year graft survival rate improved significantly as did pDDLT conditions indicated by the risk factors., Conclusions: Under the revised allocation system, opportunities for pDDLT increased, resulting in favorable recipient and donor conditions and improved survival., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Background: We developed a virtual reality (VR) education system and evaluated its clinical utility for promoting hand hygiene practices., Methods: This prospective, 2-week, randomized controlled study conducted at Okayama University Hospital, Japan, from November 2023 to January 2024, involved 22 participants (18 medical students and 4 residents). A fully immersive 360° VR system (VIVE Pro Eye) using a head-mounted display and sensing gloves was used to develop 3 health care tasks in a virtual patient room-Environmental Cleaning, Gauze Exchange, and Urine Collection. After monitoring all participants' baseline usage data of portable hand-rubbing alcohol in the first week, we randomly assigned them into 1:1 groups (VR training and video lecture groups). The primary outcome was differences in hand-rubbed alcohol use before and after intervention., Results: Before the intervention, alcohol use did not significantly differ between both groups. After the intervention, a significant increase in alcohol use was observed in the VR training group (median: 8.2 g vs 16.2 g; P = .019) but not in the video lecture group., Conclusions: Our immersive 360° VR education system enhanced hand hygiene practices. Infection prevention and control practitioners and digital technology experts must collaborate to advance the development of superior educational devices and content., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The superiority of anatomical liver resection (AR) for localized hepatocellular carcinoma (HCC) over nonanatomical liver resection (NR) remains controversial. This study aimed to investigate the impact of AR in preventing local and early HCC recurrence., Methods: A total of 280 patients who underwent initial liver resection for solitary HCC ≤5 cm in diameter were categorized into the AR and NR groups and compared using propensity score matching analysis., Results: Between the matched pairs (n = 87 in each group), the incidence rates of local and early (recurrence within 2 years after surgery) recurrences in the AR group were significantly lower than those in the NR group (13.8% vs. 28.7%, p = .025; 20.7% vs. 35.6%, p = .028, respectively). The overall survival in the AR group was better than that in the NR group (median: 13.4 vs. 7.6 years, p = .003). NR was among independent risk factors for early recurrence (odds ratio: 1.98, 95% CI: 1.1-3.6, p = .023) and prognostic factors for local recurrence (hazard ratio: 2.44, 95% CI: 1.4-4.4, p = .003)., Conclusion: AR is superior in controlling local and early recurrence postoperatively for solitary HCC ≤5 cm in diameter compared with NR., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Purpose: The present study aimed to clarify the effects of a hyperglycemic condition on the clinical consequences of long COVID. Methods: Among 643 patients who visited the outpatient clinic of our hospital from February 2021 to September 2023, long COVID patients were classified into a hyperglycemic (HG) group with casual blood glucose levels above 140 mg/dL and a normoglycemic (NG) group. The patients' backgrounds, clinical symptoms, health status including the QOL evaluation scale (EQ-5D-5L), self-rating depression scale (SDS), and F-scale questionnaire (FSSG), blood test data, and recovery periods were analyzed. Results: The NG group included 607 patients with long COVID and the HG group included 36 patients with long COVID. Patients in the HG group were older than those in the NG group (55 vs. 41 years; p < 0.001) and included a larger percentage of males (67% vs. 44%; p = 0.009). The HG group had a larger percentage of patients with moderate-to-severe conditions in the acute infection phase (28% vs. 12%; p = 0.008), a higher BMI (25 vs. 22 kg/m 2 ; p < 0.001), higher blood pressure (138/81 vs. 122/72 mmHg; p < 0.001), and a larger percentage of patients with an alcohol drinking habit (53% vs. 34%; p = 0.031). Long COVID symptoms and self-rated scales were not differed between the two groups; however, the laboratory data showed that liver and renal functions and metabolic data were significantly worse in the HG group. Although there was no apparent difference between the two groups in duration from the infection to the first visit, the HG group had a significantly longer period of recovery from long COVID (median period of 421 vs. 294 days; p = 0.019). Conclusion: A hyperglycemic state associated with other lifestyle-related diseases is associated with the prolongation of recovery from long COVID.

Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set., Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model., Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors., Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Purpose: This propensity score matching, multicenter, cross-sectional study was performed to examine the effects of various prosthetic methods for dental clinic outpatients with Kennedy Class I partial edentulism (KCIPE) on oral hypofunction, subjective frailty symptoms, and oral health-related quality of life (QOL)., Methods: Patients (n = 348) were classified into the following three groups for analysis: NT, patients with natural dentition providing intermaxillary contact in four occlusal supporting zones; RPD, patients with KCIPE who received removable partial dentures; and ISFP, patients with KCIPE who received implant-supported fixed prostheses. Participants' basic characteristics were recorded, and oral function tests were conducted. Subjective symptoms of physical and oral frailty were investigated via questionnaire. Oral health-related QOL was assessed using the Japanese short version of the Oral Health Impact Profile (OHIP-JP16). Propensity score matching was performed to adjust for patient background factors that could influence oral hypofunction in each group., Results: Compared with the ISFP group, the RPD group had significantly higher rates of poor oral hygiene, reduced occlusal force, decreased masticatory function, and declines in swallowing function and oral hypofunction; the odds ratio for oral hypofunction was 4.67. Compared with the ISFP group, the RPD group had significantly greater subjective symptoms of physical frailty and oral frailty, as well as higher OHIP scores., Conclusions: Prosthetic treatment of KCIPE affected oral hypofunction, subjective frailty symptoms, and oral health-related QOL in dental clinic outpatients., (© 2024. The Author(s).)

Purpose: To evaluate the predictive ability of combining Technetium-99m-galactosyl human serum albumin ( 99m Tc‑GSA) single-photon emission computed tomography (SPECT)/computed tomography (CT) volume and plasma clearance rate of indocyanine green (ICGK) for posthepatectomy liver failure (PHLF)., Materials and Methods: Fifty patients who underwent 99m Tc-GSA scintigraphy as a preoperative examination for segmentectomy or more from July 2021 to June 2023 were evaluated prospectively. Patients were divided into two groups according to the presence or absence of posthepatectomy liver failure (PHLF). Total functional liver volume (t-FLV) and remnant FLV (r-FLV) were measured from 99m Tc-GSA SPECT/CT image. Future liver remnant ICGK (ICGK-F) was calculated by ICGK and remnant liver volume from CT. Area under the curve (AUC) of ICGK-F, r-FLV, r-FLV/t-FLV, ICGK × r-FLV, ICGK × r-FLV/t-FLV was calculated to evaluate predictive ability of each parameter for PHLF., Results: PHLF was occurred in 7 patients. AUC of ICGK × r-FLV was significantly higher than that of ICGK-F (0.99; 95% confidence interval [CI]: 0.96-1 vs 0.82; 95%CI: 0.64-0.96; p = 0.036). There was no significant difference between the AUC of r-FLV, r-FLV/t-FLV, ICGK × r-FLV/t-FLV and that of ICGK-F, respectively., Conclusion: The combination of 99m Tc‑GSA SPECT/CT volume and ICGK can predict PHLF more accurately than ICGK-F., (© 2024. The Author(s).)

Purpose: Ureaplasma urealyticum is a rare pathogen associated with septic arthritis that predominantly affects patients with hypogammaglobulinemia. Bacterial identification of fastidious organisms is challenging because they are undetectable by routine culture testing. To the best of our knowledge, this is the first report of septic arthritis induced by U. urealyticum infection in Japan., Case Description: We describe the case of a 23-year-old Japanese female with secondary hypogammaglobulinemia (serum immunoglobulin level < 500 mg/dL), identified 8 years after treatment with rituximab. The patient presented with persistent fever and polyarthritis that were unresponsive to ceftriaxone and prednisolone. Contrast-enhanced computed tomography and gallium-67 scintigraphy revealed effusion and inflammation in the left sternoclavicular, hip, wrist, knee, and ankle joints. Although Gram staining and bacterial culture of the drainage fluid from the left hip joint were negative, the condition exhibited characteristics of purulent bacterial infection. The patient underwent empirical treatment with doxycycline, and her symptoms promptly resolved. Subsequent 16S ribosomal RNA (rRNA) gene sequencing of the joint fluid confirmed the presence of U. urealyticum, leading to the diagnosis of septic arthritis. Combination therapy with doxycycline and azithromycin yielded a favorable recovery from the inflammatory status and severe arthritic pain., Conclusion: This case highlights U. urealyticum as a potential causative agent of disseminated septic arthritis, particularly in patients with hypogammaglobulinaemia. The 16S rRNA gene analysis proved beneficial for identifying pathogens in culture-negative specimens, such as synovial fluid, in suspected bacterial infections., (© 2024. The Author(s).)

Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate whether polymorphisms of GAS6 and PROS1 , which each encode protein ligands for a family of tyrosine kinase receptors, are associated with Behçet's disease (BD) in a Japanese population., Methods: We recruited 734 Japanese patients with BD and 1789 Japanese healthy controls. In all participants, we genotyped two single-nucleotide polymorphisms (SNPs) reportedly associated with BD: rs9577873 in GAS6 and rs4857037 in PROS1 ., Results: We found that GAS6 rs9577873 was not significantly associated with BD. In contrast, PROS1 rs4857037, specifically the A allele, was associated with increased risk for BD. The A allele was also significantly associated with BD under additive and recessive genetic models. Expression analysis revealed that this allele was significantly associated with increased PROS1 expression., Conclusions: Our findings suggest that increased PROS1 expression related to the A risk allele of rs4857037 affects tyrosine kinase receptor signaling, contributing to the development of BD.

Background: Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events., Objectives: In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD., Methods: We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants' BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events., Results: A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10 -4 ). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events., Conclusion: This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD., Competing Interests: YK has received support from Amgen speaking fees, support for attending meetings and travel, and advisory board, Novartis speaking fees and advisory board, and Nippon Shinyaku grants. Mitsuhiro Takeno has received consulting and speaking fees from Amgen; research grants and speaking fees from AbbVie, Asahi Kasei, Chugai, Eisai, Tanabe-Mitsubishi, and Taisyo; and speaking fees from Astellas, Asympti, Boehringer-Ingelheim, Eli Lily, Jansen Pharma, Nippon Shinyaku, Novartis, Ono Pharmaceuticals, Takeda, UBC Japan, and Viatris. Tatsuya Atsumi has received grants from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., TEIJIN PHARMA LIMITED., Eisai Co., Ltd., and Eli Lilly Japan K.K. Tetsuya Atsumi has also received consulting fees from Sanofi K.K, GlaxoSmithKline plc, AbbVie Inc., AstraZeneca plc, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Gilead Sciences, Inc., Eli Lilly Japan K.K., and ONO PHARMACEUTICAL CO., LTD. TA has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Pfizer Inc., Alexion Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., AbbVie Inc., Nippon Boehringer Ingelheim Co., Ltd., Amgen Inc. UCB Japan Co. Ltd., AstraZeneca plc, and Eisai Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hirahara, Kirino, Soejima, Iizuka, Yoshimi, Fujieda, Atsumi, Tono, Kobayashi, Meguro, Takeuchi, Sakamaki, Takeno, Mizuki and Nakajima.)

Cholangiocarcinoma has a poor prognosis, and resection is the only curative treatment. Pembrolizumab, a programmed death receptor 1 inhibitor, has proven effective against unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or a high tumor mutation burden (TMB-H). In the present case, pembrolizumab treatment was initiated after standard chemotherapy for MSI-H and TMB-H unresectable intrahepatic cholangiocarcinoma. Intrahepatic tumor necrosis perforated the abdominal cavity. Emergency surgery was performed, but the patient died 36 days after admission. A pathological autopsy revealed that the intrahepatic tumor had almost completely disappeared.

Background: In liver transplant patients with hypoplastic portal vein (PV), when the narrowed segment is extended too deep into the dorsal side of the pancreas, it is difficult and dangerous to reconstruct the interposition graft from the upper part of the pancreas. Herein, we present a case of PV reconstruction with the autologous mesosystemic shunt vessel from the caudal side of the pancreas in a situation where the narrowed PV was deep, and we discuss the technical details., Case Presentation: A 25-year-old woman presented with cholestatic liver cirrhosis due to biliary atresia after Kasai procedure. Since her jaundice progressed, she was referred to our hospital for liver transplantation. Laboratory tests showed that her total bilirubin was elevated to 7.6 mg/dL. The Model for End-Stage Liver Disease score was 18, and the Child-Pugh score was 9 (Grade B). She underwent living donor liver transplantation (LDLT) using a right hemi-liver graft procured from her 54-year-old mother. The conventional approach from the cephalad side to the superior mesenteric vein (SMV) and splenic vein (SpV) confluence behind the pancreas was extremely difficult in this case because the confluence of SMV and SpV was close to the lower edge of the pancreas. Therefore, we decided to perform PV reconstruction from the caudal side. The main trunk of PV was documented as narrow (5 mm in diameter), for which retro-pancreatic pull-through PV reconstruction was successfully performed using her own mesosystemic shunt vessel. A contrast computed tomography (CT) scan was performed on postoperative day 5 because of an elevation of D-dimer and found a partial thrombus in the left pulmonary artery, as well as in the PV and left renal vein. Thereafter, thrombolytic therapy with low-molecular-weight heparin was started immediately and switched to a direct oral anticoagulant. The follow-up CT taken 3 months after liver transplantation revealed a patent PV without thrombus; therefore, anticoagulant therapy was discontinued. Currently, the patient has been well and active with a patent PV without anticoagulant therapy for 3 years after LDLT., Conclusions: Retro-pancreatic pull-through reconstruction of the hypoplastic PV is a feasible and effective method when conventional reconstruction is not indicated., (© 2024. The Author(s).)

Background and Objectives: Robotic distal gastrectomy (RDG) has been widely performed throughout Japan since it became insured in 2018. This study aimed to evaluate the short-term outcomes of RDG and laparoscopic distal gastrectomy (LDG) for gastric cancer using real-world data., Methods: A total of 4161 patients who underwent LDG (n = 3173) or RDG (n = 988) for gastric cancer between April 2018 and October 2022 were identified through the Japanese Diagnosis Procedure Combination Database, which covers 42 national university hospitals. The primary outcome was postoperative in-hospital mortality rate. The secondary outcomes were postoperative complication rates, time to diet resumption, and postoperative length of stay (LOS)., Results: In-hospital mortality and postoperative complication rates in the RDG group were comparable with those in the LDG group (0.1% vs. 0.0%, p = 1.000, and 8.7% vs. 8.2%, p = 0.693, respectively). RDG was associated with a longer duration of anesthesia (325 vs. 262 min, p < 0.001), similar time to diet resumption (3 vs. 3 days, p < 0.001), and shorter postoperative LOS (10 vs. 11 days, p < 0.001) compared with LDG., Conclusions: RDG was performed safely and provided shorter postoperative LOS, since it became covered by insurance in Japan., (© 2024 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-I are crucial in the diagnosis and management of GH-related diseases. However, these levels are affected by nutritional and metabolic status. To elucidate the correlations between GH and IGF-I in various conditions, a retrospective analysis was performed for adult patients in which GH levels were examined by general practitioners during the period from January 2019 to December 2021. Of 642 patients, 33 patients were diagnosed with acromegaly, 21 were diagnosed with GH deficiency (GHD), and 588 were diagnosed with non-GH-related diseases (NGRD). In contrast to the positive correlations found between the levels of GH and IGF-I in patients with acromegaly ( R =0.50; P <0.001) and patients with GHD ( R =0.39; P =0.08), a negative correlation was found in the NGRD group ( R =-0.23; P <0.001). In that group, the results of multivariable analysis showed that GH levels were predominantly influenced by gender and body mass index (BMI), whereas IGF-I levels were modulated by albumin in addition to age and GH. Of note, in the NGRD group, there was an enhanced negative correlation between GH and IGF-I under conditions of BMI < 22 and albumin < 4.0 g/dL ( R =-0.45; P <0.001), and the negative correlation between GH and IGF-I was reinforced by excluding patients with other pituitary diseases and patients taking oral steroids ( R =-0.51; P <0.001 and R =-0.59; P <0.001, respectively). Collectively, the results indicate that attention should be given to the presence of a negative correlation between serum levels of GH and IGF-I, especially in lean and low-nutritious conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oguni, Yamamoto, Nakano, Soejima, Suyama, Takase, Yasuda, Hasegawa and Otsuka.)

Background: The usefulness of inflammation-based prognostic scores for early recurrence (ER) after hepatectomy for hepatocellular carcinoma has rarely been reported. This study aimed to evaluate the potential of inflammation-based prognostic scores as predictors of ER and their relationship with tumor markers., Methods: We enrolled 338 patients who underwent hepatectomy for hepatocellular carcinoma between January 2007 and December 2021. Clinicopathological factors were compared between patients who developed ER (ER group) and those who did not develop ER (non-ER group). The association between inflammation-based prognostic scores and ER status was evaluated. These scores were compared with those of well-established tumor markers., Results: The platelet-to-lymphocyte ratio (PLR) correlated with ER of hepatocellular carcinoma, with an area under the curve (AUC) value of 0.70, sensitivity of 68.1%, and specificity of 67.7%. In patients with low tumor marker levels, the PLR showed a strong correlation with ER of hepatocellular carcinoma, with an AUC value of 0.851, sensitivity of 100%, and specificity of 76.2%. Multivariate analysis revealed that the PLR was an independent prognostic factor for ER., Conclusions: The PLR is useful and complementary to tumor markers for predicting ER after hepatectomy for hepatocellular carcinoma., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Children requiring liver transplantation generally have severe growth retardation. Recipients experience posttransplantation catch-up growth, although some show short adult heights. We aimed to determine decades-long catch-up growth trends and risk factors for short adult height following liver transplantation., Methods: We analyzed long-term height Z scores and risk factors for short adult height in a single-center retrospective cohort of 117 pediatric liver transplantation recipients who survived >5 y, with 75 of them reaching adult height., Results: Median age at transplantation was 1.3 y, and the most common primary diagnosis was biliary atresia (76.9%). Mean height Z scores pretransplantation and 1, 3, and 8 y after transplantation were -2.26, -1.59, -0.91, and -0.59, respectively. The data then plateaued until 20 y posttransplantation when mean adult height Z score became -0.88, with a median follow-up of 18.6 y. Nineteen recipients did not show any catch-up growth, and one quarter of recipients had short adult height (<5th percentile of the healthy population). Multivariate analysis identified old age (odds ratio, 1.22 by 1 y; P = 0.002), low height Z scores at transplantation (odds ratio, 0.46 by 1 point; P < 0.001), and posttransplantation hospital stay ≥60 d (odds ratio, 4.95; P = 0.015) as risk factors for short adult height. In contrast, prolonged steroid use after transplantation was not considered a significant risk factor., Conclusions: Although tremendous posttransplantation catch-up growth was observed, final adult height remained inadequate. For healthy physical growth, liver transplantation should be performed as early as possible, before growth retardation becomes severe., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Accurate assessment of renal function prior to surgery for hepatocellular carcinoma is important for patient outcome, but current methods such as the estimated glomerular filtration rate (eGFR) are inadequate. We developed a new prediction formula that incorporates preoperative computed tomography (CT) imaging data to determine renal function., Methods: We retrospectively analyzed 400 patients who underwent hepatectomy for hepatocellular carcinoma between January 2010 and December 2021. Predictors associated with renal function were identified by multivariate analysis., Results: Age, sex, body height, body weight, body surface area, body mass index, serum creatinine, and muscle areas including third lumbar vertebra total muscle area (L3 TMA) determined by preoperative CT were identified as independent predictors likely to be associated with renal function. These were used to construct a new prediction formula using multiple regression analysis performed with a stepwise method: 232.2 + (-1.17 × age) + (-89.0 × serum creatinine) + (0.28 × L3 TMA). The median difference between conventional eGFR and CCr was 47.6 ml/min (range, 1.7-137.9 ml/min), while that between the new eGFR and CCr was 14.3 ml/min (range, 0.02-64.7 ml/min). Spearman rank correlation analysis revealed that the new eGFR was more positively correlated with CCr than conventional eGFR (ρ = 0.623, P < 0.05; ρ = 0.700, P < 0.05, respectively), and hence more accurately reflected renal function., Conclusion: A new prediction formula based on L3 TMA determined by CT is more accurate than conventional eGFR for evaluating renal function., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to identify significant factors affecting the effectiveness of exercise training using information of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study., Methods: Background factors influencing the effect of exercise training were comprehensively surveyed for 2,130 patients by multivariable Cox regression analysis with the stepwise variable selection, and only significant factors were selected that were statistically distinguished from dummy noise factors using the Boruta method., Results: The analysis suggested that the use of beta-blockers, pulse pressure, hemoglobin level, electrocardiography findings, body mass index, and history of stroke at baseline potentially influenced the exercise effect on all-cause death (AD). Therefore, a hypothetical score to estimate the effect of exercise training was constructed based on the analysis. The analysis suggested that the score is useful in identifying patients for whom exercise training may be significantly effective in reducing all-caused death and hospitalization (ADH) as well as AD. Such a subpopulation accounted for approximately 40% of the overall study population. On the other hand, in approximately 45% of patients, the effect of exercise was unclear on either AD or ADH. In the remaining 15% of patients, it was estimated that the effect of exercise might be unclear for ADH and potentially rather increase AD., Conclusions: This study is the first analysis to comprehensively evaluate the effects of various factors on the outcome of exercise training in chronic heart failure, underscoring the need to carefully consider the patient's background before recommending exercise training. However, it should be noted that exercise training can improve many outcomes in a wide variety of diseases. Therefore, given the limitations involved in post-hoc analyses of a single clinical trial, the characteristics of patients to whom the results of this analysis can be applied need attention, and also further research is necessary on the relationship between the degree of exercise and the outcomes. A new clinical trial would be needed to confirm the factors detected and the appropriateness of the score., Competing Interests: YS and SG are employees of Nihon Servier Co. Ltd. and Astellas Pharma Inc., respectively; however, Nihon Servier Co. Ltd., and Astellas Pharma Inc., were not involved in this analysis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Soejima, Yoshioka, Guro, Sato, Hatakeyama, Sato, Fujimoto, Anzai and Hisaka.)

Orexins are neuronal peptides that play a prominent role in sleep behavior and feeding behavior in the central nervous system, though their receptors also exist in peripheral organs, including the adrenal gland. In this study, the effects of orexins on catecholamine synthesis in the rat adrenomedullary cell line PC12 were investigated by focusing on their interaction with the adrenomedullary bone morphogenetic protein (BMP)-4. Orexin A treatment reduced the mRNA levels of key enzymes for catecholamine synthesis, including tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanie decarboxylase (Ddc) and dopamine β-hydroxylase (Dbh), in a concentration-dependent manner. On the other hand, treatment with BMP-4 suppressed the expression of Th and Ddc but enhanced that of Dbh with or without co-treatment with orexin A. Of note, orexin A augmented BMP-receptor signaling detected by the phosphorylation of Smad1/5/9 through the suppression of inhibitory Smad6/7 and the upregulation of BMP type-II receptor (BMPRII). Furthermore, treatment with BMP-4 upregulated the mRNA levels of OX1R in PC12 cells. Collectively, the results indicate that orexin and BMP-4 suppress adrenomedullary catecholamine synthesis by mutually upregulating the pathway of each other in adrenomedullary cells.

Purpose: Here, we evaluated the usefulness of intratumoral perfusion analysis using preoperative contrast-enhanced CT (E-CT) to assess biological features of non-functional pancreatic neuroendocrine neoplasms (NF-PanNENs)., Methods: We retrospectively studied 44 patients who underwent curative surgery for NF-PanNENs. We used preoperative E-CT with compartment model analysis to calculate the tumor perfusion parameters K1 (inflow rate constant), 1/k2 (mean transit time), and K1/k2 (distribution volume). We assessed the association between perfusion parameters and biological features of NF-PanNENs, including the WHO classification tumor histopathological grade and prognosis after surgery., Results: Patients in this study had a neuroendocrine tumor (NET) G1 (n = 32) or NET G2 (n = 12). Neither NET G3 or NEC tumors were observed. Among perfusion parameters, K1 was the most accurate predictor of the high-grade tumor (AUC: 0.726). K1-low (< 0.028 s -1 ) was significantly associated with large tumors (≥ 20 mm) (p = 0.022), high mitotic index (p = 0.017), high Ki-67 index (p = 0.004), and lymphatic invasion (p = 0.025). Synchronous extra-pancreatic metastasis, including lymph node metastasis or liver metastasis, more frequently developed in K1-low patients than in K1-high patients (29% vs 4%, p = 0.025). Disease-free survival of patients with a K1-low tumor was poorer than that of patients with a K1-high tumor (p = 0.005). Furthermore, no patient with a K1-high tumor developed recurrence after initial surgery., Conclusion: The perfusion parameters obtained using E-CT were significantly associated with biological features and prognosis of NF-PanNENs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder characterized by multiple hyperproliferative polyps of the gastrointestinal tract, particularly of the colon, rectum, and stomach. SMAD4 mutations are frequently associated with multiple polyposis of the stomach; the condition causes severe bleeding and hypoproteinemia, which may progress to severe dysplasia and adenocarcinoma formation. We report our experience with the first case of total gastrectomy with pancreaticoduodenectomy following two partial jejunectomies for JPS, who presented with refractory anemia and protein-losing gastroenteropathy due to polyposis of the stomach and duodenum., Case Presentation: A 33-year-old Japanese man presented with the chief complaint of shortness of breath on exertion. His family history included gastric polyposis (mother, aunt, and cousin) and cerebral infarction (grandmother). Blood testing at the initial visit indicated iron-deficiency anemia, whereas endoscopy revealed multiple polyps in the duodenum and jejunum. Genetic testing revealed a 4 bp deletion (TGAA) in exon 5 of the SMAD4 gene; two partial small bowel resections were performed, but polyps grew in the remaining stomach, duodenum, and small intestine. The patient developed hypoalbuminemia and anemia, and required central venous nutrition and blood transfusion. However, because the hyponutrition and anemia remained poorly controlled, a total gastrectomy with concomitant pancreaticoduodenectomy was performed. Malnutrition and anemia improved, and there was no polyp recurrence in the remaining intestinal tract at 18 months after the surgery., Conclusions: We report a case of JPS with refractory anemia and protein-losing gastroenteropathy that was treated with total gastrectomy with concomitant pancreaticoduodenectomy. Although the surgery was highly invasive, the patient's nutritional status and anemia improved postoperatively, and the treatment was successful. However, to determine the appropriate surgical procedure, a detailed examination of the gastrointestinal lesions and the effects of the surgical invasion on nutritional status must be undertaken., (© 2024. The Author(s).)

Objective: To analyze 10,000 cases of living donor liver transplantation (LDLT) recipient data to elucidate outcomes with special reference to the graft-versus-recipient weight ratio (GRWR), based on the Japanese Liver Transplantation Society (JLTS) registry., Background: The JLTS registry has been accurate and complete in characterizing and following trends in patient characteristics and survival of all patients with LDLT., Methods: Between November 1989 and August 2021, 10,000 patients underwent LDLT in Japan. The procedures performed during the study period included pediatric liver transplantation (age <18 years, n = 3572) and adult liver transplantation (age ≥18 years, n=6428). Factors related to patient survival (PS) and graft survival (GS) were also analyzed., Results: The GRWR was <0.7, 0.7 to <0.8, 0.8 to <3, 3 to <5, and ≥5 in 0.2%, 2.0%, 61.8%, 31.8%, and 2.6% of pediatric patients and <0.6, 0.6 to <0.7, 0.7 to <0.8, and ≥0.8 in 8.0%, 12.7%, 17.7%, and 61.5% of adult patients, respectively. Among pediatric recipients, the PS rate up to 5 years was significantly better in cases with a GRWR ≤5 than in those with a GRWR >5. When the GRWR and donor age were combined, among adult recipients 50 to 60 years old, the early PS and GS up to 5 years were significantly better in cases with a GRWR ≥0.7, than in those with a GRWR <0.7. (P = 0.02). In adults, a multivariate analysis showed that GRWR <0.6, transplant era (<2011), donor age (>60 years), recipient age (>60 years), model for end-stage liver disease score (≥20), and center volume (<10) were significant prognostic factors for long-term PS., Conclusion: Although a satisfactory long-term PS and GS, especially in the recent era (2011-2021), was achieved in the JLTS series, a GRWR ≥5 in pediatric cases and relatively old donors with a GRWR <0.7 in adult cases should be managed with caution., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The bone morphogenetic protein (BMP) system in the adrenal cortex plays modulatory roles in the control of adrenocortical steroidogenesis. BMP-6 enhances aldosterone production by modulating angiotensin (Ang) II-mitogen-activated protein kinase (MAPK) signaling, whereas activin regulates the adrenocorticotropin (ACTH)-cAMP cascade in adrenocortical cells. A peripheral clock system in the adrenal cortex was discovered and it has been shown to have functional roles in the adjustment of adrenocortical steroidogenesis by interacting with the BMP system. It was found that follistatin, a binding protein of activin, increased Clock mRNA levels, indicating an endogenous function of activin in the regulation of Clock mRNA expression. Elucidation of the interrelationships among the circadian clock system, the BMP system and adrenocortical steroidogenesis regulated by the hypothalamic-pituitary-adrenal (HPA) axis would lead to an understanding of the pathophysiology of adrenal disorders and metabolic disorders and the establishment of better medical treatment from the viewpoint of pharmacokinetics., Competing Interests: Disclosure statement The authors have nothing to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer., Methods: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5-109) months., Results: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p &lt; 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110-2,607) preoperatively and 6,095.2 (1,612.3-14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis., Conclusions: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis., (© 2023 S. Karger AG, Basel.)

Competing Interests: The authors declare no conflict of interests for this article.

Pancreatic ductal adenocarcinoma has a particularly poor prognosis as it is often detected at an advanced stage and acquires resistance to chemotherapy early during its course. Stress adaptations by mitochondria, such as metabolic plasticity and regulation of apoptosis, promote cancer cell survival; however, the relationship between mitochondrial dynamics and chemoresistance in pancreatic ductal adenocarcinoma remains unclear. We here established human pancreatic cancer cell lines resistant to gemcitabine from MIA PaCa-2 and Panc1 cells. We compared the cells before and after the acquisition of gemcitabine resistance to investigate the mitochondrial dynamics and protein expression that contribute to this resistance. The mitochondrial number increased in gemcitabine-resistant cells after resistance acquisition, accompanied by a decrease in mitochondrial fission 1 protein, which induces peripheral mitosis, leading to mitophagy. An increase in the number of mitochondria promoted oxidative phosphorylation and increased anti-apoptotic protein expression. Additionally, enhanced oxidative phosphorylation decreased the AMP/ATP ratio and suppressed AMPK activity, resulting in the activation of the HSF1-heat shock protein pathway, which is required for environmental stress tolerance. Synergistic effects observed with BCL2 family or HSF1 inhibition in combination with gemcitabine suggested that the upregulated expression of apoptosis-related proteins caused by the mitochondrial increase may contribute to gemcitabine resistance. The combination of gemcitabine with BCL2 or HSF1 inhibitors may represent a new therapeutic strategy for the treatment of acquired gemcitabine resistance in pancreatic ductal adenocarcinoma., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: Although surgical resection offers the only chance of cure of perihilar cholangiocarcinoma and R1 resection has a poor prognosis, there is no consensus on optimal preoperative assessment of its longitudinal spread. We aimed to establish the optimal means of achieving this goal., Methods: This was a retrospective, single-center study of 61 patients who had undergone multi-detector row computed tomography, endoscopic retrograde cholangiography, intraductal ultrasonography, and mapping biopsy prior to resection of perihilar cholangiocarcinomas in our institute from January 2010 and December 2021., Results: The most accurate single methods for assessing longitudinal spread were intraductal ultrasonography and mapping biopsy (both 72.1%). A combination of all four assessment methods was accurate in 51 (83.6%) of our patients. Independent risk factors for inaccuracy were Bismuth-Corlette Type IV and high histologic-grade tumors. The R0 resection rate was higher with accurate than inaccurate assessments (90.2% vs. 30.0%, P < 0.001). R0 resection was associated with significantly better relapse-free survival than R1 resection (P = 0.006). However, overall survival did not differ between these groups., Conclusion: Preoperative assessment of longitudinal spread of perihilar cholangiocarcinomas by four different modalities is optimal, achieving 83.6% accuracy and a 90.2% R0 resection rate., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Cirrhosis is deemed to be a contributing factor to the postoperative recurrence of hepatocellular carcinoma (HCC); however, the precise impact of liver fibrosis on both cancer-specific prognoses remains unclear. This investigation sought to elucidate the effect of liver fibrosis severity on the cancer-specific prognosis., Methods: A total of 524 consecutive patients were included. Recurrence-free survival (RFS) and disease-specific survival (DSS) were compared according to fibrosis stage. Moreover, postoperative outcomes were subjected to analysis in cohorts of patients with F0 and F1-3, as well as in those with F1-3 and F4, who were carefully matched for background factors., Results: The 5-year RFS exhibited a significantly worse outcome in the F4 group compared to other stages of fibrosis: 5-year RFS - F0 (46.6%), F1-3 (33.1%), and F4 (23.5%), p = 0.03 (F0 vs. F1-3) and p < 0.01 (F1-3 vs. F4). Additionally, the 5-year DSS also presented a significantly worse prognosis in the F4 group: 5-year DSS - F0 (82.9%), F1-3 (73.6%), and F4 (57.4%), p = 0.04 (F0 vs. F1-3) and p < 0.01 (F1-3 vs. F4). In multivariate analysis, fibrosis 1, 2, 3, and 4 stage (compared with F0) (HR: 1.70, 1.81, 1.89, and 3.99, 95% confidence interval: 1.10-1.99, 1.39-2.22, 1.41-2.55, and 2.25-5.01, p = 0.022, p = 0.008, p < 0.001, and p < 0.001, respectively) was independent risk factor for RFS. After matched analysis, both RFS and DSS exhibited significantly worse prognoses in the presence of more advanced fibrosis. There was a significantly higher incidence of multiple recurrences in the F4 group than the F1-3 group, and a number of recurrences were observed both in the same hepatic segment as the resected side and in the contralateral lobe in F4 group., Discussion/conclusion: The hazard and recurrence pattern of HCC signifies that the prognosis could potentially be poor, as the hepatic fibrosis likely owing to a higher hepatocarcinogenic potential, even in the absence of progression to cirrhotic condition. The risk of de novo recurrence may also increase with the progression of this fibrosis., Competing Interests: None declared., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Post-hepatectomy bile leakage (PHBL) is a potentially fatal complication that can arise after hepatectomy. Previous studies have identified obesity as a risk factor for PHBL. In this study, we investigated the impact of sarcopenic obesity on PHBL in hepatocellular carcinoma (HCC) patients., Methods: In total, we enrolled 409 patients who underwent hepatectomy without bilioenteric anastomosis for HCC between January 2010 and August 2021. Patients were grouped according to the presence or absence of PHBL. Patient characteristics, including body mass index and sarcopenic obesity, were then analyzed for predictive factors for PHBL., Results: Among the 409 HCC patients included in the study, 39 developed PHBL. Male sex, hypertension, cardiac disease, white blood cell counts, the psoas muscle area, and visceral fat area, and intraoperative blood loss were significantly increased in the PHBL (+) group compared with the PHBL (-) group. Multivariate analysis showed that the independent risk factors for the occurrence of PHBL were intraoperative blood loss ≥370 mL and sarcopenic obesity., Conclusions: Our results show that it is important to understand whether a patient is at high risk for PHBL prior to surgery and to focus on reducing intraoperative blood loss during surgery for patients with risk factors for PHBL., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hayashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: When a partial liver graft is unable to meet the demands of the recipient, a clinical phenomenon, small-for-size syndrome (SFSS), may ensue. Clear definition, diagnosis, and management are needed to optimize transplant outcomes., Methods: A Consensus Scientific committee (106 members from 21 countries) performed an extensive literature review on specific aspects of SFSS, recommendations underwent blinded review by an independent panel, and discussion/voting on the recommendations occurred at the Consensus Conference., Results: The ideal graft-to-recipient weight ratio of ≥0.8% (or graft volume standard liver volume ratio of ≥40%) is recommended. It is also recommended to measure portal pressure or portal blood flow during living donor liver transplantation and maintain a postreperfusion portal pressure of <15 mm Hg and/or portal blood flow of <250 mL/min/100 g graft weight to optimize outcomes. The typical time point to diagnose SFSS is the postoperative day 7 to facilitate treatment and intervention. An objective 3-grade stratification of severity for protocolized management of SFSS is proposed., Conclusions: The proposed grading system based on clinical and biochemical factors will help clinicians in the early identification of patients at risk of developing SFSS and institute timely therapeutic measures. The validity of this newly created grading system should be evaluated in future prospective studies., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: Kirsten Rat Sarcoma viral oncogene homolog (KRAS) has remained undruggable for decades. KRAS has predominantly been used to evaluate the applicability of anti-Epidermal Growth Factor Receptor (EGFR) antibody drugs. However, various KRAS inhibitors have recently emerged. Unfortunately, KRAS inhibitors have not been effective against colorectal cancer. Therefore, this study aimed to determine the effects of MRTX1133, a novel KRAS G12D inhibitor, in combination with an anti-EGFR antibody, cetuximab, on signal transduction and cell proliferation., Materials and Methods: The KRAS G12D -mutated LS513 and KRAS wild-type CACO-2 human colon cancer cell lines were utilized. The KRAS G12D mutation was stably transduced into the CACO-2 cells using a retrovirus. We evaluated the effects of the drugs using the CCK-8 assay and assessed the activity of proteins related to the MAPK pathway using western blotting., Results: We demonstrated that the administration of MRTX1133, a novel KRAS G12D inhibitor, to KRAS G12D -mutated colorectal cancer cells led to feedback activation of the ERK pathway via EGFR activation, inducing drug resistance. Intriguingly, when MRTX1133 was used in combination with cetuximab, KRAS G12D -mutant colorectal cancer growth was effectively inhibited, both in vitro and in vivo., Conclusion: The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRAS G12D mutation. KRAS G12D is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Infection is a leading cause of death in patients with systemic lupus erythematosus (SLE). Alt hough hydroxychloroquine (HCQ) has been reported to inhibit infection, evidence from Asian populations remains insufficient. We investigated this effect in Japanese SLE patients., Methods: Data from the Lupus Registry of Nationwide Institutions were used in this study. The patients were ≥20 years old and met the American College of Rheumatology (ACR) classification criteria revised in 1997. We defined "severe infections" as those requiring hospitalization. We analyzed the HCQ's effect on infection suppression using a generalized estimating equation (GEE) logistic regression model as the primary endpoint and performed a survival analysis for the duration until the first severe infection., Results: Data from 925 patients were used (median age, 45 [interquartile range 35-57] years; female, 88.1%). GEE analysis revealed that severe infections were significantly associated with glucocorticoid dose (odds ratio [OR] 1.968 [95% confidence interval, 1.379-2.810], p <0.001), immunosuppressants (OR 1.561 [1.025-2.380], p =0.038), and baseline age (OR 1.043 [1.027-1.060], p <0.001). HCQ tended to suppress severe infections, although not significantly (OR 0.590 [0.329-1.058], p =0.077). Survival time analysis revealed a lower incidence of severe infections in the HCQ group than in the non-HCQ group ( p <0.001). In a Cox proportional hazards model, baseline age (hazard ratio [HR] 1.029 [1.009-1.050], p =0.005) and HCQ (HR 0.322 [0.142-0.728], p =0.006) were significantly related to incidence., Conclusion: HCQ may help extend the time until the occurrence of infection complications and tends to decrease infection rates., Competing Interests: KS received a speaker’s fee from GlaxoSmithKline PLC and research grants from Pfizer Inc. YKi received a speaker’s fee from Amgen and Novartis and research funding from Nippon Shinyaku. RY received a speaker’s fee from GlaxoSmithKline PLC, AstraZeneca PLC, and Sanofi S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hidekawa, Yoshimi, Saigusa, Tamura, Kojitani, Suzuki, Sakurai, Yoshioka, Sugiyama-Kawahara, Kunishita, Kishimoto, Higashitani, Sato, Komiya, Nagai, Hamada, Maeda, Tsuchida, Hirahara, Soejima, Takase-Minegishi, Kirino, Yajima, Sada, Miyawaki, Ichinose, Ohno, Kajiyama, Sato, Shimojima, Fujiwara and Nakajima.)

Background: The utility of the SAND balloon catheter in laparoscopic cholecystectomy for acute cholecystitis (AC) remains unclear., Methods: A retrospective cohort study of patients who underwent emergency cholecystectomy at Shinshu University was performed to evaluate the efficacy of the SAND balloon catheter in cases of AC (SAND balloon utilization: Group S, n = 44; non-utilization: Group non-S, n = 47)., Results: The duration of surgery was significantly shorter in Group S than in Group non-S (p = .031). Despite comparable incidences of blood transfusions in the two groups, intraoperative blood loss was significantly less in Group S than in Group non-S (p = .013). The incidence of postoperative intraperitoneal infection tended to be higher in Group non-S (p = .076). Within Group non-S, bile spillage during operation was found in 16 (34.0%) patients. The multivariate analysis revealed that gangrenous AC was the strongest independent risk factor for bile spillage during operation (odds ratio [OR]: 19.1; 95% confidence interval [CI]: 2.84-78.4; p = .002), followed by surgeons with ≤10 years of experience (OR: 11.3; 95% CI: 1.81-70.6; p < .010)., Conclusions: Implementation of the SAND balloon catheter in patients with AC is a safe and efficacious surgical option. This catheter is recommended in cases of gangrenous cholecystitis and for surgeons with limited experience., (© 2023 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Orexins are neuropeptides that play important roles in sleep-wake regulation and food intake in the central nervous system, but their receptors are also expressed in peripheral tissues, including the endocrine system. In the present study, we investigated the functions of orexin in adrenal steroidogenesis using human adrenocortical H295R cells by focusing on its interaction with adrenocortical bone morphogenetic proteins (BMPs) that induce adrenocortical steroidogenesis. Treatment with orexin A increased the mRNA levels of steroidogenic enzymes including StAR, CYP11B2, CYP17, and HSD3B1, and these effects of orexin A were further enhanced in the presence of forskolin. Interestingly, orexin A treatment suppressed the BMP-receptor signaling detected by Smad1/5/9 phosphorylation and Id-1 expression through upregulation of inhibitory Smad7. Orexin A also suppressed endogenous BMP-6 expression but increased the expression of the type-II receptor of ActRII in H295R cells. Moreover, treatment with BMP-6 downregulated the mRNA level of OX1R, but not that of OX2R, expressed in H295R cells. In conclusion, the results indicate that both orexin and BMP-6 accelerate adrenocortical steroidogenesis in human adrenocortical cells; both pathways mutually inhibit each other, thereby leading to a fine-tuning of adrenocortical steroidogenesis.

Background/purpose: This retrospective study aimed to investigate the risk factors for postoperative cholangitis (POC) after pancreaticoduodenectomy (PD) and the efficacy of stenting on hepaticojejunostomy (HJ)., Methods: We investigated 162 patients. Postoperative cholangitis occurring before and after discharge was defined as early-onset POC (E-POC) and late-onset POC (L-POC), respectively. Risk factors for E-POC and L-POC were identified using univariate and multivariate logistic regression analyses. Propensity score matching (PSM) between the stenting group (group S) and the non-stenting group (group NS), and subgroup analysis in patients with risk factors were performed to evaluate the efficacy of stenting on HJ in preventing POC., Results: Body mass index (BMI) ≥ 25 kg/m 2 and preoperative non-biliary drainage (BD) were risk factors for E-POC and L-POC, respectively. PSM analysis revealed that E-POC occurrence was significantly higher in group S than in group NS (P = .045). In the preoperative non-BD group (n = 69), E-POC occurrence was significantly higher in group S than in group NS (P = .025)., Conclusions: BMI ≥ 25 kg/m 2 and preoperative non-BD status were risk factors for E-POC and L-POC, respectively. Stenting on HJ implants did not prevent POC after PD., (© 2023 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation., Methods: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020., Results: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates., Conclusions: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Advanced esophageal cancer is occasionally accompanied by difficulty swallowing owing to esophageal stenosis or tracheoesophageal fistula formation. Esophageal bypass surgery and stent insertion are considered feasible palliative management options. The aim of this study was to evaluate the short-term outcomes of these palliative treatments., Materials and Methods: Patient data were obtained from a large-scale inpatient database of 42 National University Hospitals in Japan. Patients with advanced esophageal cancer who underwent esophageal bypass surgery or stent insertion between April 2016 and March 2021 were included in this study. One-to-one propensity score matching of patients who underwent bypass surgery or stent insertion was performed. The primary outcomes were time to diet resumption and length of hospital stay after surgery. The secondary outcome was the incidence of postoperative complications., Results: In 43 propensity score-matched pairs, the incidence of postoperative respiratory complications was significantly higher in the bypass group than in the stent group (32.6% vs. 9.3%, P = 0.008). Postoperative length of hospital stay was longer in the bypass group than in the stent group (24 vs. 10 d, P < 0.001). Logistic regression analysis revealed that stent insertion was associated with a decreased risk of respiratory complications (odds ratio 0.077, P < 0.007). Among patients who underwent the interventions (bypass surgery or stent insertion) and subsequently underwent anticancer therapy (chemotherapy/radiotherapy) during hospitalization, the interval between the intervention and anticancer therapy was longer in the bypass group than in the stent group (25 vs. 7 d, P = 0.003)., Conclusions: Esophageal stent insertion provides better short-term outcomes than bypass surgery in patients with advanced unresectable esophageal cancer., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of the present study was to clarify the effects of arginine vasopressin (AVP) on ovarian steroid production and its functional relationship to the ovarian bone morphogenetic protein (BMP) system. The results showed that AVP treatment significantly increased gonadotropin- and forskolin-induced progesterone synthesis by primary culture of rat granulosa cells and human granulosa cells, respectively. In contrast, estradiol production was not significantly affected by AVP. Treatment with AVP significantly increased forskolin-induced cAMP synthesis by human granulosa cells and mRNA levels of the progesterogenic enzymes CYP11A1 and HSD3B2 in the cells. On the other hand, AVP also enhanced BMP-15-induced phosphorylation of SMAD1/5/9 and ID1 transcription. It was further revealed that the expression levels of BMP receptors, including ALK3, ALK6 and BMPR2, were upregulated by AVP. Collectively, the results indicate that AVP stimulates progesterone production via the cAMP-PKA pathway with upregulation of BMP signaling that inhibits progesterone production, which may lead to fine adjustment of progesterone biosynthesis by granulosa cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Kirsten rat sarcoma (KRAS) oncogene was "undruggable" until sotorasib, a KRAS G12C selective inhibitor, was developed with promising efficacy. However, inhibition of mutant KRAS in colorectal cancer cells (CRC) is ineffective due to feedback activation of MEK/ERK downstream of KRAS. In this study, we screened for combination therapies of simultaneous inhibition to overcome sotorasib resistance using our previously developed Mix Culture Assay. We evaluated whether there was an additive effect of sotorasib administered alone and in combination with two or three drugs: trametinib, a MEK inhibitor, and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody. The MAPK pathway was reactivated in KRAS G12C -mutated cell lines treated with sotorasib alone. Treatment with KRAS and MEK inhibitors suppressed the reactivation of the MAPK pathway, but upregulated EGFR expression. However, the addition of cetuximab to this combination suppressed EGFR reactivation. This three-drug combination therapy resulted in significant growth inhibition in vitro and in vivo. Our data suggest that reactive feedback may play a key role in the resistance signal in CRC. Simultaneously inhibiting KRAS, MEK, and EGFR is a potentially promising strategy for patients with KRAS G12C -mutated CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although chronic kidney disease (CKD) after liver transplantation (LTx) is a common complication in adults, its long-term significance after pediatric LTx remains unclear. We examined the decades-long transition of renal function and revealed the risk factors for late-onset CKD after pediatric LTx in a single-center retrospective cohort of 117 pediatric LTx recipients who survived >5 y., Methods: The estimated glomerular filtration rate (eGFR) and CKD stages were calculated using serum creatinine. Risk factor analysis for late-onset CKD was performed in 41 patients whose eGFR could be evaluated at >20 y after LTx., Results: The median age at LTx was 1.3 y, and most primary diagnoses were biliary atresia (77%). The mean pre-LTx and 1, 5, 10, 20, and >20 y post-LTx eGFRs were 180, 135, 131, 121, 106, and 95 mL/min/1.73 m 2 , respectively, with a median renal follow-up period of 15 y. The eGFR declined by 47% at >20 y after LTx ( P  < 0.001). CKD was observed in 8%, 19%, and 39% of cases at 10, 20, and >20 y after LTx, respectively. In patients receiving cyclosporine, trough levels were 1.5 times higher in those with CKD up to 10 y after LTx. The multivariate analysis showed that older age at LTx (odds ratio, 1.3 by 1 y; P  = 0.008) and episodes of repeated/refractory rejection (odds ratio, 16.2; P  = 0.002) were independent risk factors of CKD >20 y after LTx., Conclusions: In conclusion, renal function deteriorates slowly yet steadily after pediatric LTx. Long-term careful surveillance is essential after pediatric LTx, especially in repeated/refractory rejection or long-term high trough-level use of cyclosporine cases., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUND The incidence of septic arthritis of a native joint caused by group B streptococcus (GBS, Streptococcus agalactiae) has been on the rise in non-pregnant women. GBS commonly colonizes the female genital tract. However, only a few reports have discussed serious cases of GBS infection, endocarditis, and joint infection associated with the Papanicolaou (Pap) smear test, which is routinely conducted to detect cervical cancer. Specifically, to the best of our knowledge, there have been few reports about arthroscopic treatment for septic arthritis of the ankle caused by GBS. CASE REPORT A 60-year-old woman, who had previously completed the treatment of total laparoscopic hysterectomy with bilateral adnexectomy and postoperative chemotherapy for ovarian cancer, underwent a routine Pap smear test. Four weeks later, she suddenly presented with high fever and abdominal pain. The pain and swelling in her left ankle gradually worsened. Finally, septic arthritis of the ankle was diagnosed, and thus the patient underwent emergent arthroscopic irrigation and debridement. GBS was isolated from both the ankle fluid and blood culture. After surgical intervention and intravenous antibiotic administration, the patient's symptoms gradually improved. Four months later, the patient had no ankle pain or restriction of ankle motion. CONCLUSIONS Although cervical cytology tests are essential in screening for cervical cancer, transient bacteremia can be induced by the tests. Thus, physicians must watch out for the development of septic arthritis caused by GBS when patients present with fever or swollen joints after a recent Pap smear test. Emergent diagnosis and appropriate surgical intervention is also important.