Language：English  

DOI： 10.1038/s41698-026-01457-3

PubMed

Authorship：Corresponding author   Language：English   Publisher：Annals of Gastroenterological Surgery  

Background: The role of anatomical resection (AR) in hepatocellular carcinoma (HCC) remains controversial, particularly for tumors ≤ 5 cm without vascular invasion. We aimed to evaluate the long-term outcomes of AR versus non-anatomical resection (NAR) in solitary HCC presumed negative for microvascular invasion (MVI) and intrahepatic metastasis (IM). Methods: We retrospectively analyzed 303 patients with solitary HCC who underwent hepatectomy between 2002 and 2019. Predictive factors for MVI and IM were identified, and 214 patients with solitary HCC ≤ 5 cm and predicted absence of MVI and IM were further analyzed. We compared the perioperative and oncological outcomes between the AR (n = 94) and NAR (n = 120) groups. Subsequently, we conducted propensity score matching (n = 41 per group) and performed subgroup analyses based on tumor size. Results: Des-γ-carboxy prothrombin > 150 mAU/mL was identified as an independent predictor for MVI and IM. Compared with the NAR group, the AR group had a significantly longer operative time, greater blood loss, and higher rate of complications, but showed no significant differences in recurrence-free survival and overall survival. Recurrence-free survival and overall survival remained comparable between the two groups after propensity score matching. Subgroup analyses by tumor size (0–2.0 and 2.1–5.0 cm) showed no prognostic advantage for AR over NAR. Conclusions: For solitary HCC ≤ 5 cm without predicted MVI and IM, NAR and AR result in comparable long-term outcomes. The resection strategy should prioritize remnant liver function over anatomical extent.

DOI： 10.1002/ags3.70157

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: Lymph node metastasis (LNM) is strongly associated with a poor survival in patients with intrahepatic cholangiocarcinoma (ICC). However, the indications for lymph node dissection (LND) are controversial. This study assessed the accuracy of preoperative imaging for detecting LNM. METHODS: Eighty-nine patients who underwent curative resection for ICC between 2001 and 2022 were enrolled and analyzed retrospectively. Lymph node status was evaluated preoperatively using contrast-enhanced computed tomography (CT) and positron emission tomography (PET)/CT. Patients were grouped according to their LND status (LND or no LND). Patients in the LND group were further grouped according to pathological LNM status (pN+, LNM-positive; and pN0, LNM-negative). RESULTS: Adequate LND was performed in 44 (49.4%) patients, among whom LNM was diagnosed in 17 (38.6%). The 3-year overall survival rates in patients with LND/pN+, LND/pN0, and no LND were 16.2%, 70.0%, and 70.7%, respectively. The corresponding 3-year recurrence-free survival rates were 11.8, 52.6, and 42.6%, respectively. A lymph node diameter > 8 mm on preoperative CT was an independent predictor of LNM. The maximum standardized uptake value (SUVmax) on PET/CT was significantly associated with LNM. CONCLUSION: Lymph node diameter and SUVmax predicted LNM in patients with resectable ICC. A preoperative lymph node evaluation can ensure optimal treatment outcomes.

DOI： 10.1007/s00595-025-03172-1

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PubMed

Language：English   Publisher：Annals of Surgical Oncology  

In the original online version of this article, Yuki Nakayama's name was misspelled. The original article was corrected.

DOI： 10.1245/s10434-026-19191-2

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality. Although atezolizumab plus bevacizumab (ATZ/BEV) is the standard therapy, only a subset of patients achieves durable responses. Cyclic GMP-AMP synthase (cGAS) regulates innate immunity, but its clinical role in HCC is unclear. PATIENTS AND METHODS: Patients with primary HCC were retrospectively analyzed and divided into cohort 1 (353 patients who underwent hepatectomy without prior therapy) and cohort 2 (42 patients who received ATZ/BEV after recurrence). In cohort 1, cGAS expression was quantified by immunohistochemistry and analyzed for correlations with clinicopathological features, disease-free survival (DFS), overall survival (OS), and independent prognostic factors. In cohort 2, cGAS was assessed for associations with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS: In cohort 1, 25.4% of patients had high cGAS expression (immunohistochemistry score ≥ 3). Although cGAS expression was unrelated to clinicopathological factors, it was associated with shorter DFS (2.37 versus 3.72 years; p = 0.019) and OS (6.19 years versus not reached; p = 0.002). Multivariate analysis identified cGAS positivity as an independent predictor of poor prognosis. Conversely, in cohort 2, high cGAS expression correlated with longer PFS after ATZ/BEV (12.6 versus 6.5 months; p = 0.020) and higher ORR (43.8% versus 11.5%; p = 0.0173) and DCR (93.8% versus 65.4%; p = 0.0361). CONCLUSIONS: cGAS functions as a dual biomarker, predicting poor prognosis after hepatectomy but favorable response to immunotherapy. These findings underscore the clinical relevance of cGAS and its potential to guide personalized HCC treatment.

DOI： 10.1245/s10434-025-19058-y

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PubMed

Language：Japanese   Publisher：(一社)日本インターベンショナルラジオロジー学会  

Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publisher：Liver International  

Background: Patatin-like phospholipase domain 3 (PNPLA3) I148M (rs738409 C>G) variant has been reported as a risk factor for metabolic dysfunction-associated steatotic liver disease/steatohepatitis and contributes to hepatic fibrosis and hepatocellular carcinoma (HCC); however, its role in recurrence after liver resection remains unclear. This study aimed to evaluate the effect of PNPLA3 variants on HCC recurrence after liver resection. Methods: One hundred sixteen patients with non-viral HCC who underwent curative liver resection were retrospectively analysed. PNPLA3 rs738409 genotype was identified using blood-derived genomic DNA. Recurrence-free survival (RFS) was compared across genotypes, and multivariate analysis was performed to identify the independent risk factors for recurrence. Postoperative changes in fibrosis indexes over 2 years were also evaluated according to genotype. Results: The number of patients in each PNPLA3 genotype group was as follows: CC (n = 20), CG (n = 55) and GG (n = 41). The CG/GG group showed significantly poorer RFS than the CC group, and multivariate analysis identified the PNPLA3 CG/GG genotype as an independent risk factor, especially for late recurrence. To better evaluate the effect on the remnant liver, patients with early recurrence were excluded from the study. In the CG/GG group, the fibrosis indices worsened over the 2 years following surgery, whereas they remained stable in the CC group. Among the patients with CG/GG, those with worsening fibrosis had a significantly higher rate of late recurrence. Conclusions: Patients with the PNPLA3 CG/GG genotype, especially those with progressive fibrosis, have a high risk of recurrence after liver resection. PNPLA3 genotyping may help identify patients at high risk of late recurrence who require careful long-term surveillance.

DOI： 10.1111/liv.70531

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

DOI： 10.1245/s10434-026-19270-4

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver Cancer  

INTRODUCTION: Intermediate-stage hepatocellular carcinoma (HCC) presents varying tumor burdens. For patients unsuitable for transcatheter arterial chemoembolization (TACE) due to high tumor burden, recent guidelines recommend systemic therapy. This study evaluates the efficacy and safety of atezolizumab plus bevacizumab for TACE-unsuitable patients with unresectable intermediate-stage HCC beyond up-to-seven criteria. METHODS: This prospective, phase II, single-arm, non-blinded study enrolled TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria, Child-Pugh A, no previous systemic therapy, and ECOG Performance Status score of 0-1 from 35 sites in Japan. Patients received atezolizumab 1,200 mg and bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate by modified RECIST (mRECIST). Key secondary endpoints included the objective response rate (ORR) and safety. Exploratory endpoints examined individual changes in tumor size, comparison by inverse probability weighting (IPW) of data with retrospective historical data of TACE-treated patients, and conversion rate to a curative intent therapy. RESULTS: In total, 74 patients were enrolled from December 2020 to September 2021 (median follow-up, 15.1 months). The 6-month PFS rate by mRECIST was 66.8% (90% CI: 56.8, 75.0), and the lower limit of the 90% CI exceeded the pre-specified threshold of 55%. ORR by mRECIST was 40.5%. After treatment with atezolizumab plus bevacizumab, 10 patients, including 5 patients who had a tumor burden beyond the up-to-11 criteria at baseline, were able to transition to curative intent therapy. PFS by mRECIST by IPW was 9.2 months with atezolizumab plus bevacizumab versus 5.7 months with TACE (hazard ratio 0.67, p = 0.029). Adverse events (AEs), mostly hypertension, proteinuria, and malaise, were common. AEs requiring corticosteroids occurred in 10 patients (13.5%). CONCLUSION: Atezolizumab plus bevacizumab appears beneficial as first-line treatment for TACE-unsuitable patients with unresectable intermediate-stage unresectable HCC beyond up-to-seven criteria. Future strategies utilizing multimodal approaches may further improve outcomes.

DOI： 10.1159/000546899

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

AIM: The cystine/glutamate antiporter xCT facilitates cystine uptake and glutathione synthesis and suppresses ferroptosis. However, its role in hepatocellular carcinoma (HCC), particularly in glucose metabolism and disulfidptosis, remains unclear. We examined the prognostic value of xCT expression and tumor 18F-fluorodeoxyglucose (FDG) uptake as well as their association with tumor biology. METHODS: We retrospectively analyzed 345 patients with HCC who underwent hepatic resection. Immunohistochemical staining for xCT was performed in all 345 cases, and its associations with clinicopathological characteristics and survival were evaluated. Among these, 108 patients also underwent preoperative 18F-FDG positron emission tomography/computed tomography (PET/CT). In this subset, tumor FDG uptake was quantified and its relationship with xCT expression and patient prognosis was assessed. RESULTS: Patients with xCT-positive tumors had significantly worse overall survival compared with those with xCT-negative tumors (10-year, 42.6% vs. 75.2%; log-rank test, p < 0.0001). Among 108 patients with HCC who underwent PET/CT, xCT positivity was an independent predictor of poor prognosis in multivariate analysis (hazard ratio, 3.17; 95% confidence interval, 1.47-6.87; p = 0.0034). In addition, xCT expression correlated with FDG uptake (p = 0.0335). Importantly, tumors that were both xCT-positive and had high FDG uptake exhibited the poorest prognosis (log-rank test, p = 0.0405). CONCLUSIONS: High xCT expression combined with elevated FDG uptake may identify a subset of patients with HCC who have poor prognoses and dual resistance to ferroptosis and disulfidptosis. These findings highlight the potential of xCT as both a prognostic biomarker and therapeutic target for aggressive HCC.

DOI： 10.1111/hepr.70116

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PubMed

Publisher：Annals of Gastroenterological Surgery  

Background: Small-for-size syndrome (SFSS) after adult living-donor liver transplantation (LDLT) is a poor prognostic condition. Splenectomy (Spx) has recently been reported to help prevent SFSS and improve outcomes. This study aimed to identify risk factors for SFSS that occur despite Spx at the time of LDLT. Methods: This single-center retrospective study included 973 LDLT recipients from 2001 to 2024. Of these, 577 who underwent concomitant Spx were analyzed. SFSS grading followed the 2023 International Liver Transplantation Society consensus criteria. Prognostic factors associated with SFSS grade B/C, which required perioperative portal vein inflow control, were identified. Results: SFSS grade B/C occurred in 105 patients (18.2%) and was associated with significantly worse prognosis than grade 0/A (1-year survival: 93.9% vs. 81.9%, p < 0.0001). The grade B/C group had higher levels of Model for End-stage Liver Disease (MELD) score (median 18 vs. 15, p < 0.0001), neutrophil-to-lymphocyte ratio (NLR) (3.9 vs. 2.7, p < 0.0001), donor age (37 vs. 40 years, p = 0.0370), and donor body mass index (BMI) (22.7 vs. 21.8 kg/m², p = 0.0093). Multivariate logistic regression identified NLR of ≥ 4.5, MELD score of ≥ 30, and donor age of ≥ 50 years, as independent predictors. Conclusions: SFSS grade B/C still occurred in nearly one in five patients who underwent Spx for SFSS risk mitigation during LDLT. Patients with a high recipient NLR, MELD score, or donor age are at increased risk of SFSS despite Spx. Future strategies should emphasize careful donor selection and perioperative portal inflow modulation for high-risk cases.

DOI： 10.1002/ags3.70181

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

BACKGROUND: Living donor liver transplantation is the definitive treatment for decompensated cirrhosis. While the prognosis for high Model for End-Stage Liver Disease (MELD) patients is well-studied, risk factors in low MELD patients remain unclear. This study aimed to identify prognostic risk factors for low MELD cases. METHODS: We analyzed 838 adult living donor liver transplantation patients from September 1998 to April 2024 and divided them into low MELD (≤15) and high MELD (>15) groups. The low MELD group was further categorized into early and non-early graft loss subgroups. The risk factors for recipient survival were analyzed. RESULTS: Of the 838 patients, 408 (48.7%) were in the low MELD group, and 430 (51.3%) were in the high MELD group. The survival rates were significantly higher in the low MELD group than in the high MELD group. In the low MELD group, 5.1% (21 patients) experienced early graft loss, and 94.9% (387 patients) were classified as non-early graft loss. Independent risk factors for early graft loss included donor body mass index ≥25 kg/m2, absence of simultaneous splenectomy, and postoperative complications. One year survival rates were significantly lower in patients with more risk factors. CONCLUSION: Donor body mass index, absence of simultaneous splenectomy, and postoperative complications were identified as independent risk factors for poor prognosis in living donor liver transplantation patients with low MELD. Surgeons must focus on performing meticulous surgeries to minimize the risk of complications.

DOI： 10.1016/j.transproceed.2025.12.005

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PubMed

Authorship：Corresponding author   Language：English   Publisher：Surgery Today  

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Machine learning (ML) may enable the noninvasive prediction of histopathological features using clinical and imaging data. This study evaluated the utility of ML in predicting vessels that encapsulate tumor clusters (VETC) and tumor differentiation in HCC. We retrospectively analyzed 232 patients who underwent hepatic resection for solitary HCC (≤ 5 cm). Histological assessment was used to determine the VETC status and tumor differentiation. Contrast-enhanced CT images were processed using BiomedCLIP to extract 512-dimensional image feature vectors, which were combined with clinical data and analyzed using a support vector machine classifier. The model performance was evaluated using five-fold cross-validation with precision, recall, and F1-score. VETC-positive tumors were significantly associated with a poor survival. Models using clinical data alone demonstrated limited predictive performance (F1 = 0.469 for VETC; F1 = 0.473 for differentiation). The incorporation of image features modestly improved VETC prediction (F1 = 0.599) but did not enhance the prediction of tumor differentiation. Image-based models did not outperform the clinical models. VETC is a histopathological marker associated with a poor prognosis in HCC. While ML models showed limited predictive accuracy, further optimization of imaging analysis and data integration may improve noninvasive histological prediction.

DOI： 10.1007/s00595-026-03317-w

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PubMed

Language：English   Publisher：Journal of Gastroenterology  

Background: TP53 mutations are among the most frequent alterations in biliary tract cancer (BTC), but their prognostic relevance and predictive value for immune checkpoint inhibitors (ICI) remain unclear. We assessed clinico-molecular features, prognosis, and ICI efficacy by TP53 status in advanced BTC. Methods: Patients with advanced BTC from Japan and the United States who underwent tissue- or plasma-based next-generation sequencing were retrospectively analyzed. Tissue-based sequencing was used for the primary analysis, and plasma ctDNA sequencing was evaluated as an exploratory cohort. Outcomes were compared between TP53 wild-type (WT) and TP53-mutated groups. Treatment–TP53 interactions for non-ICI versus ICI-containing regimens were assessed using multivariable Cox models. Whole-transcriptome sequencing data were analyzed using TIDE and Hallmark gene set enrichment analysis. Results: Among 336 patients in the tissue-based cohort, 177 (52.7%) had TP53-mutated tumors. SMAD4, ERBB2, PTEN and CCNE1 co-alterations were enriched in TP53-mutated tumors, whereas IDH1, BAP1, and FGFR2 fusions were more frequent in WT tumors. TP53 mutations were independently associated with shorter PFS, whereas OS showed a similar but nonsignificant trend (PFS: HR 1.32, P = 0.04; OS: HR 1.32, P = 0.09). TP53 mutations were associated with shorter PFS in the non-ICI cohort but numerically longer PFS in the ICI cohort, with a significant treatment–TP53 interaction for PFS (P < 0.01). Similar trends were observed in the plasma cohort. Transcriptomic analyses (n = 59; all MSS) showed lower TIDE scores in TP53-mutated tumors. Conclusion: TP53 mutations were associated with poor prognosis and may predict greater benefit from ICI, supporting biomarker-driven stratification.

DOI： 10.1007/s00535-026-02439-9

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Language：English   Publisher：Hepatology  

Background & Aims: – Fontan-associated liver disease (FALD) could lead to liver cirrhosis and hepatocellular carcinoma (HCC). The prognosis of FALD patients is worse when HCC develops. Therefore, better understanding of the mechanisms of FALD hepatocarcinogenesis is critical. We investigated the genomic and transcriptomic signatures of FALD HCC. Approach & Results: – Ten patients with FALD HCCs, two patients with non-Fontan congenital heart surgery (CHS) HCC, and one patient with FALD focal nodular hyperplasia (FNH) were enrolled. Whole-genome sequencing and transcriptome sequencing were performed, and the results were compared with other etiology-related HCCs in common databases. FALD HCCs exhibited comparable tumor mutation burdens to those of HCCs in the databases, as well as mutation signatures related to DNA double-strand break repair deficiency. These features were shared by non-Fontan CHS HCCs and FALD FNH, suggesting that post-operative stress has an impact on genomic alterations. Of note, FALD and non-Fontan CHS HCCs showed a higher amount of copy number alterations and structural variants, including short deletions and translocations, which were rarely detected in FALD FNH. These structural variants were implicated in frequently altered genes of HCC, suggesting a possible trigger of hepatocarcinogenesis. Transcriptome analysis revealed that individual FALD and non-Fontan CHS HCCs were grouped into the reported HCC subclasses, namely progenitor phenotype, rather than an uncommon HCC subclass. Conclusions: – Genomic mutational profiles of FALD and non-Fontan CHS HCCs are distinct from HCCs with other etiologies. Copy number alterations and transcriptional profiles in FALD HCCs classified these into a poor-prognosis group of HCCs.

DOI： 10.1097/HEP.0000000000001693

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Language：English   Publisher：Surgery Today  

Purpose: To investigate the independent predictors of progression-free survival (PFS) after gemcitabine, cisplatin, and durvalumab (GCD) therapy for advanced biliary tract cancer (BTC), including the thyroid-stimulating hormone (TSH) ratio pre- and post-GCD. Methods: The subjects of this retrospective analysis were 29 patients receiving GCD for advanced BTC. The cutoff TSH ratios were determined by a receiver operating characteristic (ROC) curve for PFS. The independent predictors of PFS after GCD were determined by univariate and multivariate analyses. Results: The median PFS was 4.9 (range, 0.9–16.8) months. The objective response and disease control rates were 13.0% and 52.2%, respectively. The cutoff values of the TSH ratio after one and two cycles were 0.97 [area under the ROC curve (AUROC): 0.86, 95% confidence interval (CI): 0.70–1.00], p = 0.02] and 1.2 (AUROC: 0.820, 95% CI: 0.664–0.976), respectively. Multivariate analysis identified pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥ 5 [hazard ratio (HR): 6.27, 95% CI: 1.83–21.5, p = 0.004] and TSH ratio after two cycles of < 1.2 (HR: 3.25, 95% CI: 1.25–8.46, p = 0.02) as independent predictors of PFS. Conclusion: The TSH ratio after two GCD cycles of < 1.2 and a pretreatment NLR ≥ 5 are potential prognostic factors for poor PFS.

DOI： 10.1007/s00595-025-03227-3

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PubMed

Publisher：Annals of Gastroenterological Surgery  

Background: Regional disparities in surgical resources may influence the delivery and sustainability of gastroenterological surgery, particularly in countries experiencing rapid population aging and depopulation. Methods: This nationwide cross-sectional study used data from the Japanese National Clinical Database to examine temporal trends (2013–2023) in surgical volume, surgeon supply, and annual operative volume per surgeon for colectomy, gastrectomy, and pancreaticoduodenectomy. Analyses were conducted at the prefectural level and stratified by population density and surgeon experience. Results: A total of 955 168 colectomies, 514 155 gastrectomies, and 126 008 pancreaticoduodenectomies were analyzed. Colectomy volume increased despite declining surgeon numbers in medium- and high-density areas, resulting in increased operative volume per surgeon. Gastrectomy volume decreased nationwide, whereas pancreaticoduodenectomy volume increased across all regions, accompanied by a reduction in surgeon supply and a rise in procedures per surgeon. By 2023, operative volume per surgeon was largely comparable across population density categories. Notably, surgeons with ≥ 20 years of experience were disproportionately represented in low-density areas. Conclusions: Although regional differences in population density persist, surgeon workload for major gastroenterological procedures has converged across regions in recent years. However, surgical care in low-density areas depends heavily on senior surgeons, raising concerns regarding generational transition and long-term sustainability of gastroenterological surgical services in Japan.

DOI： 10.1002/ags3.70239

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Language：Japanese   Publisher：(株)アークメディア  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver International Official Journal of the International Association for the Study of the Liver  

BACKGROUND AND AIMS: The phase II REPLACEMENT study showed promising clinical benefit from atezolizumab plus bevacizumab in transcatheter arterial chemoembolization (TACE)-naïve patients with intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-7 criteria, meeting its primary endpoint of progression-free survival (PFS). Here, we report the final overall survival (OS) analysis. METHODS: Enrolled patients were naïve to TACE with unresectable intermediate-stage HCC beyond up-to-7 criteria, had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and received no previous systemic therapy. Atezolizumab 1200 mg and bevacizumab 15 mg/kg were administered every 3 weeks. The primary endpoint was the 6-month PFS rate by modified Response Evaluation Criteria in Solid Tumours for HCC (mRECIST); secondary endpoints included OS, PFS by RECIST version 1.1, objective response rate (ORR) and safety. RESULTS: Overall, 74 patients were enrolled between December 2020 and September 2021. At the clinical cut-off date (March 31, 2024), median follow-up was 33.6 months. Median PFS by mRECIST was 9.1 months (95% CI 7.1-10.2). Median OS was 33.8 months (95% CI 22.6-not estimable). ORR was 40.5% (95% CI 29.3-52.6), with 12.2% of patients having a complete response. Overall, 82.4% of patients received subsequent therapy. All-cause adverse events (AEs) were observed in 98.6% of patients, most commonly hypertension (71.6%) and proteinuria (54.1%). Grade 3/4 AEs occurred in 43.2% of patients; no Grade 5 AEs were reported. CONCLUSIONS: These results show that atezolizumab plus bevacizumab can be an alternative treatment option for patients with intermediate-stage HCC beyond up-to-7 criteria who are deemed unsuitable for TACE. TRIAL REGISTRATION: jRCTs071200051.

DOI： 10.1111/liv.70379

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：ESMO Open  

Background: E7386 is an orally active inhibitor reported to block the CBP/β-catenin interaction. We present data from the dose-escalation and expansion part 1 of Study 103 (phase I) of E7386 in patients with advanced, unresectable, or recurrent (A/U/R) solid tumors. Patients and methods: This open-label study was conducted in Japan. In dose-escalation, eligible patients aged ≥20 years were diagnosed with A/U/R solid tumors with no alternative standard/effective therapies. In the expansion part, eligible patients were diagnosed with A/U/R colorectal cancer (two or more prior systemic anticancer therapies) or other gastrointestinal tumors (one or more prior systemic anticancer therapy). The primary objective was assessment of safety and tolerability. Secondary objectives were assessment of pharmacokinetic (PK) and antitumor activity. Efficacy was assessed by investigators using RECIST v1.1. Results: Fifty-five enrolled patients (dose-escalation: n = 36; expansion: n = 19) received one or more dose of E7386. The most frequent tumor was colorectal cancer (dose-escalation: 55.6%; expansion: 84.2%). Over half of those enrolled received more than three prior systemic anticancer medications. In dose-escalation, dose-limiting toxicities (grade 3 decreased appetite) occurred in two patients [160 mg twice daily (b.i.d.) cohort]; the recommended dose was 120 mg b.i.d. Most patients (dose-escalation/expansion) experienced treatment-emergent adverse events (TEAEs; 97.2%/94.7%): the most frequent TEAEs were nausea (83.3%/84.2%) and vomiting (61.1%/73.7%). These were primarily low-grade in severity and well managed with antiemetics in patients receiving up to 120 mg b.i.d. No patients died due to TEAEs. In dose-escalation, two patients achieved partial response (PR): one with small bowel carcinoma (APC/KRAS/TP53 mutations); one with a desmoid tumor (APC mutation). No PRs were observed in the expansion part. PK exposure increased with doses (range: 10-160 mg b.i.d.) following single and repeat-dose administrations, although large inter-subject variability was observed. Conclusions: In heavily pretreated patients with advanced solid tumors, E7386 demonstrated a manageable safety profile and a dose-dependent PK profile. PRs were noted in patients with small bowel carcinoma or desmoid tumor.

DOI： 10.1016/j.esmoop.2025.105893

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Language：English   Publisher：Surgery Today  

Purpose: Human-induced pluripotent stem cells (iPSCs) have the potential to differentiate into cells of various organs. Hepatocytes derived from iPSCs (i-Heps) have attracted much attention as an alternative treatment for liver transplantation in patients with liver failure. However, it is challenging to create sufficient i-Heps for clinical treatment, highlighting the need to develop an easier and more efficient culture method. In this study, we examined the effect of quiescent iPSC-derived stellate cells (i-Stes) on i-Hep proliferation. Methods: i-Stes and i-Heps were differentiated from iPSCs. Results: i-Stes expressed higher levels of hepatocyte growth factor (HGF) than the human hepatic stellate cell line LX-2. In addition, quiescent i-Sted promoted i-Hep proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway in i-Heps, which was impaired by the activation of i-Sted with transforming growth factor beta. Conclusion: This study provides evidence that i-Sted can effectively induce i-Hep proliferation through HGF activation of the MAPK signaling pathway. Quiescent—but not activated—i-Stes may contribute to the creation of large numbers of i-Heps.

DOI： 10.1007/s00595-025-03061-7

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

患者は10歳代男性.小児期にデスモイド腫瘍摘出術と浸潤を伴う上腸間膜静脈の合併切除を施行した.術後再発なく経過するも,13年後に多量の黒色便で受診,精査の結果,上腸間膜静脈の閉塞に伴い回腸静脈が拡張,十二指腸と結腸肝彎曲部の静脈瘤を認め,十二指腸静脈瘤出血と診断した.保存的に止血を得られ,待機的手術とした.術中上腸間膜静脈は癒着のため剥離困難,門脈本幹と回腸静脈間は15cm離れていたため,浅大腿静脈グラフトを使用し吻合した.吻合後に回腸静脈圧は低下,十二指腸静脈瘤は消失した.本症例は若年で全身状態も良好であり,異所性静脈瘤に対して外科的な門脈系の血行再建術を選択し良好な結果を得られた.異所性静脈瘤の確立した治療法はなく,症例に応じて内視鏡やカテーテル治療が選択されることが多いが,患者の状態や各治療法の特徴を踏まえた上で,外科手術を選択することも念頭に入れて治療を行っていくことが重要である.(著者抄録)

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：Japanese   Publisher：(株)アークメディア  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

BACKGROUND: The oncological criteria of resectability for HCC were reported by the Japanese Expert Consensus 2023. The relationship between classification at recurrence and prognosis is unclear in cases with surgical resection in the initial treatment. Factors that predict recurrence patterns are also unknown. METHODS: Data were analyzed retrospectively from 937 patients who underwent hepatic resection for primary HCC at 10 facilities. Kaplan-Meier analyses of overall survival (OS) and recurrence-free survival (RFS) after hepatic resection defined according to resectability classification, resectable (R), borderline resectable (BR) 1, and BR2, were performed. In patients who underwent curative resection for R-HCC, we examined the classification and prognosis at the time of recurrence, as well as the factors associated with BR1 or BR2 recurrence. RESULTS: RFS and OS rates were significantly better in the R group than in the BR1 and BR2 groups (P < 0.01). Prognosis was worse in patients whose initial HCC was resected with R and whose recurrence was BR1 or BR2 (P < 0.01). Male sex, α-fetoprotein > 12 ng/dL, Des-γ-carboxy prothrombin > 150 mAU/mL, tumor size > 5 cm, poor differentiation, and microscopic vascular invasion were predictors of BR1 or BR2 recurrence within 2 years after curative resection for R-HCC. We developed a scoring system based on these six factors, which stratified not only prognosis but also recurrence pattern. CONCLUSIONS: Our results extend this framework by demonstrating the prognostic significance at the time of recurrence and provide factors to predict high-risk recurrence.

DOI： 10.1007/s10147-025-02840-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

DOI： 10.1245/s10434-025-17889-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

BACKGROUND: Signal-regulatory protein alpha (SIRPα) has recently garnered attention for its role in the immune system, commonly referred to as the "don't eat me" signal. However, the relationship between SIRPα expression in tumor cells and prognosis in patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC) has been scarcely reported. PATIENTS AND METHODS: A total of 117 patients who underwent hepatectomy for ICC were enrolled in this study. Immunohistochemical staining was performed to evaluate SIRPα, programmed cell death-ligand 1 (PD-L1), and cluster of differentiation 8 (CD8). The relationships between SIRPα expression, clinicopathological characteristics, and patient outcomes were analyzed. RESULTS: The macrophage-SIRPα-positive group exhibited a higher rate of lymph node metastasis (p = 0.0013). The tumor-cell-SIRPα-positive group showed lower carcinoembryonic antigen levels (p = 0.0068) and fewer cases of the perihilar type (p = 0.0165). In multivariate analysis, SIRPα positivity in tumor cells was identified as an independent prognostic factor for both disease-free survival (p = 0.0198) and overall survival (p = 0.0089). Notably, SIRPα positivity in tumor cells showed no significant correlation with PD-L1 expression or CD8-positive tumor-infiltrating T cells in ICC. CONCLUSIONS: Our findings demonstrate that SIRPα expression in tumor cells is more critical than its expression in macrophages for predicting the prognosis of patients with ICC following hepatic resection.

DOI： 10.1245/s10434-025-17813-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Hepato Biliary Pancreatic Sciences  

BACKGROUND: Few studies have evaluated allografts that were declined before the acceptance for deceased-donor liver transplantation. We aimed to elucidate the characteristics of these allografts and assess their transplantation outcomes. METHODS: We analyzed data from 730 adult liver allografts transplanted between July 2010 and March 2024. Clinical characteristics of the transplanted allografts were evaluated according to the number of declines, and the outcomes of the recipients were analyzed. RESULTS: Transplanted allografts were categorized into three groups: ≥ 5 declined (n = 41), 1-4 declined (n = 104), and no declined group (n = 585). The ≥ 5 declined group exhibited high liver enzyme levels and steatosis. Within this group, the Japan Risk Index and total ischemic time (TIT) were identified as poor prognostic factors. Notably, in cases where TIT exceeded 10 h, a poor prognosis was observed in the ≥ 5 declined group. CONCLUSION: Abnormal liver functions or steatosis were observed in the ≥ 5 declined group. Shortening the TIT could contribute to an improved prognosis after transplantation.

DOI： 10.1002/jhbp.70015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

PURPOSE: Liver metastases from colorectal cancer (CRLM) are a major determinant of the prognosis of metastatic colorectal cancer. Although curative resection is recommended for resectable CRLM, recurrence remains a challenge and the criteria for patient selection and repeat resection are still unclear. We conducted this study to evaluate the outcomes of metastatic lesion resection with curative intent (R0 resection), to identify the factors associated with recurrence, and to establish the feasibility of repeat metastasectomy. METHODS: This single-center retrospective study analyzed 135 patients with synchronous CRLM, who underwent surgical resection or received chemotherapy between January, 2013 and March, 2023. RESULTS: R0 resection was achieved in 62 (45.9%), with a median recurrence-free survival of 12.3 months. Recurrence developed in 50 (80.6%) of these patients and 28 underwent repeat R0 resection. Initial R0 resection was associated with significantly improved overall survival (OS; hazard ratio [HR], 0.12; p < 0.01) and repeat R0 resection after recurrence improved survival further (HR, 0.32; p = 0.019). Conversion surgery, performed in 42 of 114 patients (36.8%) initially treated with chemotherapy, was significantly associated with the absence of extrahepatic metastases and H1 liver metastases. CONCLUSIONS: These findings highlight the importance of individualized treatment strategies for optimizing CRLM outcomes.

DOI： 10.1007/s00595-025-03125-8

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Language：Japanese   Publisher：(一財)日本消化器病学会  

肝移植は末期肝不全や進行肝細胞癌に対する唯一の根治的治療法であり,日本においては生体肝移植を中心に高度な発展を遂げ,良好な治療成績が蓄積されてきた.一方で,脳死ドナーの極端な不足が依然として深刻な課題であり,移植を待ちながら命を落とす患者も少なくないのが現状である.本稿では,本邦における肝移植医療の実態と制度的・臨床的な問題点を明確化し,今後の戦略として,臓器の機能温存と評価を可能にする機械灌流技術の臨床応用,さらにはmiRNAやLRRN2といった分子バイオマーカーを活用したマージナルドナー評価手法の有用性と将来的な可能性について,最新の知見を踏まえて詳述した.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

BACKGROUND: Ferroptosis, a form of programmed cell death, is a potential target for cancer therapy. Metazoan SpoT Homolog 1 (MESH1) possesses intracellular NADPH phosphatase activity, which has been linked to ferroptosis. However, the molecular effects on the ferroptosis in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate the relationship between MESH1 expression and the prognosis of patients with HCC, as well as its impact on ferroptosis in HCC cells. METHODS: We used resected specimens from patients to assess the relationship between MESH1 expression and prognosis. HCC cell lines were used to evaluate the impact of MESH1 expression on the cell phenotype and ferroptosis through various assays, RNA sequencing, and an animal experiment with xenograft mice model. RESULTS: We found that high MESH1 expression correlated with good outcomes. Further investigation demonstrated that MESH1 also exhibits NADPH phosphatase activity in HCC, contributing to increased sensitivity to ferroptosis when the ferroptosis inducer was used. Similar results were observed with other ferroptosis inducers, sorafenib and lenvatinib. Notably, RNA sequencing analysis of cells with MESH1 KD revealed a correlation between intracellular iron homeostasis and MESH1 levels. These results suggested that MESH1 also can affect ferroptosis sensitivity through changing intracellular iron levels. Tumors derived from MESH1 KD cells in xenograft mice showed reduced sensitivity to sorafenib and lenvatinib, further supporting the role of MESH1 ferroptosis regulation. CONCLUSION: This study suggests that MESH1 influences intracellular redox and iron regulatory pathways, both of which are linked to cellular processes associated with ferroptosis.

DOI： 10.1007/s10147-025-02818-x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Minimally invasive liver surgery (MILS), such as laparoscopic and robotic hepatectomy, has been developed and is an effective alternative to traditional open hepatectomy. Although surgical techniques and postoperative management have improved, many institutions continue to perform routine postoperative abdominal drainage. In open hepatectomy, abdominal drainage after uncomplicated hepatectomy increases overall and wound-related complications without a reduction in the risk of intra-abdominal fluid collections that require intervention. The aim of this study was to elucidate the feasibility of non-routine abdominal drainage for patients who undergo MILS for tumors located outside the posterosuperior area. METHODS AND ANALYSIS: This study is a multicenter randomized controlled trial and will recruit 182 patients who undergo MILS. The study duration is three years, including a 2-year registration duration. Participants will be randomly assigned to either the non-routine drainage group or the routine drainage group (ratio 1:1) to prove non-inferiority. The primary study outcome is the incidence of in-hospital postoperative complications of Clavien-Dindo grade ≥ II. The secondary study outcomes are length of postoperative hospital stay, incidences of specific postoperative complications and all postoperative complications, and surgery-related mortality. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the institutional review board (No. 20232008). The results of this study will be published in international peer-reviewed journals.

DOI： 10.1097/SP9.0000000000000049

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Surgical Research  

INTRODUCTION: Clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD) is one of the most life-threatening complications. Early drain removal after PD is recommended in the clinical setting; however, the risk stratification for CR-POPF to guide drain removal is not widely recognized. METHODS: This single-center retrospective study included patients who underwent PD between 2013 and 2024. In total, 280 patients were divided into training (n = 196) and validation (n = 84) cohorts by random sampling. The predictive impact of CR-POPF was evaluated using receiver operating characteristic curves of perioperative factors in the training cohort. Based on a probability formula, a predictive model of CR-POPF was established. RESULTS: CR-POPF occurred in 29.1% of 196 patients in the training cohort. Postoperative day 5 C-reactive protein and drain fluid amylase levels were the strongest diagnostic values in patients with CR-POPF (area under the receiver operating characteristic curve, area under the ROC curve: 0.787 and 0.750, respectively). Logistic regression analysis provided the prediction index (10.5 × C-reactive protein [mg/dL] + 0.01 × drain fluid amylase [IU/L] ± 21.8 [add if the pancreas is soft; subtract if it is hard]) was defined as a new prognostic model for the probability of CR-POPF. A higher CR-POPF prediction index was an independent prognostic factor in the multivariate analysis. Finally, the clinical feasibility of the CR-POPF prediction index was confirmed in the validation cohort. CONCLUSIONS: The CR-POPF index could guide safe early drain removal, which may help surgeons to implement appropriate drain management after PD.

DOI： 10.1016/j.jss.2025.06.028

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Water-Jet (WJ) dissection is an innovative technique for liver surgery that uses high-pressure saline jets to selectively dissect liver parenchyma while preserving vascular and biliary structures. Compared to the Cavitron Ultrasonic Surgical Aspirator (CUSA), WJ offers advantages such as reduced thermal damage, lower blood loss, and shorter operative times. These benefits are particularly important in living-donor liver transplantation (LDLT), where donor safety and rapid recovery are critical. This WORLD trial ("W"ater-Jet versus CUSA f"o"r Liver Pa"r"enchymal Transection in "L"iving "D"onor Liver Transplantation) aims to compare the efficacy and safety of WJ and CUSA in LDLT. METHODS AND ANALYSIS: This single-blind, randomized controlled trial will include 48 living liver donors, allocated in a 1:1 ratio to the WJ or CUSA group. Experienced surgeons will perform liver parenchymal transection using standardized protocols. The primary endpoint is transection speed (cm2/min), with secondary outcomes including operative time, blood loss, complication rates, length of postoperative hospital stays, and postoperative liver function tests. Statistical analysis will assess the non-inferiority of WJ using JMP and R software, with a one-sided α of 2.5% and 80% power. ETHICS AND DISSEMINATION: This study protocol was approved by the institutional review board of Kyushu University (No. 20232001). The study is registered in UMIN-CTR as UMIN000051662. Written informed consent will be obtained from all participants. The results will be published in a peer-reviewed journal and will be presented at medical meetings.

DOI： 10.1097/SP9.0000000000000048

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Authorship：Corresponding author   Language：English   Publisher：Hepatology Research  

DOI： 10.1111/hepr.14223

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology and Hepatology Australia  

BACKGROUND AND AIM: This study aimed to compare the therapeutic effects and safety of lenvatinib (LEN) plus transcatheter arterial chemoembolization (LEN-TACE) and atezolizumab plus bevacizumab (Atez/Bev) as the first-line therapies in patients with intermediate-stage hepatocellular carcinoma (HCC) beyond the up-to-seven criteria. METHODS: We enrolled 768 patients with HCC treated with first-line systemic therapy, and 154 patients were enrolled and categorized into either the LEN-TACE therapy (n = 42) or Atez/Bev (n = 112) groups. After propensity score matching (PSM), 72 patients (LEN-TACE group, n = 36; Atez/Bev group, n = 36) were analyzed. RESULTS: After PSM, the median progression-free survival showed no significant differences between the LEN-TACE and Atez/Bev groups (8.5 [95% confidence interval (CI): 6.1-10.7] months vs. 8.6 (95% CI: 5.3-12.1) months, respectively; p = 0.973). Regarding median overall survival (OS), no significant differences were noted between the LEN-TACE and Atez/Bev groups (37.3 [95% CI: 31.2-60.2] months vs. 32.4 (95% CI: 19.5-NE) months, respectively; p = 0.183). Regarding adverse events (AEs) of grade ≥ 3, no significant difference was observed between the two groups. Multivariate analysis revealed that the ALBI grade 1 and low AFP levels were independent factors for OS. CONCLUSION: LEN-TACE therapy may be one of the effective treatment strategies in intermediate-stage HCC patients beyond the up-to-seven criteria.

DOI： 10.1111/jgh.17024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

PURPOSE: Liver function is a key prognostic factor in patients with hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score is an objective method to assess liver function severity, but its calculation is complex and challenging to implement in clinical practice. This study evaluated the prognostic utility of the EZ-ALBI score, which uses a simpler and more accessible calculation method, in patients undergoing resection for small HCC (≤3 cm). METHODS: The study included 1161 patients who underwent hepatectomy for small HCC. Data from these patients were analyzed, with 837 patients in dataset A and 324 in dataset B, considering the differences in surgical procedures between facilities. RESULTS: There was a strong correlation between the ALBI and EZ-ALBI scores across all patients, with a correlation coefficient of 0.974 (p < 0.0001). Comparison between the EZ-ALBI Grade 1 (n = 647) and Grade 2 (n = 514) groups showed that Grade 2 had significantly poorer liver function, shorter operative time, and higher rates of postoperative complications. In dataset A, patients in the EZ-ALBI Grade 2 group had significantly worse overall survival than those in Grade 1 (p < 0.0001). Similar trends were observed in dataset B, where Grade 2 was associated with significantly worse disease-free survival and overall survival. Univariate and multivariate analyses identified the EZ-ALBI score as an independent prognostic factor for OS in both datasets, with Grade 1 patients showing a better prognosis. CONCLUSION: The EZ-ALBI score is a valuable prognostic tool for assessing outcomes after resection of small HCC.

DOI： 10.1111/hepr.14210

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Gastroenterology  

DOI： 10.11405/nisshoshi.122.520

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Language：Japanese   Publisher：金原出版(株)  

＜文献概要＞adenomatoid tumorは中皮細胞由来の良性腫瘍であり,生殖器系の臓器に生じることが多く,副腎原発はまれである。今回我々は,肝浸潤を伴った副腎原発adenomatoid tumorの1例を経験したことから,画像における術前診断の可能性について文献的考察を加え報告する。

Language：Japanese   Publisher：(株)アークメディア  

Language：Japanese   Publisher：金原出版(株)  

＜文献概要＞神経内分泌腫瘍(neuroendocrine neoplasm;NEN)は,NET(neuroendocrine tumor)とNEC(neuroendocrine carcinoma)の総称であり,さまざまな臓器を原発とし,産生ホルモンによりさまざまな症状を起こし得る神経内分泌細胞を由来とする腫瘍である。また,NENは発生する臓器により分類が異なり,膵・消化管,肺の2つの分類がそれぞれ用いられている。NENの約70%は膵・消化管由来であり,25%は肺由来,5%はその他の臓器由来とされる。そのなかでも,特に膵・消化管のNENは初診時に転移性であることが多く,膵NENの4割は同時性転移を認め5年生存率は40%程度である。転移臓器は肝が最多で28～77%とされる。また,転移の有無は,腫瘍の悪性度分類の次に重要な予後因子となる。本稿では膵・消化管NENの肝転移に対する切除適応や成績を中心に解説する。

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: To validate the reliability of fibrosis markers as predictors of graft survival in living donor liver transplantation (LDLT) recipients. Methods: We reviewed data retrospectively, from 163 patients who underwent adult LDLT with preoperative measurements of type IV collagen (CIV), Mac-2 binding protein glycosylation isomer (M2BPGi), and hyaluronic acid (HA). Patients were divided into high and low groups for each biomarker, based on optimal cutoff values, and graft loss within 6 months was evaluated in each group. Results: The high CIV level group showed significantly lower 6-month graft survival rates and significantly higher rates of postoperative sepsis and sepsis from pneumonia. However, the groups with high and low M2BPGi levels and those with high and low HA levels did not show significant differences in 6-month graft survival rates or rates of postoperative sepsis. Multivariate analysis revealed that a CIV level ≥ 590 was a significant predictor of graft loss within 6 months, postoperative sepsis, and sepsis from pneumonia. Conclusion: Unlike other fibrosis markers, preoperative CIV levels can predict graft survival, postoperative sepsis, and sepsis from pneumonia after LDLT.

DOI： 10.1007/s00595-024-02941-8

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞【ポイント】◆術後出血を疑う場合はバイタルを安定させ造影CTを行う.縫合のみならず止血材など様々な手技に精通しておく.◆術後肝不全は呼吸循環管理,腎保護,感染・便秘・門脈血栓対策など幅広い全身管理が肝要である.◆術後胆汁漏には交通型と離断型があり,離断型は難治性である.どこでどう漏れているのかまず把握する.

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Medicine  

AIM: With advances in systemic therapy, the number of patients with hepatocellular carcinoma (HCC) who can undergo hepatic resection has increased in recent years, but there are no reports evaluating the immune status in the peritumoral area. METHODS: We enrolled 14 patients who underwent hepatic resection after lenvatinib (LEN, n = 7) or atezolizumab plus bevacizumab (ATZ/BEV, n = 5) therapy. Tumor-infiltrating lymphocytes (TILs), including CD3+ and CD8+ TILs, in the peritumoral area were evaluated by hematoxylin and eosin staining and immunohistochemistry. RESULTS: The median TIL counts after LEN and ATZ/BEV therapy were 32 and 92 cells/0.237 mm2, respectively (p = 0.0044). The median CD3+ TIL counts after LEN and ATZ/BEV therapy were 26 and 71 cells/0.237 mm2, respectively (p = 0.0057). The median CD8+ TIL counts after LEN and ATZ/BEV therapy were 14 and 42 cells/0.237 mm2, respectively (p = 0.0044). CONCLUSION: TIL counts, including those of CD3+ and CD8+ TILs, in the peritumoral area were significantly higher after ATZ/BEV than after LEN therapy.

DOI： 10.1002/cam4.70445

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver Transplantation  

Liver transplantation is the definitive treatment for advanced liver cirrhosis with portal hypertension. In Japan, the scarcity of deceased donors leads to reliance on living donors, often resulting in smaller grafts. Managing portal venous pressure (PVP) is critical to prevent fatal posttransplant complications. This study explored the possibility of predicting intraoperative PVP. We analyzed 475 living donor liver transplant cases from 2006 to 2023, excluding those with acute liver failure or prior splenectomy or splenic artery embolization. Patients were divided into a training group (n = 425) and a test group (n = 50). We evaluated the correlation between preoperative factors and PVP at laparotomy to predict PVP at laparotomy and closure. The predictive model was validated with the test group data. PVP at laparotomy could be predicted using correlated preoperative factors: prothrombin time (p < 0.001), predicted splenic volume (p < 0.001), and presence of a portosystemic shunt (p = 0.002), as follows: predicted PVP at laparotomy (mm Hg)=25.818 - 0.077 × (prothrombin time [%]) + 0.004 × (predicted splenic volume [mL]) - 2.067 × (1: with a portosystemic shunt) (p < 0.001; R = 0.346). In addition, PVP at closure could be predicted using correlated operative factors, including measured PVP at laparotomy, as follows: predicted PVP at closure (mm Hg)=14.268 + 0.149 × (measured PVP at laparotomy [mm Hg]) - 0.040 × (GV/SLV [%]) - 0.862 × (1: splenectomy [if yes]) - 3.511 × (1: splenic artery ligation without splenectomy [if yes]) (p < 0.001; R = 0.339). This study demonstrated the feasibility of predicting intraoperative PVP using preoperative factors in patients with decompensated cirrhosis undergoing liver transplant. This predictive approach could refine surgical planning, potentially improving patient outcomes.

DOI： 10.1097/LVT.0000000000000433

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Background and purpose: In recent years, new systemic therapies have been developed for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the prognosis of patients with unresectable HCC treated with R0 hepatectomy after systemic therapy. Methods: Data from 27 patients who underwent hepatectomy for HCC after systemic therapy at six facilities were analyzed retrospectively. Cancer-specific survival (CSS) and recurrence-free survival (RFS) after hepatectomy were investigated using Kaplan–Meier curves. We examined the prognostic value of the oncological criteria of resectability for HCC reported by the Japanese Expert Consensus 2023. Results: R0 resection was performed in 24 of the 27 patients. Using the Response Evaluation Criteria in Solid Tumors, 0 patient had a complete response, 16 had a partial response, 6 had stable disease, and 2 had progressive disease. Median CSS was not evaluated, but the median RFS was 17.8 months. Patients with resectable and borderline resectable (BR) 1 cancers had a better prognosis than those with BR2 cancers. The group whose oncological criteria were improved by systemic therapy had a lower recurrence rate than the group whose oncological criteria were maintained, but no difference was observed in CSS. Conclusions: The findings of this study suggest that hepatectomy after systemic therapy may improve the prognosis of HCC patients.

DOI： 10.1007/s00595-024-02930-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: Infectious complications, particularly post-transplant sepsis, have a critical impact on postoperative outcomes. This study examined the effects of perioperative synbiotic treatment on postoperative outcomes in patients receiving early enteral nutrition. Methods: We reviewed 210 living-donor liver transplantation procedures and retrospectively analyzed the postoperative outcomes with and without perioperative synbiotic treatment (live lactic acid bacteria, bifidobacteria, and oligosaccharides) 5 days before and after living-donor liver transplantation. Results: The synbiotic group (n = 34) had significantly fewer male donors (38.2% vs. 61.9%, p = 0.011) and a higher proportion of ABO-incompatible grafts (52.9% vs. 25.6%, p = 0.021) than the non-synbiotic group (n = 176). The incidence of sepsis was significantly lower in the synbiotic group than in the non-synbiotic group (0% vs. 7.4%, p = 0.029), with a lower incidence rate of sepsis due to bacteremia with intestinal bacteria (0% vs. 4.6%, p = 0.089). There were no significant differences in the proportions of acute rejection, small-for-size graft syndrome, or postoperative liver function between the two groups. Furthermore, there was no significant difference in the graft survival rates after LDLT between two groups. (p = 0.24). Conclusion: Perioperative synbiotic treatment prevents post-transplant sepsis, even with early enteral nutrition.

DOI： 10.1007/s00595-024-02918-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Microvascular invasion (MVI) affects the prognosis and treatment of hepatocellular carcinoma (HCC); however, its preoperative diagnosis is challenging. Analysis of computed tomography (CT) images using radiomics can detect MVI, but its effectiveness depends on the imaging conditions. We compared the efficacies of radiomics, clinical, and combined models for predicting MVI in HCC using nonstandardized scanning protocols. Methods: This multicenter study included 533 patients who underwent hepatic resection for HCC. Patients were divided randomly into training (n = 426) and test groups (n = 107). We manually extracted 3D CT features in hepatic arterial, portal venous, and venous phases. The radiomics model was trained by machine learning. A logistic regression model was developed based on clinical information, and a fused model was created integrating clinical information and radiomics prediction score (Rad_Score). We calculated areas under the receiver operating characteristic curves (AUCs) for the radiomics, clinical, and mixed models in the test groups. Results: The clinical model incorporated hepatitis B virus surface antigen, tumor diameter, and log-transformed α-fetoprotein and des-gamma-carboxyprothrombin. The AUCs of the radiomics and clinical models were comparable (p = 0.76). Rad_Score was not an independent significant factor in the fused model (p = 0.40) and its addition did not improve the accuracy of the clinical model alone (p = 0.51). Conclusions: A clinical model is as effective as a CT radiomics model for predicting MVI status in patients with HCC based on real-world scanning data, and integration of both models does not improve the predictive performance compared with a clinical model alone.

DOI： 10.1111/hepr.14149

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

The Duct of Luschka represents a rare form of accessory biliary ducts. There are no reported cases of the Duct of Luschka in living donor hepatectomy. We report a 36-year-old man with the Duct of Luschka who underwent living-donor hepatectomy. Preoperative drip infusion cholangiography with computed tomography (DIC-CT) identified the Duct of Luschka originating from the right hepatic duct to the cystic duct. By choosing the left and caudate lobe hepatectomy, the Duct of Luschka was left intact during the procedure. The donor recovered uneventfully posthepatectomy, and the recipient also did not experience biliary complications. This case underscores the importance of preoperative DIC-CT and surgical planning, including graft selection, to prevent postoperative bile leaks.

DOI： 10.1016/j.transproceed.2025.02.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Precision Oncology  

PURPOSE: This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2-amplified biliary tract cancer (BTC). METHODS: This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS: Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2-amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION: HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

DOI： 10.1200/PO-24-00718

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PubMed

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞・肝細胞癌患者の背景肝は障害を伴うことが多く,肝障害の進行に伴って肝硬変にいたり,その結果,門脈圧亢進症を呈することも少なくない.・欧米のガイドラインでは門脈圧亢進症の存在は,肝切除ではなく肝移植を適応としているが,本邦では肝予備能が保たれていれば門脈圧亢進症を伴っていても肝切除を行うことがある.・肝硬変が進行すると,肝予備能の低下だけではなく血小板減少や難治性食道静脈瘤,難治性胸腹水など複雑な病態を呈し,周術期を通して肝細胞癌に対する肝切除に難渋することが多い.・門脈圧亢進症の病態を的確に把握し術前・術後管理に十分対策していれば,万一の合併症に迅速に対応することができる.

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞肝癌の中でも,特に肝細胞癌は慢性肝炎や肝硬変を背景肝に有するためサルコペニアの合併率が高いことが知られている.肝細胞癌に対する肝切除術において,サルコペニアの合併は予後不良因子であることから,初診時の握力や検査結果をもとにしたわれわれの術前介入のプロトコールを紹介する.加えて,全身薬物療法におけるサルコペニアの影響に関して薬物による相違点を検討する.

Language：English   Publisher：シュプリンガー・ジャパン(株)  

肝細胞癌(HCC)に対しアテゾリズマブ+ベバシズマブ併用療法(ATZ/BEV)を施行した患者の血清LDHと予後および腫瘍代謝の関連を検討した。当院で2018年4月～2023年12月までの66例を対象とした。ATZ/BEVの1回目および2回目投与前のLDHに基づき、低下群32例と増加群34例に分けて予後を評価するとともに、18F-FDG PET/CTでLDHと腫瘍代謝の関連を解析した。無増悪生存期間(PFS)についてはLDH増加群は低下群より有意に不良であった(6.1ヵ月vs11.4ヵ月)。多変量解析でLDH増加はPFS不良の独立リスク因子であった。また、220U/Lをカットオフ値としてベースラインLDH高値群22例と低値群44例に分けて比較したところ、PFSやOSに有意差は認めなかったが、LDH高値群は18F-FDG SUVmax高値と有意に相関した。また、ATZ/BEV療法が腫瘍代謝に与える影響をRNAシーケンシングで解析したところ、ATZ/BEV療法後の検体でミトコンドリア経路の下方制御を認めた。以上より、LDHはHCCの予後マーカーおよび腫瘍代謝指標となる可能性が示唆された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: We aimed to define borderline resectable colorectal liver metastases (CRLM) based on the analysis of risk factors for early surgical failure and investigate the efficacy of neoadjuvant chemotherapy in these patients. Methods: This was a retrospective analysis of a multi-institutional cohort of patients diagnosed with technically resectable CRLM. Early surgical failure within 6 months of liver surgery was defined as ESF6. We classified CRLM into three grades (A, B, and C) according to the definition of the Japanese Society for Cancer of the Colon and Rectum. Results: Among the 249 patients with technically resectable CRLM, 46 (18.5%) developed ESF6. The survival rate of these patients was significantly lower than that of the patients without ESF6. In the multivariate analysis of synchronous CRLM patients, no neoadjuvant chemotherapy, Grade B/C, and Charlson comorbidity index ≥ 3 were independent predictors of ESF6. Among patients with synchronous and Grade B/C CRLM, ESF6 rates, surgical failure-free survival, and overall survival in the neoadjuvant chemotherapy group were significantly better relative to the upfront surgery group. Conclusions: Patients with synchronous and Grade B/C CRLM are at a high risk of early surgical failure, have a poor long-term prognosis, and can be defined as borderline resectable and good candidates for neoadjuvant chemotherapy.

DOI： 10.1007/s00595-024-02920-z

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver Cancer  

INTRODUCTION: TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited. METHODS: A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro. RESULTS: Patients were divided into TIGAR-positive (n = 80, 20.7%) and -negative (n = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ des-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (p < 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (p = 0.0450), larger number of CD68-positive macrophages (p = 0.0058), larger number of programmed death-ligand 1-positive cases (p = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (p = 0.0004). In vitro, TIGAR knockdown decreased cell motility and induced ferroptosis. TIGAR knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by TIGAR knockdown was inhibited by liproxstatin and baicalein treatment. The combination of TIGAR knockdown and lenvatinib further induced ferroptosis. CONCLUSION: High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.

DOI： 10.1159/000540180

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PubMed

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞移植医療は多岐に及ぶ知識や技術,経験が求められるが,レシピエントを助けたいと願うドナーがいてはじめて成り立つ医療である.だからこそ,われわれ医療者もその思いに応えられる熱意が必要であり,疲弊することなくその熱意を持続できる環境づくりが不可欠となる.多職種のチーム体制を確立させ,分業化をよりすすめることが,将来的に医師の多様な働き方に対応できるような環境づくりの一歩となるのではないかと考える.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Reactivation of hepatitis B virus (HBV) after liver transplantation (LT) remains a problem; thus, development of more effective HBV reactivation prophylaxis is desirable. We evaluated the efficacy of a combination of a long-term nucleotide analog (NA), such as entecavir (ETV) or tenofovir alafenamide (TAF), and short-term hepatitis B immunoglobulin (HBIG) in preventing HBV reactivation and compared it with conventional HBV prophylaxis. Methods: Between February 1999 and August 2023, 135 patients underwent living-donor liver transplantation for liver cirrhosis or acute liver failure caused by HBV infection or received an LT from a hepatitis B core antibody-positive donor. Recipients who had undergone LT were classified as being in the first or second era (namely until September 2017 and from October 2017), respectively, and outcomes of prophylaxis against HBV reactivation were compared between the two eras. Results: In the second era, recipients with HBV-related disease or who had received hepatitis B core antibody-positive liver received combination therapy with short-term HBIG and an NA such as TAF and ETV long-term. The duration of HBIG treatment was markedly shorter than in the first era in both categories of patients and HBIG could be discontinued in all cases. Surprisingly, we observed HBV reactivation in the first era, but not in the second era, in both groups. Conclusions: We have established a protocol for prophylaxis against HBV reactivation using a combination of short-term HBIG and long-term NA. This protocol was found to be sufficient to prevent HBV reactivation after LT.

DOI： 10.1111/hepr.14110

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PubMed

Language：English   Publisher：Asian Journal of Endoscopic Surgery  

Introduction: This study aimed to update the literature and present findings from a national survey on the current use and perceived utility of indocyanine green (ICG) fluorescence imaging in laparoscopic and robotic kidney surgeries, as discussed at the Consensus Meeting on Anatomy on the Border. Methods: This study consisted of two parts. First, a narrative review of previous studies on ICG application in kidney surgeries was conducted. Second, a questionnaire for urologists certified in laparoscopic surgery was created to evaluate current practices regarding ICG usage. Results: Nine studies on ICG use in partial nephrectomy were reviewed. The sole randomized controlled trial (RCT) found no significant benefit of ICG-guided robotic-assisted partial nephrectomy (RAPN), although the majority of observational studies suggested potential advantages. The lack of methodological standardization remains a major barrier to its wider implementation. Of the 114 urologists contacted, 32 (28%) responded, most of whom had over 20 years of surgical experience. Among the respondents, 31% reported using ICG in renal surgeries: 20% used it exclusively in RAPN, 60% in RAPN in combination with other procedures, and 20% in other surgeries. The dosing varied, but over half of the respondents used 12.5 mg per injection. Conclusion: Although observational data indicate the potential utility of ICG in renal surgery, the RCT finding is inconclusive, and its current use among urologists remains limited. Nevertheless, ICG holds promise for a broader application in urological procedures.

DOI： 10.1111/ases.70184

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PubMed

Language：English   Publisher：Asian Journal of Endoscopic Surgery  

Introduction: The liver, lungs, and kidneys are all parenchymal organs and are useful targets for indocyanine green (ICG) fluorescence. We created a consensus statement on the appropriate use and precautions for ICG in liver, lung, and kidney surgery. Methods: We conducted a comprehensive literature search and questionnaire survey for expert surgeons in each area. Results: We extracted 11 articles related to the liver, 23 to the lung, and 8 to the kidney. A total of 86 facilities, 50 facilities, and 32 surgeons responded to the questionnaire survey for the liver, lung, kidney, respectively. ICG fluorescence is widely employed for segment delineation of the liver, lung, and kidney and has been reported to exhibit high efficacy. The dosage and timing greatly vary depending on the target organ and administration route. Tumor localization via ICG fluorescence is widely performed in the liver area, with numerous reports highlighting its high efficacy. Contrarily, in the lung and kidney, despite the existence of clinical studies, ICG fluorescence has not been generally performed in clinical practice. There have been no reported complications or adverse experiences related to the use of ICG agents, indicating their safety for clinical use. Conclusion: This survey, along with a literature review, has elucidated the current consensus of liver, lung, and kidney surgeons regarding ICG fluorescence.

DOI： 10.1111/ases.70175

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PubMed

Language：Japanese   Publisher：The Japan Society for Transplantation  

<p>【背景・目的】プレバイミスは腎移植後のサイトメガロウイルス(CMV)感染症発症抑制効果が、バルガンシクロビル(VGCV)に対して非劣性、かつ骨髄抑制が少ないことが報告されている。従来のVGCV投与量(900mg/日)では骨髄抑制の副作用が多く、当科では、重篤な患者の多い肝移植後は減量(450mg/日x週3回)し投与を行ってきたが、2024年6月以降、プレバイミスを導入しており、本検討ではその有効性と安全性について検討する。【対象・方法】2023年11月から2024年5月の生体肝移植(LDLT)症例をVGCV群(n=20)、2024年6月から2025年4月のLDLT症例をプレバイミス群(n=26, 480mg/日x毎日)とした。LDLT後1ヶ月以内にCMVpp65抗原陽性細胞を検出した割合と副作用の頻度、タクロリムス(TAC)血中濃度の変化を比較検討した。【結果】CMV感染症の発症はなく、CMVpp65抗原陽性細胞の検出割合は、プレバイミス群で有意に低かった(VGCV群35% vsプレバイミス群3.8%, p＜0.05)。VGCV減量投与を行っている本検討では両群共に骨髄抑制の発症率に差はなく、副作用によるプレバイミスの中止症例は認めなかった。TACの血中濃度を同等に維持(10 ng/ml)するために必要なプログラフの内服量は、プレバイミス群で約半分に減量された(VGCV群4.0mg vs プレバイミス群 2.1mg, p＜0.05)。【まとめ】プレバイミスは肝移植後CMV再活性化予防として有効、かつ安全に投与可能なことが示された。</p>

DOI： 10.11386/jst.60.supplement_s283_1

CiNii Research

Language：Japanese   Publisher：The Japan Society for Transplantation  

<p>【背景・目的】 生体肝移植(LDLT)は、一般に「too sick for transplant」とされるHigh MELD患者において、適応や治療意義がいまだ議論されている。近年、手術手技や周術期管理の進歩により、この「too sick」な病態に対しても挑戦的治療が可能となりつつある。本研究では、High MELD患者に対するLDLTの妥当性およびその治療戦略の有効性を再評価する。</p><p>【方法】2024年12月までに施行された成人LDLT 852例を対象に、MELDによりL群(＜20, n=642),M群(20-29, n=160),H群(≧30, n=50)に分類し術後成績を比較検討した。</p><p>【結果】 Grade B以上の過小グラフト症候群（SFSS）はH群で最も高頻度（L群24.3%、M群36.3%、H群51.5%、p＜0.01）。敗血症の発症率やグラフト生存率には有意差なしだが、時代後期(2015年-)では1年生存率の改善がみられ、特にH群における改善が顕著（76.0%→80.0%、p＜0.05）であった。また、H群では左葉グラフトの1年生存率が右葉に比して有意に低値（61.0% vs. 89.2%、p＜0.05）、特に50歳未満ドナーからの右葉グラフトを用いた症例では良好な成績であった。</p><p>【結論】 High MELD患者、すなわち“too sick”とされる症例に対しても、生体肝移植は適切なグラフト選択と周術期戦略により、近年その成績が著しく改善している。とりわけ右葉グラフトの選択は、十分な肝容積を確保しうる有効な戦略であり、この極めて重篤な病態における治療の鍵を握る。</p>

DOI： 10.11386/jst.60.supplement_s219_2

CiNii Research

Language：Japanese   Publisher：The Japan Society for Portal Hypertension  

<p>患者は10歳代男性．小児期にデスモイド腫瘍摘出術と浸潤を伴う上腸間膜静脈の合併切除を施行した．術後再発なく経過するも，13年後に多量の黒色便で受診，精査の結果，上腸間膜静脈の閉塞に伴い回腸静脈が拡張，十二指腸と結腸肝弯曲部の静脈瘤を認め，十二指腸静脈瘤出血と診断した．保存的に止血を得られ，待機的手術とした．術中上腸間膜静脈は癒着のため剥離困難，門脈本幹と回腸静脈間は15 cm離れていたため，浅大腿静脈グラフトを使用し吻合した．吻合後に回腸静脈圧は低下，十二指腸静脈瘤は消失した．本症例は若年で全身状態も良好であり，異所性静脈瘤に対して外科的な門脈系の血行再建術を選択し良好な結果を得られた．異所性静脈瘤の確立した治療法はなく，症例に応じて内視鏡やカテーテル治療が選択されることが多いが，患者の状態や各治療法の特徴を踏まえた上で，外科手術を選択することも念頭に入れて治療を行っていくことが重要である．</p>

DOI： 10.11423/jsph.31.255

CiNii Research

Language：Japanese   Publisher：The Japan Society for Transplantation  

<p>【背景】最近欧米からも移植医のburn outに関する報告が相次いでおり、移植医療における喫緊の課題である。当科の施策として1.摘出チームを4人から3人へ減らし、2.提供病院付近の宿泊施設で休息後に集合、3.クーラーボックスの軽量化、など業務改善に努めてきた。また積極的に若手スタッフによる執刀を増やし、モチベーションの保持に努めている。【対象・方法】2003年10月から2025年3月まで、当科で行った脳死肝グラフト摘出を、新体制に変えた2017年前後で2群に分け、摘出チーム人数、宿泊施設利用、交通費、執刀者の経験年数を比較した。【結果】交通費の確認が可能であった81例のうち、旧体制15例中4人で摘出したのは12例(80%)で新体制では66例中8例(12%)と新体制で少なかった(p＜0.0001)。宿泊施設利用は旧体制13%に対し新体制74%と増加し(p＜0.0001)、交通費の合計は228,261円vs228,056円と差はなかった(p=0.99)。旧体制で卒後15年以内の若手外科医による執刀は15.6%に対し、新体制では48.6%と若手の執刀機会が増加していた(p=0.0008)。【考察】4人体制を3人にすることで休息者ができ、交通費負担を増やすことなく集合前の宿泊施設利用で摘出チームの休息も増えた。また若手外科医による執刀が多いことで、モチベーションも保ちながらburn-outせずに症例を積み重ねている。</p>

DOI： 10.11386/jst.60.supplement_s388_2

CiNii Research

Language：Japanese   Publisher：The Japan Society for Transplantation  

<p>【背景・目的】肝移植は肝細胞癌（HCC）に対する有力な治療法だが、日本の肝癌診療ガイドラインでは、Child Cのみが適応とされている。一方、欧米では腫瘍条件が適合すればChild Aにも肝移植が選択されている。現在日本でもChild B肝硬変に対する肝移植は保険適応となったが、HCCに関しては併存条件が記載されているに留まっており、Child AのHCCに対する移植報告は極めて限定的である。本研究では、Child A及びBのHCCに対する生体肝移植(LDLT)と肝切除（HR）の成績を比較し、適応拡大の可能性を検討した。</p><p>【方法】 今回、改正臓器移植法施行後かつDAAが保険適応となった2011年以降の症例を対象。当院で施行されたLDLT (n=159, total n=309)及び初発HCCに対するHR (n=208)を対象とし、術後成績について比較検討。</p><p>【結果】(1) 日本基準内HCCに対するHRではChild Aの1y/5y-OSが99.3/79.8%、Child Bが80.3/62.5%と肝機能により予後が層別化された（P＜0.05）。一方、LDLT群ではChild A～C間でOSに有意差は認めなかった。(2) Child BではLDLTがHRよりRFS・OSともに有意に良好だったが、Child Aでは有意差なし。ただしICG-R15＞15%のChild Aでは、HRがLDLTより有意に予後不良（P＜0.05）。Child BのLDLTではDCP＞300が独立予後不良因子。</p><p>【まとめ】2010年代以降の症例においてもChild B及びICG高値のChild Aに対するLDLTはHRより良好な成績を示し、移植適応拡大の可能性を示唆する結果となった。</p>

DOI： 10.11386/jst.60.supplement_s217_1

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Oncology  

PURPOSE Durable partial response (PR) and durable stable disease (SD) are often seen in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab (atezo-bev).This study investigates the outcome of these patients and the histopathology of the residual tumors.PATIENTS AND The IMbrave150 study's atezo-bev group was analyzed.PR or SD per RECIST v1.1 METHODS lasting more than 6 months was defined as durable.For histologic analysis, a comparable real-world group of patients from Japan and Taiwan who had undergone resection of residual tumors after atezo-bev was investigated.RESULTS In the IMbrave150 study, 56 (77.8%) of the 72 PRs and 41 (28.5%) of the 144 SDs were considered durable.The median overall survival was not estimable for patients with durable PR and 23.7 months for those with durable SD.The median progression-free survival was 23.2 months for patients with durable PR and 13.2 months for those with durable SD.In the real-world setting, a total of 38 tumors were resected from 32 patients (23 PRs and nine SDs) receiving atezo-bev.Pathologic complete responses (PCRs) were more frequent in PR tumors than SD tumors (57.7% v 16.7%, P 5.034).PCR rate correlated with time from atezo-bev initiation to resection and was 55.6% (5 of 9) for PR tumors resected beyond 8 months after starting atezo-bev, a time practically corresponding to the durable PR definition used for IMbrave150.We found no reliable radiologic features to predict PCR of the residual tumors.CONCLUSION Durable PR patients from the atezo-bev group showed a favorable outcome, which may be partly explained by the high rate of PCR lesions.Early recognition of PCR lesions may help subsequent treatment decision.

DOI： 10.1200/JCO.24.00645

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PubMed

Language：Japanese   Publisher：(株)北隆館  

日本における肝移植の最新動向と研究の進展について,3つの焦点に絞って概説する。まず,高齢者に対する肝移植では,現在70歳以上の患者にも安全な移植が可能であり,今後は適応基準の見直しおよび適切な患者選択と術前評価により良好な予後が期待されている。また,マージナルドナーからの肝グラフトの利用が注目される中,肝機能の評価技術に関する基礎的研究の進展が不可欠であり,今後は血液検査による非侵襲的バイオマーカーの活用が期待される。さらに,機械灌流技術によるグラフト機能の温存と選択も今後の肝移植の成功を支える重要な手法であり,その臨床実装と技術改善によって肝移植の臨床成績が向上し,待機中の患者への治療提供が拡大することが期待される。(著者抄録)

Language：Japanese   Publisher：(株)アークメディア  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Radiology  

Purpose: Liver resection is currently considered the most effective treatment for patients with liver cancer. To the best of our knowledge, no study has investigated the association between gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings and liver regeneration in patients who underwent hemihepatectomy. We aimed to clarify the relationship between the signal intensity (SI) of the liver parenchyma on gadoxetic acid-enhanced MRI and the degree of liver regeneration in patients who underwent hemihepatectomy. Materials and methods: Forty-one patients who underwent gadoxetic acid-enhanced MRI before hemihepatectomy were enrolled. We calculated the liver-to-erector spinae muscle SI ratio (LMR) in the hepatobiliary phase and the precontrast images. ΔLMR was calculated using the following equation: ΔLMR = (LMR in the hepatobiliary phase−LMR in the precontrast image)/LMR in the precontrast image. The preoperative and postoperative remnant liver volumes (LVs) were calculated using CT volumetry. We calculated the resection rate (RR) and liver regeneration index (LRI) using the following formulas: RR = Resected LV/Total LV × 100 and LRI = (postoperative remnant LV−preoperative remnant LV)/preoperative remnant LV × 100. The relationships among LRI, imaging, and clinicopathological factors were analyzed. Results: Univariate analysis showed RR and ΔLMR showed a positive correlation with LRI (ρ = 0.4133, p = 0.0072 and ρ = 0.7773, p < 0.001, respectively). Spleen volume showed a negative correlation with LRI (ρ = −0.3138, p = 0.0486). Stepwise multiple regression analysis showed ΔLMR and RR were independently correlated with LRI (β coefficient = 44.8771, p = 0.0198 and β coefficient = 1.9653, p < 0.001, respectively). Conclusion: ΔLMR may serve as a preoperative predictor of liver regeneration in patients undergoing hemihepatectomy.

DOI： 10.1007/s11604-024-01629-w

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

Background: Ferroptosis is a cell death caused by iron-dependent accumulation of lipid peroxidation. Transferrin receptor (TFR) is a ferroptosis-related protein responsible for iron transport. The detailed biologic role of TFR in intrahepatic cholangiocarcinoma (ICC) is not fully elucidated. Methods: The study enrolled 92 ICC patients who had undergone hepatic resection. Immunohistochemistry (IHC) assays were performed for TFR protein expression. The regulation of malignant activity and the effect on sensitivity to the ferroptosis-inducer artesunate by TFR were investigated in vitro. Results: Using IHC staining, 23 patients were categorized as TFR-positive. The TFR-positive group had a significantly larger tumor size and more microscopic vascular invasion. In the multivariate analysis, TFR positivity was an independent poor prognostic factor. In vitro TFR-knockdown (KD) significantly decreased the intracellular iron levels and the cell proliferation, migration, and invasion rates. Artesunate treatment significantly decreased cell viability, whereas cisplatin promoted ferroptosis. When iron transport into cells was inhibited by TFR-KD, ferroptosis was significantly suppressed. Expression of PD-L1 was induced by cisplatin, with a further increase observed when artesunate and cisplatin were used in combination. Conclusions: Transferrin receptor is a poor prognostic factor for ICC and contributes to sensitivity to ferroptosis.

DOI： 10.1245/s10434-024-16065-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Malignant melanomas occur most commonly in the skin, mucous membranes, or choroid. Clitoral malignant melanomas are extremely rare. Stage IV malignant melanomas have a poor prognosis, and molecularly targeted agents or immune checkpoint inhibitors are recommended. However, surgical resection is reportedly a valid option for improving the prognosis of patients with oligometastases, defined as a small number of metastases that can be completely resected. In this report, we describe hepatic resection for a recurrent liver metastasis in a patient who had undergone removal of a clitoral malignant melanoma 9 years previously. CASE PRESENTATION: An 82 year-old woman presented with a black nodule on her clitoris. Total resection of the nodule resulted in a diagnosis of clitoral malignant melanoma (pT4bN0M0, pStage IIC; UICC 8th edition). A follow-up computed tomography scan 4 years later revealed a single 5 mm mass in the lower lobe of the right lung, prompting partial resection of the right lung. Pathological examination of the operative specimen revealed a pulmonary metastasis of malignant melanoma. The patient was treated with pembrolizumab monotherapy as adjuvant chemotherapy for 1 year. A follow-up computed tomography scan 9 years after surgical removal of the primary lesion revealed an 18 mm mass in segment II of the liver, prompting robot-assisted laparoscopic left lateral sectionectomy. The provisional diagnosis of metastatic malignant melanoma in the liver was confirmed by histopathological examination of the operative specimen. The patient was treated with pembrolizumab monotherapy as postoperative adjuvant chemotherapy for 1 year. No further recurrence was detected at the 1.5 year follow-up. CONCLUSION: We performed hepatectomy for oligometastasis of clitoral malignant melanoma, an extremely rare entity. Surgery has the potential to prolong the prognosis of patients with oligometastasis.

DOI： 10.1186/s40792-024-02058-7

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Publisher：南江堂  

DOI： 10.15106/j_geka86_1288

CiNii Research

Language：Japanese   Publisher：(一社)日本移植学会  

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞再肝切除に対するロボット支援や腹腔鏡下手術といった低侵襲手術では,前回手術内容の把握や,術前3Dシミュレーションをもとにした精密な術前準備が重要である.低侵襲再肝切除は,適切なポート配置による癒着剥離,肝十二指腸靱帯のテーピング,インドシアニングリーン(ICG)蛍光法を用いた腫瘍の同定により安全に施行が可能である.再肝切除においても低侵襲手術は有用であり,合併症の軽減と良好な治療成績が期待される.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Cancer  

Background: Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC. Methods: We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360. Results: Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32–0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis. Conclusion: Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

DOI： 10.1038/s41416-024-02834-0

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Management of patients with colorectal liver metastases (CRLMs) requires a multidisciplinary approach. For patients with progression of RAS mutant tumors, the choice of angiogenesis inhibitors can be controversial. Here, we report a patient with RAS mutant CRLMs achieving long-term disease-free survival with repeated R0 resections and perioperative treatment, especially aflibercept + FOLFIRI (5-fluorouracil, levofolinate, irinotecan), which may have prevented long-term recurrence. CASE PRESENTATION: The patient was a 37 year-old woman diagnosed with RAS mutant transverse colon cancer with 19 LMs. As the metastases were limited to the liver, we introduced systemic chemotherapy aiming at conversion surgery. After six cycles of bevacizumab + FOLFOXIRI (5-fluorouracil, levofolinate, oxaliplatin, irinotecan), we performed partial hepatectomy for all LMs, and left hemicolectomy for the primary tumor after another four cycles of bevacizumab + FOLFIRI. Three months after surgery, the patient presented with massive ovarian metastases with carcinomatous ascites. We conducted bilateral oophorectomy, and initiated aflibercept + FOLFIRI therapy considering the possibility of resistance to bevacizumab. The patient was recurrence-free for 2 years during aflibercept + FOLFIRI treatment. After its discontinuation, two distant metastases developed. Both were resectable and the patient achieved recurrence-free survival of 2 years and 3 months after the last operation (6 years since initiation of treatment), without additional chemotherapy. CONCLUSIONS: We believe that multidisciplinary treatment aimed at complete resection could lead to long-term survival even in patients with repeated recurrence of CRLMs. Aflibercept + FOLFIRI could be effective in controlling metastasis of RAS mutant colon cancer even after treatment with bevacizumab.

DOI： 10.1186/s40792-024-02033-2

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Language：Japanese   Publisher：医学図書出版(株)  

肝細胞癌の薬物療法の進歩は目覚ましく,現在8レジメンが使用可能となっている。レンバチニブやアテゾリズマブ+ベバシズマブ併用療法のような奏効率が高い薬物療法の使用により,その後の外科治療や局所療法などを組み合わせた集学的治療により根治が得られる機会が増えてきている。また,肝細胞癌の腫瘍学的切除可能性分類が提唱され,切除可能かどうかを判断する共通言語が定められた。本稿では,肝細胞癌に対する薬物療法後の外科治療の現状とその成績について,データが多く集積されつつあるレンバチニブおよびアテゾリズマブ+ベバシズマブ併用療法を中心に概説する。(著者抄録)

Language：Japanese   Publisher：(株)アークメディア  

Authorship：Corresponding author   Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

<p>肝細胞癌に対する肝移植の保険適用は5-5-500基準内もしくはミラノ基準内であり，肝細胞癌治療アルゴリズムではChild-Pugh分類C症例に推奨されている．肝移植は良好な治療成績をあげているが，一定数の再発を認める．術前因子や病理学的因子を用いた再発予測の検討や，ダウンステージの有用性が報告されている．肝移植後再発症例の予後不良因子として移植後早期再発，AFP高値，根治治療不能が報告されており，mTOR阻害剤を用いた免疫抑制剤の調節，可能な場合における積極的外科治療や局所療法の介入，マルチキナーゼ阻害剤を中心とした薬物療法のシークエンス治療が，肝移植後再発の治療において重要となる．</p>

DOI： 10.11405/nisshoshi.121.729

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CiNii Research

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s40792-024-02014-5

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Language：Japanese   Publisher：(一財)日本消化器病学会  

肝細胞癌に対する肝移植の保険適用は5-5-500基準内もしくはミラノ基準内であり,肝細胞癌治療アルゴリズムではChild-Pugh分類C症例に推奨されている.肝移植は良好な治療成績をあげているが,一定数の再発を認める.術前因子や病理学的因子を用いた再発予測の検討や,ダウンステージの有用性が報告されている.肝移植後再発症例の予後不良因子として移植後早期再発,AFP高値,根治治療不能が報告されており,mTOR阻害剤を用いた免疫抑制剤の調節,可能な場合における積極的外科治療や局所療法の介入,マルチキナーゼ阻害剤を中心とした薬物療法のシークエンス治療が,肝移植後再発の治療において重要となる.(著者抄録)

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Sarcopenia is reportedly associated with a poor prognosis in patients who undergo living-donor liver transplantation (LDLT), most of whom are not able to tolerate muscle strengthening exercise training. Myostatin is one of the myokines and a negative regulator of skeletal muscle growth. The clinical feasibility of an electrical muscle stimulation (EMS) system, which exercises muscle automatically by direct electrical stimulation, has been reported. In this study, we aimed to determine the effect of perioperative application of SIXPAD, which is a type of EMS system, with reference to the serum myostatin and sarcopenia in LDLT patients. Method: Thirty patients scheduled for LDLT were divided into a SIXPAD group (n = 16) and a control group (n = 14). In the SIXPAD group, EMS was applied to the thighs twice daily. The serum myostatin was measured in samples obtained before use of SIXPAD and immediately before LDLT. The psoas muscle index (PMI) at the level of the third lumbar vertebra and the quadriceps muscle area were compared on computed tomography images before use of SIXPAD and 1 month after LDLT. Results: The preoperative serum myostatin was found to be higher in LDLT patients than in healthy volunteers and EMS significantly reduced the serum myostatin. Electrical muscle stimulation prevented a postoperative reduction not only in the area of the quadriceps muscles but also in the PMI despite direct stimulation of the thigh muscles. Conclusion: Stimulation of muscles by EMS decreases the serum myostatin and helps to maintain skeletal muscle in patients who have undergone LDLT.

DOI： 10.1111/hepr.14027

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DOI： 10.1097/01.tp.0001065652.38684.34

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DOI： 10.1097/01.tp.0001068216.93552.f1

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

Authorship：Corresponding author   Language：English   Publisher：(一社)日本外科学会  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes. Methods: We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT). Results: There were 32 patients categorized as the LDH-decrease group. Kaplan–Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of ¹⁸F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways. Conclusion: Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.

DOI： 10.1007/s00595-024-02914-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation  

Background. The consensus that portal venous pressure modulation, including splenectomy (Spx), prevents portal hypertension-related complications after living-donor liver transplantation (LDLT) has been established. However, little evidence about the risk factors for graft loss after simultaneous Spx during LDLT is available. This study aimed to identify the independent predictors of graft loss after simultaneous Spx during LDLT. Methods. Data of 655 recipients who underwent LDLT between 1997 and 2021 were collected and separated into the simultaneous Spx group (n=461) and no-Spx group (n=194). Results. The simultaneous Spx group had significantly lower serum total bilirubin levels, drained ascites volumes, and prothrombin time-international normalized ratios on postoperative day 14 than the no-Spx group (P<0.001 for each). Incidences of small-for-size graft syndrome (P<0.001), acute cellular rejection (P=0.002), and sepsis (P=0.007) were significantly lower in the Spx group. Graft survival of the Spx group was significantly better than that of the no-Spx group (P<0.001; hazard ratio [HR], 1.788; 95% confidence interval, 1.214-2.431). A multivariate analysis revealed that 3 variables, platelet count ≤4.0×10⁴/mm³ (P=0.029; HR, 2.873), donor age ≥60 y old (P=0.013; HR, 6.693), and portal venous pressure at closure ≥20 mm Hg (P=0.010; HR, 3.891), were independent predictors of graft loss within 6 mo after simultaneous Spx during LDLT. Conclusions. Spx is a safe inflow modulation procedure with a positive impact on both postoperative complications and prognosis for most patients. However, patients with the 3 aforementioned independent factors could experience graft loss after LDLT.

DOI： 10.1097/TP.0000000000004952

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastrointestinal Surgery  

Purpose: Although the incidence of recipients and donors with overweight and obesity is increasing worldwide, few reports have focused on outcomes of preoperative weight reduction (WR) in living-donor liver transplantation (LDLT). Therefore, we examined the outcomes and the impact of WR on the postoperative course. Methods: We analyzed 217 consecutive LDLT procedures performed from 2017 to 2022. We divided the recipients and donors into a WR group and non-WR group. Results: Twenty-two recipients (10.1%) achieved WR (preoperative recipient WR [RWR] group), reducing their weight by 6.8% ± 6.0% within 2.2 ± 1.4 months with a significant decrease in body mass index (BMI) (P < .0001). The RWR group showed no significant differences in short-term postoperative outcomes (operative factors, postoperative liver function tests, amount of ascites, and morbidity) or in the graft survival rate as a long-term outcome (P = .24) compared with the non-RWR group. Forty-one donors (18.9%) achieved WR (preoperative donor WR [DWR] group), reducing their weight by 9.7% ± 6.3% within 3.2 ± 5.8 months with a significant decrease in BMI (P < .0001). Compared with the non-DWR group, the DWR group showed no significant differences in short-term postoperative outcomes between themselves and recipients or in the graft survival rate (P = .49). Furthermore, WR resulted in an increase to 32 donor-eligible and 6 recipient-eligible patients. Conclusion: WR in LDLT recipients and donors had no harmful effect on postoperative outcomes and should lead to increase recipients’ chance of undergoing LDLT and to expand the donor pool.

DOI： 10.1016/j.gassur.2024.04.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

Aim: There is limited evidence regarding the feasibility of living-donor liver transplantation (LDLT) for patients aged over 70. The aims of this study were to assess postoperative outcomes in elderly recipients and to ascertain the potential feasibility and acceptability of LDLT. Methods: Data were collected from 762 recipients, including 26 in the elderly group (aged ≥70) and 736 in the younger group (aged <70), and reviewed even by propensity score matching (PSM). Results: No significant differences were observed in the frequency of postoperative complications between the two groups. Additionally, both groups exhibited a comparable 30-day mortality rate after LDLT (3.9% in both) and similar hospital stays (36 days vs. 40 days). The 1-, 3-, and 5-year graft survival rates in the elderly group were 92.0%, which was comparable to those in the younger group (p = 0.517), as confirmed by PSM. Notably, all donors for elderly patients were the children of the recipients, with an average age of 41.6 years, and grafts from donors aged ≥50 years were not utilized, signifying the use of high-quality grafts. Our inclusion criterion for elderly recipients was strictly defined as an ECOG-PS score of 0–2, which played a pivotal role in achieving favorable postoperative outcomes. Conclusion: LDLT can be performed safely for elderly patients aged 70 years or older, provided they have a preserved PS and receive high-quality grafts from younger donors, inevitably all children of elderly recipients. This approach yields acceptable long-term outcomes. Consequently, age alone should not serve as an absolute contraindication for LDLT.

DOI： 10.1002/ags3.12769

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: To evaluate the short term-outcomes of venous reconstruction using a round ligament-covered prosthetic vascular graft and assess its effectiveness in the prevention of prosthetic vascular graft migration in right‑lobe living donor liver transplantation (LDLT). Methods and results: Thirty patients underwent reconstruction of the middle hepatic vein (MHV) tributaries during right lobe LDLT between January, 2021 and October, 2022. These patients were divided into the autologous vascular graft group (A group, n = 24) and the round ligament-covered prosthetic vascular graft group (RP group, n = 6). The computed tomography (CT) density ratio of the drainage area in the posterior segment of patent grafts was significantly higher in the RP group than in the A group (0.91 vs. 1.06, p = 0.0025). However, the patency rates of reconstructed MHV tributaries in the A and RP groups were 61% and 67%, respectively, with no significant difference between the groups (p = 0.72). Prosthetic vascular graft migration did not occur in the RP group. Conclusion: Venous reconstruction using round ligament-covered prosthetic vascular grafts is a feasible and simple method to prevent prosthetic vascular graft migration in right-lobe LDLT.

DOI： 10.1007/s00595-024-02793-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: The Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) have been updated based on living donor LT data to include either the Milan criteria (MC) or the 5-5-500 rule, which requires a nodule size of ≤5 cm, ≤5 nodules, and an alpha-fetoprotein (AFP) level ≤500 ng/mL. We aimed to validate the 5-5-500 rule and the MC for deceased donor LT (DDLT). Methods: Using national registry data from the United States from 2010 to 2014, we separated DDLT patients into four groups based on the MC and the 5-5-500 rule. The AFP values were stratified into categories: ≤100, 101–300, 301–500, and >500 ng/mL. Results: The 5-year survival rate was significantly lower for patients in the groups within MC/beyond 5-5-500 (56.3%) or beyond MC/5-5-500 (60.7%) than for patients in the groups within MC/5-5-500 (76.2%) and beyond MC/within 5-5-500 (72.3%) (p < 0.01). Hepatocellular carcinoma recurrence at 5 years was highest for the within MC/beyond 5-5-500 (25.4%) group, followed by the beyond MC/within 5-5-500 (13.1%), beyond MC/5-5-500 (9.6%), and within MC/5-5-500 (7.4%) groups. The stratified 5-year survival rates after DDLT were 76.5%, 72.4%, 58.4%, and 55.6% in the AFP ≤100, 101–300, 301–500, and >500 categories, respectively (p < 0.01). Conclusion: The 5-5-500 rule guides the appropriate selection of patients with HCC for DDLT. Patients with AFP levels from 300 to 500 ng/mL had inferior outcomes even when they met the 5-5-500 rule, so further investigation is needed to guide their treatment.

DOI： 10.1111/hepr.14017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Some patients with refractory esophagogastric varices require surgery, such as gastric devascularization and splenectomy (Hassab’s procedure). However, these patients are at risk of perioperative morbidities when undergoing devascularization to develop collateral vessels. We performed a more simplified procedure, splenectomy, and en bloc gastropancreatic fold division (GPFD) with hand-assisted laparoscopic surgery. Four patients with refractory esophagogastric varices and portal hypertension underwent splenectomy and GPFD. We reviewed patients’ perioperative laboratory and morphological data, operative variables, and postoperative outcomes. Esophagogastric varices improved in 3 (75%) of the 4 patients. In one patient, esophageal varices (F1RC0) were observed 3 years after surgery, but they required no treatment and only received follow-up. Treatment with splenectomy and GPFD is not only less invasive than Hassab’s procedure but also provides effective outcomes for refractory esophagogastric varices.

DOI： 10.1007/s00595-023-02780-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Living-donor liver transplantation (LDLT) is an established treatment for patients with end-stage liver disease or acute liver failure, and outflow reconstruction is considered one of the most vital techniques in LDLT. To date, many strategies have been reported to prevent outflow obstruction, which can be refractory to liver dysfunction and can cause life-threatening graft loss or mortality. In addition, in this era of laparoscopic hepatectomy in donor surgery, especially LDLT using a left liver graft, it has been predicted that cutting the hepatic vein with automatic linear staplers will lead to more outflow-related problems than with conventional open hepatectomy because of the short neck of the anastomosis orifice. We herein review 10 cases of venoplasty performed with a novel venous cuff system using a donor’s round ligament around the hepatic vein in LDLT with a left lobe graft, which makes anastomosis of the hepatic vein sterically easy for postoperative venous patency.

DOI： 10.1007/s00595-023-02791-w

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

70歳以上のレシピエントにおける生体肝移植(LDLT)の成績を調べるとともに、LDLTの実施可能性を評価した。1997年5月～2022年4月に当院でLDLTを施行された762例を対象とした。LDLTの適応疾患は、C型肝炎による肝硬変が240例、胆汁うっ滞性肝硬変が152例、急性肝不全が86例、アルコール中毒が81例、B型肝炎が63例、非アルコール性脂肪肝炎が53例、自己免疫性肝炎が21例、その他が66例であった。患者を70歳以上の高齢群26例(男性30.8%、平均71.2±1.6歳)と70歳未満の736例(男性45.8%、平均53.2±11.3歳)に分けて比較した。その結果、両群ともLDLT後の30日死亡率および入院期間は同程度であった。高齢群の1年、3年、5年目の移植肝生着率は92.0%であり、これは若年者群の生着率と同程度であった。高齢群のドナーはいずれもレシピエントの子供(平均41.6歳)であり、50歳以上のドナーからの移植例はなかった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver Transplantation  

DOI： 10.1097/LVT.0000000000000308

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Language：Japanese   Publisher：(株)先端医学社  

慢性肝疾患患者では,門脈の血流が障害されることにより門脈圧亢進症を発症しやすく,食道・胃静脈瘤の発生や,脾機能亢進症・脾腫を伴うことで血小板数が低下し出血リスクが高まる.慢性肝疾患患者において,静脈瘤などからの出血予防は生命予後の改善に大きく寄与することから,これらの病態に対する治療として脾臓摘出術や部分的脾動脈塞栓(PSE)が発展してきた.治療機器の開発や手技の工夫により両治療法の治療成績は向上し,安全に施行することが可能となっている.しかし,治療侵襲や合併症を伴うのも事実であるため,患者の状態,施設の特色などから総合的に判断して治療法を選択する必要がある.(著者抄録)

Publisher：日本メディカルセンター  

DOI： 10.19020/cg.0000003026

CiNii Research

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞本邦の肝細胞癌(HCC)に対する肝移植の保険適用(5-5-500基準内あるいはミラノ基準内)は欧米で用いられている基準と比較しても広い基準である.肝細胞癌治療アルゴリズムでは,肝移植はChild-Pugh C症例で同基準内に留まっているものに推奨されている.肝移植後の成績は大変良好であるにもかかわらず,肝予備能が許容されるかぎり,肝切除,焼灼療法,塞栓療法,肝動注,薬物療法などが行われ,肝機能不良となった症例に肝移植が施行される.HCCに対してチロシンキナーゼ阻害剤や免疫チェックポイント阻害剤が使用可能となり,肝移植前のdown stageあるいは移植後再発病変の治療にこれらの薬物療法を使用した報告が見られるようになった.これらの報告とわれわれの経験を概説する.

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver International  

Background & Aims: Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl-CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood. Methods: We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC. Results: Patients were divided into ACSL4-positive (n = 72, 20.1%) and ACSL4-negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α-fetoprotein (p =.0180) and more histological liver fibrosis (p =.0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p <.0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer-associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC. Conclusion: ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer-associated fibroblasts and anti-tumour immunity.

DOI： 10.1111/liv.15839

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Language：Japanese   Publisher：(株)アークメディア  

Publisher：金原出版  

DOI： 10.18888/op.0000003803

CiNii Research

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology and Hepatology Australia  

Aim: Pretreatment peripheral blood markers have value in predicting the treatment outcome of various cancers. In particular, the eosinophil count has recently gained attention. However, no study has reported the influence of the pretreatment eosinophil count on the outcomes of atezolizumab plus bevacizumab (ATZ/BEV), which is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (u-HCC). Methods: We enrolled 114 patients with u-HCC treated with ATZ/BEV (n = 48) or lenvatinib (n = 66). The patients receiving ATZ/BEV or lenvatinib were divided into two groups by calculating the cutoff value of the pretreatment eosinophil count. The groups were compared regarding the clinicopathological characteristics, outcomes, and incidence of adverse events (AEs). Results: Twenty-three of 48 patients (47.9%) who received ATZ/BEV therapy were categorized as the ATZ/BEV-eosinophil-high group, which had better responses than the ATZ/BEV-eosinophil-low group (P = 0.0090). Kaplan–Meier curves revealed a trend toward significantly better progression-free survival (PFS) in the ATZ/BEV-eosinophil-high group than the ATZ/BEV-eosinophil-low group (the median PFS: 4.7 months in the ATZ/BEV-eosinophil-low group vs 12.6 months in the ATZ/BEV-eosinophil-high group; P = 0.0064). Multivariate analysis showed that a low eosinophil count was an independent risk factor for worse PFS after ATZ/BEV therapy (P = 0.0424, hazard ratio: 2.24, 95% confidence interval: 1.02–4.89). AEs (≥ grade 3) were significantly more likely to occur in the ATZ/BEV-eosinophil-high group (P = 0.0285). The outcomes did not significantly differ between the LEN-eosinophil-high group and the LEN-eosinophil-low group. Conclusion: A high pretreatment eosinophil count predicted a better response to ATZ/BEV therapy for u-HCC and was associated with the incidence of AEs (≥ grade 3).

DOI： 10.1111/jgh.16441

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Language：Japanese   Publisher：金原出版(株)  

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Publisher：Journal of Clinical Oncology  

Background: In biliary tract cancer (BTC), TP53 is the most commonly altered gene and may co-occur with KRAS alteration. The presence of a co-alterations in of TP53 and KRAS is associated with poor prognosis in many cancers. In patients (pts) with advanced BTC, the prognostic implications of such co-alterations have not been fully investigated. Methods: This is a pooled analysis of SCRUM-Japan GOZILA and MONSTAR-SCREEN-1 and -2 studies. Genomic profiling was conducted with Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Pts with advanced BTC receiving systemic therapy were included in this study. Results: Among 636 pts with advanced BTC, 85 had TP53/KRAS co-alteration, 293 had TP53, 44 had KRAS, and 214 had neither KRAS nor TP53 alteration (WT/WT). Tumors with TP53 alteration had significantly higher level of tumor mutation burden (TMB) compared to the other groups (3.8 mut/Mb for TP53/KRAS, 5.0 mut/Mb for TP53, 2.8 mut/Mb for KRAS, and 2.5 mut/Mb for WT/WT, respectively, P<0.001). In addition, the frequency of microsatellite instability-high (MSI-High) in the TP53/KRAS group (11.0%) was significantly higher compared to the TP53 group (3.1%, P<0.05), and the WT/WT group (0.6%, P<0.001), respectively. The objective response rate of first-line therapy in the TP53/KRAS group (8.2%) was significantly lower than in the other groups (20.8% for TP53, 23.3% for KRAS, and 19.7% for WT/WT groups, P=0.035). There was no pts treated with durvalumab plus gemcitabine and cisplatin. Two pts with TP53/KRAS alteration and MSI-High received pembrolizumab monotherapy, and partial response was achieved with a progression-free survival of 9.4 and 22.0 months. The median overall survival (OS) for pts treated with first-line therapy of the TP53/KRAS, KRAS, TP53, and WT/WT groups were 13.6 (95% confidence interval [CI], 11.5-15.5), 14.3 (95%CI, 9.7-25.9), 18.8 (95%CI, 16.9-20.6), and 22.7 months (95%CI, 20.4-25.9), respectively. Multivariate analysis identified TP53/KRAS alteration (hazard ratio [HR] 2.14, 95%CI 1.43-3.22, P<0.001), number of detected variants (≥2) (HR 1.50, 95%CI 1.04-2.16, P=0.029), locally advanced (HR 1.72, 95%CI 1.05-2.83, P=0.033), and metastatic status (HR 1.78, 95%CI 1.39-2.28, P<0.001) as independent prognostic factors for shorter OS. Conclusions: Patients with advanced BTC with co-occurring TP53/KRAS alterations have worse prognosis. Interestingly, the presence of these co-alterations was associated with a higher likelihood of MSI-High phenotype.

DOI： 10.1200/JCO.2024.42.3_suppl.538

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Publisher：Journal of Clinical Oncology  

Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.

DOI： 10.1200/JCO.2024.42.3_suppl.544

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Publisher：金原出版  

DOI： 10.18888/op.0000003667

CiNii Research

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s40792-024-01807-y

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

Background: There is limited published information regarding the expression of mechanistic target of rapamycin (mTOR) in vessels that encapsulate tumor cluster (VETC)-positive hepatocellular carcinoma (HCC). The mTOR inhibitor, everolimus, has been approved as an immunosuppressant for use in HCC patients after living donor liver transplantation (LDLT). Methods: Using a database of 214 patients who underwent LDLT for HCC, we examined the mTOR protein and angiopoietin-2 (Ang-2) in VETC-positive HCC by immunohistochemical staining. The presence of VETC and mTOR expression were evaluated in both primary and recurrent HCC lesions. Results: Forty-three of the 214 patients (20.1%) were VETC-positive, and 29 of these 43 patients (67.4%) expressed mTOR. Relative Ang-2 expression was significantly higher in the mTOR-positive than in the mTOR-negative group (p = 0.037). Thirty-four of the 214 patients experienced HCC recurrence after LDLT; 20 of these were operable. The primary lesions of six of these 20 patients were VETC-positive; five of these six patients also had VETC-positive recurrent lesions (p < 0.001). The expression of mTOR was significantly higher in the VETC-positive lesions (p = 0.0018). Conclusions: We showed that mTOR expression was higher in the VETC-positive primary and recurrent lesions than in the VETC-negative ones.

DOI： 10.1002/ags3.12735

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: To clarify the Japan criteria (JC), as proposed in 2019, in order to identify the most appropriate treatment methods for hepatocellular carcinoma (HCC) recurrence and assess the feasibility of pre-living donor liver transplantation (LDLT) downstaging within these criteria. Methods: The subjects of this study were 169 LDLT patients with HCC recurrence. We performed univariate and multivariate analyses of the factors contributing to HCC recurrence after LDLT and clarified the post-transplant outcomes of pre-LDLT downstaging. Results: Univariate and multivariate analysis identified beyond the JC (p = 0.0018) and a neutrophil-to-lymphocyte ratio > 2.01 (p = 0.029) as independent risk factors. Patients who met the JC had significantly higher recurrence-free and overall survival rates after LDLT (p < 0.0001) than those who did not (p = 0.0002). The post-transplant outcomes of patients within the JC after downstaging were significantly better than those of patients beyond the JC (p = 0.034) and equivalent to those within the JC without downstaging. Conclusion: Even for HCC recurrence, the JC could play an important role in deciding on the best treatment strategy, and downstaging within the JC had good post-transplant outcomes.

DOI： 10.1007/s00595-023-02710-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

TP53-induced glycolysis and apoptosis regulator (TIGAR) is an important gene that encodes a regulatory enzyme of glycolysis and reactive oxygen species (ROS) detoxification and is associated with worse prognosis in various cancers. Ferroptosis is a recently identified type of programmed cell death that is triggered by iron-dependent lipid peroxidation. There are no reports on the prognostic impact of TIGAR on intrahepatic cholangiocarcinoma (ICC), and its role in ferroptosis is unclear. Ninety ICC patients who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. The regulation of malignant activity by TIGAR and the association between ferroptosis and TIGAR were investigated in vitro. Twenty-two (24.4%) patients were categorized into TIGAR-high and -low groups by immunohistochemical staining. There were no noticeable differences in background factors between the two groups, but TIGAR positivity was an independent prognostic factor in disease-free survival (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.04–3.85, p = 0.0378) and overall survival (HR, 2.10; 95% CI, 1.03–4.30, p = 0.00422) in a multivariate analysis. In vitro, TIGAR knockdown (KD) decreased cell motility (cell proliferation/migration/invasion/colony-forming capabilities) and elevated ROS and lipid peroxidation. This indicated that TIGAR KD induced ferroptosis. TIGAR KD-induced ferroptosis was suppressed using liproxstatin. TIGAR KD decreased the expression of glutathione peroxidase 4, known as factor-suppressing ferroptosis. The combination of TIGAR KD with cisplatin significantly induced more ferroptosis. In conclusion, TIGAR is associated with poor outcomes in ICC patients and resistance to ferroptosis.

DOI： 10.1111/cas.15981

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: To investigate the prognostic value of the preoperative albumin–lymphocyte–platelet–C-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated the relationship between the ALPC index and the phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels. Methods: Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival and overall survival in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC. Results: A high preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage, and low rate of microscopic intrahepatic metastasis in the training dataset. A high preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. A higher preoperative ALPC index was an independent predictor of longer recurrence-free survival and overall survival in the training and testing datasets. A high ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells. Conclusions: We showed that a high ALPC index was an independent prognostic factor for patients with HCC undergoing curative hepatic resection.

DOI： 10.1111/hepr.13958

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Language：Japanese   Publisher：金原出版(株)  

Language：Japanese   Publisher：(株)アークメディア  

Authorship：Corresponding author   Language：English   Publisher：(一社)日本外科学会  

症例は50歳代男性。非代償性アルコール性肝硬変のため肝移植を希望していた。ドナーはマルファン症候群(MS)に罹患していた50歳代男性で、脳動脈瘤による脳出血のため脳死と判定されていた。本ドナーにはMSに関連した大動脈解離の既往があり、過去に上行弓部大動脈全置換術、大動脈基部置換術、胸部下行大動脈置換術、腹部大動脈置換術、大動脈瘤切除術+人工血管置換術を受けていた。そのため、肝臓を切除する際、人工血管でない正常動脈まで肝臓を切除し、総肝動脈を再建に用いた。術中に肝動脈の生検を行ったところ正常であった。脳死肝移植は問題なく進行し、動脈吻合が完了した。手術時間は621分、出血量は804mlであった。術後経過は良好で、2週間毎日超音波ドップラー検査を行い、吻合血管の血流が正常であることを確認した。重大な術後合併症はみられず、術後18日目に退院した。術後1年経過時点でも全身状態に問題はなかった。

Authorship：Corresponding author   Language：Japanese   Publisher：The Japan Society of Hepatology  

<p>Since April 2022, robot-assisted liver resection has been covered by insurance, and strict institutional standards and guidelines from the Japanese Society of Hepato-Biliary-Pancreatic Surgery and the Japanese Society of Endoscopic Surgery have been proposed for its safe introduction, setting forth the criteria for proctors certified by the societies. Robotic precision surgical techniques are expected to enable safer liver resection. However, several issues must be addressed for widespread use of robot-assisted liver resection, such as overcoming the learning curve of the robotic technique and establishing evidence through prospective case registries in terms of short- and long-term outcomes.</p>

DOI： 10.2957/kanzo.64.595

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Jgh Open  

Background and Aim: Many recent studies have shown a relationship between various systemic diseases and the gut microbiota (GM), with the gut–liver axis receiving particular attention. In contrast, no report has comprehensively shown the effects of GM on the pathophysiology of patients undergoing living donor liver transplantation (LDLT). Method: We enrolled 16 recipients who underwent LDLT for liver cirrhosis, and 17 donors constituted the reference group. We examined the differences in GM between recipients and donors. We also examined the relationships between GM, short-chain fatty acids, and portal vein pressure (PVP) in recipients. Results: There was no significant difference in alpha-diversity between the recipients and donors, but there was variation in beta-diversity among the recipients. The abundance of the phylum Bacteroidetes was significantly higher in recipients than in donors (P = 0.016), and it was positively correlated with PVP (r = 0.511, P = 0.043). Propionic acid, which is a component of short-chain fatty acids, was positively correlated with PVP (r = 0.544, P = 0.0295), the phylum Bacteroidetes (r = 0.677, P = 0.004), and total bilirubin concentration (r = 0.501, P = 0.048). Propionic acid was negatively correlated with serum albumin concentration (r = −0.482, P = 0.043). Conclusion: Our findings suggest relationships between fecal Bacteroidetes levels, propionic acid concentrations, and PVP in patients with liver cirrhosis undergoing LDLT.

DOI： 10.1002/jgh3.13018

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

Purpose: Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. Methods: The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. Results: For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. Conclusion: TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

DOI： 10.1245/s10434-023-14053-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

DOI： 10.1245/s10434-023-14054-6

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

Background: Six-month adjuvant chemotherapy with S-1 is standard care for resected pancreatic cancer in Japan; however, the optimal duration has not been established. We aimed to evaluate the impact of duration of adjuvant chemotherapy with S-1. Methods: We performed a multicenter, randomized, open-label, phase II study. Patients with histologically proven invasive pancreatic ductal carcinoma, pathological stage I–III, and no local residual or microscopic residual tumor were eligible. Patients were randomized 1:1 to receive 6- or 12-month adjuvant chemotherapy with S-1. The primary endpoint was 2-year overall survival (OS). Secondary endpoints were disease-free survival (DFS) and feasibility. Results: A total of 170 patients were randomized (85 per group); the full analysis set was 82 in both groups. Completion rates were 64.7% (6-month group) and 44.0% (12-month group). Two-year OS was 71.5% (6-month group) and 65.4% (12-month group) (hazard ratio (HR): 1.143; 80% confidence interval CI 0.841–1.553; P = 0.5758). Two-year DFS was 46.4% (6-month group) and 44.9% (12-month group) (HR: 1.069; 95% CI 0.727–1.572; P = 0.6448). In patients who completed the regimen, 2-year DFS was 56.5% (6-month group) and 75.0% (12-month group) (HR: 0.586; 95% CI 0.310–1.105; P = 0.0944). Frequent (≥ 5%) grade ≥ 3 adverse events comprised anorexia (10.5% in the 6-month group) and diarrhea (5.3% vs. 5.1%; 6- vs. 12-month group, respectively). Conclusions: In patients with resected pancreatic cancer, 12-month adjuvant chemotherapy with S-1 was not superior to 6-month therapy regarding OS and DFS.

DOI： 10.1007/s10147-023-02399-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Surgeon  

Background: Increasing evidence indicates that increased systemic inflammation is correlated with poorer cancer-specific survival in various cancer types. This study aimed to evaluate the prognostic value of various combinations of inflammatory factors in patients who underwent surgical resection for pancreatic cancer (PC). Methods: We retrospectively analyzed 97 consecutive patients with PC who underwent pancreatectomy. We assessed the predictive impact for recurrence using a combination of 5 inflammatory markers and focused on the lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses using the Cox proportional hazards model. Results: Low preoperative LCR was correlated with low serum hemoglobin, low serum albumin concentration, high frequency of microscopic vascular invasion, and high frequency of microscopic perineural invasion. The low LCR group had significantly worse RFS and OS. Lower preoperative LCR was an independent predictor of shorter RFS and OS in this cohort. Discussion: Preoperative LCR is a novel and convenient prognostic marker for patients with PC. Patients with low LCR may require more favorable intensive therapy.

DOI： 10.1177/00031348221117034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

Background: This study aimed to elucidate the effect of early enteral nutrition on graft loss within 12 h after living-donor liver transplantation (LDLT) using propensity score-matching analysis and subsequently examine the risk factors for graft loss after LDLT. Methods: We retrospectively reviewed the data of 467 LDLT patients who were assigned to the early and non-early groups based on the optimal cutoff value of 12 h for the starting time of early enteral nutrition after LDLT to predict graft loss. Results: The 1-year graft survival rate of the early group before propensity score-matching was 92.1%, whereas the 1-year graft survival rate of the non-early group was 86.2%. There was no significant difference between the 2 groups (P = .067). The incidences of early allograft dysfunction (EAD), small-for-size graft (SFSG) syndrome, acute cellular rejection (ACR), and sepsis were not statistically different between the 2 groups (P = .12, .91, .46, and .056, respectively). After propensity score-matching, the 1-year graft survival rate of the early group was 94.4%, whereas the 1-year graft survival rate of the non-early group was 85.4% (P = .034). The incidences of EAD, SFSG syndrome, and ACR were not statistically different between the 2 groups (P = .43, .81, and .24, respectively). However, the incidence of sepsis was statistically different between the 2 groups (non-early: 10.7% vs early: 3.6%, P = .038). Conclusion: Early enteral nutrition within 12 h after LDLT may contribute to better graft survival in LDLT patients by preventing sepsis.

DOI： 10.1016/j.transproceed.2023.07.029

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

切除後の膵癌患者に対するS-1による術後補助化学療法の効果を投与期間で比較するため、6ヵ月を標準期間として12ヵ月と比較する多施設共同無作為化非盲検第II相試験を実施した。組織学的に浸潤性膵管癌が証明され、病理学的病期がI-III期で、局所残存腫瘍または顕微鏡的残存腫瘍のない患者を適格とし、6ヵ月群82例(60歳以上70例)と12ヵ月群82例(60歳以上76例)を比較した。その結果、レジメン完了率は6ヵ月群が64.7%、12ヵ月群が44.0%であった。2年生存率(OS)は6ヵ月群が71.5%、12ヵ月群が65.4%であった(ハザード比[HR]1.143;80%CI 0.841～1.553;P=0.5758)、2年無病生存率(DFS)はそれぞれ46.4%と44.9%であった(HR 1.069、95%CI 0.727～1.572、P=0.6448)。レジメンを完了した患者の2年DFSは56.5%(6ヵ月群)、75.0%(12ヵ月群)であった。5%以上の頻度で認められたグレード3以上の有害事象は、食欲不振(6ヵ月群で10.5%)および下痢(6ヵ月群と12ヵ月群でそれぞれ5.3%と5.1%)であった。以上より、切除された膵癌患者において、S-1による12ヵ月の術後補助化学療法は、OSとDFSに関して6ヵ月の治療より優れていなかった。

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Asian Journal of Endoscopic Surgery  

Purpose: Textbook outcome (TO) is a novel composite measure of clinical outcomes that can be used to measure the quality of surgical outcomes. The aim of this cohort study was to propose TO criteria for laparoscopic cholecystectomy for acute cholecystitis and to identify reasons for TO failure and individual patient factors that predispose to failure. Methods: We retrospectively analyzed data for 189 patients with acute cholecystitis who underwent laparoscopic cholecystectomy. TO was defined as laparoscopic cholecystectomy without conversion to open cholecystectomy, intraoperative complications, postoperative complications (Clavien–Dindo classification ≥2), prolonged length of stay (≥10 days), readmission within 30 days, or mortality. Results: TO was achieved in 154 of 189 patients who underwent laparoscopic cholecystectomy for acute cholecystitis. Medical costs were lower in the TO-achieved group than in the TO-failure group. Factors associated with TO failure on multivariate analysis were age > 70 years, hemoglobin <11.9 g/dL, and white blood cells >18 000 / μL (all P <.05). Conclusions: Applying TO to patients with acute cholecystitis allowed us to evaluate the overall quality of care related to hospitalization. TO may provide better assessment of the quality of care and help determine the treatment choice and reduce costs.

DOI： 10.1111/ases.13238

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

Autoimmune encephalitis after liver transplantation (LT) is a rare disorder. This is because patients are usually in an immunosuppressed state after LT. Here, we report a rare case of autoantibody-negative autoimmune-encephalitis-induced coma after living-donor (LD) LT. A 45-year-old woman who underwent LDLT for primary biliary cholangitis (PBC) was brought to our hospital with the chief complaint of cognitive deficiency and an episode of memory loss. Physical examination, laboratory tests, and cerebrospinal fluid analysis revealed no significant findings. However, diffusion-weighted magnetic resonance imaging showed hyperintensity in the bilateral hippocampus. No autoantibodies associated with autoimmune encephalitis were detected. The diagnosis of antibody-negative autoimmune encephalitis was made on the basis of low immunosuppressive drug levels in the blood (indicative of poor adherence) and the presence of PBC as the autoimmune disease. The patient regained consciousness after intravenous methylprednisolone pulse therapy and plasma exchange. This case highlights that when examining patients with impaired consciousness after LDLT, it is important to consider autoimmune encephalitis as a potential diagnosis.

DOI： 10.1016/j.transproceed.2023.07.005

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Language：Japanese   Publisher：医学図書出版(株)  

術後膵液瘻(postoperative pancreatic fistula:POPF)は発生頻度の高い膵切除術後合併症であり,適切なタイミングでドレナージを行う必要がある。従来は経皮的ドレナージが主流であったが,近年では内視鏡治療,とくにEUSガイド下経消化管ドレナージ(EUS-guided transluminal drainage:EUS-TD)の報告が増えている。EUS-TDで用いるステントとして,主に経鼻胆道ドレナージチューブ,ダブルピッグテイル型プラスチックステント,lumen-apposing metal stent,などがあり,POPFの部位,大きさ,性状に応じて,適切なステント選択を心がける必要がある。事前に外科医と情報共有のうえで,内視鏡治療にあたることが重要である。(著者抄録)

Language：Japanese   Publisher：(一社)日本肝臓学会  

Language：Japanese   Publisher：(一社)日本肝臓学会  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi:10.1016/j.transproceed.2023.07.029

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Hepato Biliary Pancreatic Sciences  

Purpose: To evaluate the prognostic impact of dynamic gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in patients with hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed the data of 206 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI and hepatectomy and quantitatively evaluated the signal intensity ratio of the tumor to the surrounding liver tissue in the portal phase (SIRPP). We verified the survival rates and assessed the prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS) using SIRPP. Results: Multivariate analysis revealed that the independent predictive factors for poorly-differentiated HCC were α-fetoprotein > 20 ng/mL (hazard ratio [HR]: 3.1909, 95% confidence interval [CI]: 1.3464–7.5622, p =.0084) and SIRPP ≤ 0.85 (HR: 3.7155, 95% CI: 1.521–9.076, p =.004). The 5-year OS and RFS rates in the high and low SIRPP groups were 83.2 and 52.1%, respectively (p <.0001) and 49.7 and 18.5%, respectively (p =.0003). Multivariate analysis revealed that SIRPP ≤ 0.68 was an independent prognostic factor related to OS (HR: 4.4537, 95% CI: 1.6581–11.9626, p =.003). Conclusion: The SIRPP of preoperative Gd-EOB-DTPA-enhanced MRI might predict the histological differentiation and prognosis of HCC.

DOI： 10.1002/jhbp.1345

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Language：Japanese   Publisher：(一社)日本移植学会  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Surgical Case Reports  

Surgical therapy following lenvatinib (LEN) plus transarterial chemoembolization (TACE) is a useful therapeutic option for intermediate-stage hepatocellular carcinoma (HCC). A 66-year-old man with a history of hepatitis C was detected four masses in the caudate lobe and segment 6/7 of the liver, with a maximum lesion diameter of 14 cm by computed tomography. The patient was diagnosed with intermediate-stage HCC and received LEN plus TACE. After resuming LEN for 8 weeks, computed tomography showed weakened stained areas of the tumors, and no new lesions. Thus, the patient was evaluated as having a partial response in the modified Response Evaluation Criteria in Solid Tumors. The patient underwent hepatic caudate lobectomy, partial hepatectomy of S6/7, and S6 microwave coagulation therapy for radical resection. The patient is currently alive and recurrence-free at 12 months postoperatively. In patients with multiple HCC lesions, hepatic resection combined with local therapy might be an effective treatment option.

DOI： 10.1093/jscr/rjad485

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

Background: The hemoglobin–albumin–lymphocyte–platelet (HALP) score is a combination index that assesses nutritional status and systemic inflammatory response and is reported to predict prognosis in several cancer types. However, researches about the usefulness of the HALP score in intrahepatic cholangiocarcinoma (ICC) are limited. Methods: This was a single-center, retrospective study of 95 patients who underwent surgical resection for ICC between 1998 and 2018. We divided patients into two groups by calculating the cutoff value of the HALP score and examined clinicopathological characteristics, prognosis, and sarcopenia. Tumor-infiltrating lymphocytes (TILs), CD8 + TILs, and FOXP3 + TILs were evaluated by immunohistochemical staining of resected tumors. Results: Of 95 patients, 22 were HALP-low. The HALP-low group had significantly lower hemoglobin (p = 0.0007), lower albumin (p = 0.0013), higher platelet counts (p < 0.0001), fewer lymphocytes (p < 0.0001), higher CA19-9 levels (p = 0.0431), and more lymph node metastasis (p = 0.0013). Multivariate analysis revealed that the independent prognostic factors for disease-free survival were maximum tumor size (≥ 5.0 cm) (p = 0.0033), microvascular invasion (p = 0.0108), and HALP score (≤ 25.2) (p = 0.0349), and that factors for overall survival were lymph node metastasis (p = 0.0020) and HALP score (≤ 25.2) (p = 0.0014). The HALP-low group contained significantly more patients with sarcopenia (p = 0.0015). Immunohistochemistry showed that counts of CD8 + TILs were significantly lower in the HALP-low group (p = 0.0075). Conclusions: We demonstrated that low HALP score is an independent prognostic factor for ICC patients undergoing curative hepatic resection and is associated with sarcopenia and the immune microenvironment.

DOI： 10.1007/s10147-023-02358-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1038/s41416-023-02189-y.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Journal of Gastroenterology  

We herein describe three patients with Fontan-associated liver disease who developed hepatocellular carcinoma (HCC). The first patient was a 28-year-old woman who had undergone the Fontan operation (FO) at the age of 4 years. She was diagnosed with HCC (cT4aN0M0, Stage IVA, UICC 8th edition), for which she underwent extended posterior right sectionectomy and partial hepatectomy of S2. She developed recurrence of peritoneal dissemination after 12 months, and she was alive 18 months after surgery. The second patient was a 43-year-old man who had undergone the FO at the age of 3 years. He was diagnosed with HCC (cT2N0M0, Stage II), for which he underwent laparoscopic-assisted partial hepatectomy of S3. He remained free from recurrent HCC for 17 months. The third patient was a 21-year-old woman who had undergone the FO at the age of 3 years. She was diagnosed with HCC (cT3N0M0, Stage III), for which she underwent laparoscopic-assisted partial hepatectomy of S2 and S4. She remained free from recurrent HCC for 30 months. We reviewed 18 surgical cases of HCC arising from Fontan-associated liver disease, including our 3 cases, and found that a high preoperative alpha-fetoprotein concentration might be a predictor of HCC recurrence.

DOI： 10.1007/s12328-023-01795-w

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: We aimed to evaluate the association between the intraoperative indocyanine green (ICG) fluorescence imaging (FI) pattern, preoperative magnetic resonance imaging (MRI) findings using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), preoperative diffusion-weighted imaging (DWI) of MRI, and histological differentiation of hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed the data for 80 tumors of 64 patients. Intraoperative ICG FI patterns were classified into cancerous or rim-positive type. We evaluated the signal intensity ratio of the tumor and the surrounding liver tissue in the portal phase (SIRPP) and intensity in the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced MRI, the apparent diffusion coefficient (ADC) in the DWI of MRI, and clinicopathologic factors. Results: In the rim-positive group, the rate of poorly differentiated HCC and hypointensity type in HBP were significantly higher, and SIRPP and ADC were significantly lower than the rim-negative group. In the cancerous group, the rate of well or moderately differentiated HCC and hyperintensity type in HBP, SIRPP, and ADC were significantly higher than the noncancerous group. Multivariate analysis identified low SIRPP, low ADC, and hypointensity type in HBP as the significant predictive factors for rim-positive HCC and high SIRPP, high ADC, and hyperintensity type in HBP as the significant predictive factors for cancerous HCC. The positive rate of programmed cell death 1-ligand 1 and vessels that encapsulate tumor clusters status of the rim-positive HCC and HCC with low SIRPP were significantly higher than the control group. Conclusions: The intraoperative ICG FI pattern of HCC closely correlated with histological differentiation, preoperative SIRPP and intensity type in the Gd-EOB-DTPA MRI, and preoperative ADC in the DWI of MRI.

DOI： 10.1111/hepr.13902

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Authorship：Corresponding author   Language：English   Publisher：シュプリンガー・ジャパン(株)  

肝細胞癌(HCC)を発症したFontan手術関連肝疾患の3例を報告した。症例1は28歳女性で、4歳時にFontan手術(FO)を受けた。HCC(cT4aN0M0、Stage IVA、UICC第8版)と診断され、拡大右葉後区域切除およびS2の肝部分切除を受けた。術後12ヵ月目に腹膜播種再発が認められ、手術後18ヵ月の時点で存命中である。症例2は43歳男性で、FOを3歳時に受けた。HCC(cT2N0M0、Stage II)と診断され、腹腔鏡補助下S3部分切除を受けた。術後17ヵ月間HCCの再発は認められていない。症例3は21歳女性で、FOを3歳時に受けた。HCC(cT3N0M0、Stage III)と診断され、腹腔鏡補助下S2およびS4肝部分切除を受けた。術後30ヵ月間、HCCの再発は認められていない。Fontan関連肝疾患由来のHCCは、本報の3例を含めこれまで18例報告があり、術前AFP高値がHCC再発の予知因子である可能性が示唆された。

Publisher：南江堂  

DOI： 10.15106/j_geka85_863

CiNii Research

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞開腹肝切除術を安全に施行するためには下大静脈,肝静脈出血を避けることが重要である.出血を低減する備えとして,低中心静脈圧麻酔などの呼吸循環管理や肝流入血遮断が有用である.術中操作として,短肝静脈の引き抜き損傷や肝静脈分枝の股裂損傷を避ける操作が第一である.万一の出血時には,闇雲な熱凝固ではなく,出血点を十分に評価し適切な方法で止血を行うことが重要である.

DOI： 10.1200/JCO.2023.41.16_suppl.4125

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score reflects the immune system and the nutritional status of patients, and prognosis in various cancers. However, the HALP score in hepatocellular carcinoma has not been reported. Methods: Data were analyzed retrospectively from Child–Pugh A patients undergoing hepatic resection for single hepatocellular carcinoma ≤5 cm. For cross-validation, patients were divided into the training (332 patients) and validation cohort (210 patients). In the training cohort, we divided patients into two groups by appropriate cut-off value of the HALP score, and univariable and multivariable analyses were conducted for disease-free and overall survival (OS) between two groups. In the validation cohort, we examined OS by Kaplan–Meier analysis in the same cut-off value of the HALP score in the training cohort. Results: The HALP-low group was significantly older (p = 0.0003), had fewer hepatitis B surface antigen-positive patients (p = 0.0369), higher prothrombin time (p = 0.0141), lower fibrosis-4 index (p = 0.0206), bigger maximum tumor size (p = 0.0196), and less histological liver fibrosis (p = 0.0077). Multivariate analysis showed that the independent prognostic factors for disease-free survival were fibrosis-4 index ≥2.67 (p = 0.0008), simple nodular type with extranodular growth or confluent multinodular type (p = 0.0221), and intrahepatic metastasis (p = 0.0233), and that for OS were fibrosis-4 index ≥2.67 (p = 0.0020), HALP ≤45.6 (p = 0.0228), and poor differentiation (p = 0.0305). In the validation cohort, Kaplan–Meier analysis revealed the trend toward significantly impaired OS (p = 0.0220) in the HALP-low group. Conclusion: We showed that a low HALP score is the independent prognostic factor for Child–Pugh A patients undergoing curative hepatic resection for single and small hepatocellular carcinoma.

DOI： 10.1111/hepr.13885

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Surgical Oncology  

Background: Signal regulatory protein alpha (SIRPα), expressed in the macrophage membrane, inhibits phagocytosis of tumor cells via CD47/SIRPα interaction, which acts as an immune checkpoint factor in cancers. This study aimed to clarify the clinical significance of SIRPα expression in hepatocellular carcinoma (HCC). Methods: This study analyzed SIRPα expression using RNA sequencing data of 372 HCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of our 189 HCC patient cohort. The correlation between SIRPα expression and clinicopathologic factors, patient survival, and intratumor infiltration of immune cells was investigated. Results: Overall survival (OS) was significantly poorer with high SIRPα expression than with low expression in both TCGA and our cohort. High SIRPα expression correlated with lower recurrence-free survival (RFS) in our cohort. High SIRPα expression was associated with higher rates of microvascular invasion and lower serum albumin levels and correlated with greater intratumor infiltration of CD68-positive macrophages and myeloid-derived suppressor cells (MDSCs). Multivariate analysis showed that SIRPα expression and high infiltration of CD8-positive T cells and MDSCs were predictive factors for both RFS and OS. Patients with high SIRPα expression and infiltration of CD8-positive T cells and MDSCs had significantly lower RFS and OS rates. In spatial transcriptomics sequencing, SIRPα expression was significantly correlated with CD163 expression. Conclusions: High SIRPα expression in HCC indicates poor prognosis, possibly by inhibiting macrophage phagocytosis of tumor cells, promoting MDSC infiltration and inducing antitumor immunity. Treatment alternatives using SIRPα blockage should be considered in HCC as inhibiting macrophage antitumor immunity and MDSCs.

DOI： 10.1245/s10434-022-13058-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Surgeon  

Backgroud: The systemic inflammation score (SIS), which is based on the preoperative lymphocyte-to-monocyte ratio (LMR) and serum albumin (Alb) level, is a prognostic indicator for several cancer types. However, the prognostic significance of the SIS in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: Seventy-eight patients who underwent radical surgery for PDAC were categorized as follows: SIS 0 (LMR ≥3.51 and Alb ≥4.0 g/dl), n = 26; SIS 1 (LMR <3.51 or Alb <4.0 g/dl), n = 29 and SIS 2 (LMR <3.51 and Alb <4.0 g/dl), n=23. Results: The tumour size sequentially increased in SIS 0, 1 and 2 groups. A higher SIS was associated with increased vascular invasion, perineural invasion and surgical margin positivity rate. Recurrence-free survival (RFS) rates between the SIS 1 and 2 groups showed no significant difference However, patients of the SIS 1 and 2 groups had poorer outcomes than those of the SIS 0 group for RFS. Overall survival (OS) rates between the SIS 1 and 2 groups also showed no significant difference. However, patients of the SIS 1 and 2 groups had poorer outcomes than those of the SIS 0 group for OS. The SIS was an independent prognostic factor for RFS and OS. Discussion: The SIS is a simplified prognostic factor for patients with PDAC.

DOI： 10.1177/00031348221086782

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Cellular and Infection Microbiology  

Introduction: We examined the neutralizing antibody production efficiency of the second and third severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine doses (2^nd- and 3^rd-dose) and neutralizing activity on mutant strains, including, the Ancestral, Beta and Omicron strains using green fluorescent protein-carrying recombinant SARS-CoV-2, in living-donor liver transplantation (LDLT) recipients. Methods: The patients who were administered vaccines other than Pfizer- BioNTechBNT162b2 and who had coronavirus disease 2019 in this study period were excluded. We enrolled 154 LDLT recipients and 50 healthy controls. Result: The median time were 21 days (between 1^st and 2^nd vaccination) and 244 days (between 2^nd and 3^rd vaccination). The median neutralizing antibody titer after 2^nd-dose was lower in LDLT recipients than in controls (0.46 vs 1.00, P<0.0001). All controls had SARS-CoV-2 neutralizing antibodies, whereas 39 LDLT recipients (25.3%) had no neutralizing antibodies after 2^nd-dose; age at vaccination, presence of ascites, multiple immunosuppressive treatments, and mycophenolate mofetil treatment were significant risk factors for nonresponder. The neutralizing activities of recipient sera were approximately 3-fold and 5-fold lower than those of control sera against the Ancestral and Beta strains, respectively. The median antibody titer after 3^rd-dose was not significantly different between recipients and controls (1.02 vs 1.22, p=0.0758); only 5% recipients was non-responder. The neutralizing activity after third dose to Omicron strains were enhanced and had no significant difference between two groups. Conclusion: Only the 2nd-dose was not sufficiently effective in recipients; however, 3rd-dose had sufficient neutralizing activity against the mutant strain and was as effective as that in healthy controls.

DOI： 10.3389/fcimb.2023.1197349

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.3389/fcimb.2023.1197349

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aims: The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor-infiltrating lymphocytes (TILs). Methods and Results: We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n = 18) and negative (n = 74) FGFR2 groups. The FGFR2-positive group contained more men (p < 0.0001) and had lower serum albumin (p = 0.0355) and higher carcinoembryonic antigen (p = 0.0099). Furthermore, multivariable analyses revealed that the FGFR2-positive group had worse disease-free survival (DFS) (p = 0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5 cm) (p = 0.0011), tumor localization (perihilar type) (p = 0.0180), and FGFR2 positivity (p = 0.0029). There was no significant difference in TILs count between the two groups. Conclusion: We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC.

DOI： 10.1111/hepr.13875

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Publisher：南江堂  

DOI： 10.15106/j_geka85_489

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Cancer  

Background: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. Methods: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. Results: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). Conclusion: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

DOI： 10.1038/s41416-023-02189-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Journal of Gastroenterology  

A combined therapy of atezolizumab and bevacizumab (atezo/bev) is used as the first-line treatment for unresectable hepatocellular carcinoma (HCC). In this study, we report the case of curative hepatic resection in a 77-year-old man who initially had unresectable advanced-stage HCC with lung metastases. This rare hepatectomy conversion was owing to the administration of atezo/bev. Notwithstanding the side effects of immune-related adverse event hepatitis and intratumoral hemorrhage developed during atezo/bev treatment; after seven treatment cycles, the patient’s tumor markers normalized, the tumor shrank markedly, and the metastasis disappeared. Subsequently, conversion therapy with hepatic resection was performed, and pathology confirmed complete tumor necrosis. No cancer recurrence was observed at the 8-month postoperative follow-up, and the patient remained drug free.

DOI： 10.1007/s12328-022-01744-z

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞臓器移植において免疫抑制は必須であり,易感染性の宿主に対して,免疫抑制下の感染症対策が非常に重要である.本稿では,肝移植後の免疫抑制下における感染症対策について,細菌性感染症,ウイルス性感染症,真菌性感染症に関してそれぞれ概説した.

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

The association between tumor microenvironment (TME) and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC) progression is poorly understood. This study aimed to reveal whether specific microRNAs (miRNAs) in extracellular vesicles (EVs) derived from CAFs were involved in ICC progression. Conditioned medium (CM) and EVs in the CM of CAFs and normal fibroblasts (NFs) derived from ICC specimens were used to investigate the effects on tumor cell lines. miRNA microarray assay was used to examine the miRNAs of EVs derived from CAFs and NFs in ICC, and the effects of miR-493-5p on tumor cell lines were examined. Additionally, databases were used to identify miR-493-5p targets, and the relationship between prognosis of ICC patients and cocaine- and amphetamine-regulated transcript propeptide (CARTPT), one of the targets of miR-493-5p, expression in ICC tissues was retrospectively analyzed. Compared with NF-derived CM and EVs, CAF-derived CM and EVs promoted cell lines in proliferation, scratch, migration, and invasion assays. miRNA microarray analysis revealed that miR-493-5p was significantly increased in CAF-derived EVs compared to NF-derived EVs. Tumor cell lines transfected with miR-493-5p were promoted in proliferation and scratch assays. Immunohistochemical staining was performed on 76 ICC specimens; both overall and recurrence-free survival rates were significantly worse in the CARTPT-negative group. Univariate and multivariate analyses showed that low CARTPT expression was an independent poor prognostic factor for overall and recurrence-free survival. Overall, our data suggest that CAFs in the ICC TME suppress CARTPT in tumor cells and promote tumor cells via miR-493-5p in EVs.

DOI： 10.1111/cas.15644

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：大道学館出版部  

食道癌手術症例における入院前周術期支援の介入の有無と術後合併症との関連について検討し、入院前周術期支援の有用性について検証した。2018年4月～2020年9月にかけて、食道癌手術症例120例を、入院前周術期支援を開始した2019年10月前後で入院時支援介入なし群75例と介入あり群45例に分類した。術後合併症は全体で51例(43%)に認められ、内容としては最多が肺炎で16例(13.9%)、嚥下障害・反回神経麻痺が14例(12.2%)、不整脈8例(7.0%)であった。介入なし群での合併症頻度は75例中37例(49%)であったのに対して、介入あり群で45例中14例(31%)と介入あり群の方が合併症の発生頻度が低かった。周術期支援による術後合併症の減少が示唆される結果が得られ、他癌腫への応用も視野に、周術期支援の充実を図ることが重要と考えられた。

Publisher：金原出版  

DOI： 10.18888/op.0000003119

CiNii Research

Authorship：Corresponding author   Language：Japanese   Publisher：The Japan Society of Hepatology  

<p>To organize the current status and understanding of liver resection in the treatment of hepatocellular carcinoma, a questionnaire survey was conducted. The Kyushu Liver Surgery Study Group was sponsoring 15 institutions including hepatologists and liver surgeons. Regarding the excision borderline, hepatologists felt limited by numbers and Vps, while surgeons felt limited by Vvs. In the case of BCLC-B, hepatologists had few choices for resection even if the treatment succeeded. Surgeons chose treatment for the conversion surgery attempt in the case of portal vein proximity, but hepatologists chose resection as a result after successful treatment. For the conversion attempt, most hepatologists hoped to use drug therapy or local treatment. It has become clear that hepatologists and surgeons must further change their mindset to perform hepatic resection and local or systemic therapy in the treatment of hepatocellular cancer.</p>

DOI： 10.2957/kanzo.64.1

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1016/j.transproceed.2022.09.031

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1111/hepr.13834

Language：English  

Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide, and the mortality rate of patients with unresectable HCC is very high. Microsatellite instability (MSI) is an essential biomarker for response to immune checkpoint inhibitors (ICI) in various tumors. However, the frequency of MSI in HCC is low (1.11%). There is only one case report of MSI-high HCC, and it is not well understood how high MSI affects the tumor microenvironment of HCC. Hence, we describe an interesting patient with unresectable MSI-high HCC, including the evaluation of immune status in the tumor microenvironment. A 68-year-old man presented to our department with HCC in liver segment 1. Contrast-enhanced CT revealed a liver tumor of 6.0 cm in maximum size. The patient underwent extended left and caudate lobectomy of the liver for HCC. Four months after surgical resection, contrast-enhanced computed tomography (CECT) detected 13 recurrent nodules. The patient was diagnosed with unresectable hepatocellular carcinoma recurrence, and we decided to administer systematic chemotherapy. Lenvatinib was administered over approximately 2 years as a first-line treatment, which resulted in intrahepatic tumor shrinkage. However, follow-up CECT showed new lesions, hepatogastric mesentery lymph node swelling, and peritoneal dissemination. After MSI-high status was identified, the patient began to receive pembrolizumab (200 mg, every 3 weeks). Eleven cycles of pembrolizumab therapy were administered over approximately 8 months, during which the diameter of the hepatogastric mesentery lymph node swelling and peritoneal dissemination showed shrinkage but later re-increased. As the third- and fourth-line therapy has been administered, the tumors and lymph nodes have shrunk. We report a rare case in which multikinase inhibitors were effectively used to treat MSI-high HCC.

DOI： 10.1007/s13691-022-00585-4

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PubMed

Language：Japanese   Publisher：金原出版(株)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Although the survival rate after living-donor liver transplantation (LDLT) is improving, sepsis still limits the prognosis. Immune dysfunction and sarcopenia are often observed in LDLT patients, and increase susceptibility to infection. Brain-derived neurotrophic factor (BDNF) is a myokine produced by immune cells and skeletal muscle. We aimed to determine whether serum BDNF could be a feasible biomarker for sepsis of LDLT patients. Methods: We measured serum samples from 124 patients who underwent LDLT and 9 healthy volunteers for BDNF. We examined its correlation with incidence rate of sepsis. To clarify the source of BDNF, we examined its expression in lymphocytes, skeletal muscle cells, and hepatocytes. Results: Patients who experienced sepsis showed worse short-term survival. Preoperative serum BDNF was lower in LDLT patients compared with healthy volunteers, and was also lower in Child–Pugh C compared with Child–Pugh A or B. Serum BDNF was inversely correlated with Model for End-Stage Liver Disease and controlling nutritional status (CONUT) scores, but had a weak positive correlation with skeletal muscle mass index (SMI). Multivariate analysis revealed that serum BDNF was independently associated with sepsis. Preoperative serum BDNF was a better predictor of sepsis in LDLT patients than CONUT score or SMI. Serum BDNF was positively correlated with lymphocyte counts, especially T cells. In vitro, T cells and skeletal muscle cells produced BDNF. Conclusions: Preoperative serum BDNF could be a predictive biomarker for sepsis after LDLT, by reflecting the systemic condition including hepatic function, nutritional status, and immune status.

DOI： 10.1111/hepr.13834

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Authorship：Corresponding author   Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は68歳男性で、肝S1の肝細胞癌について造影CTで最大径6.0cmの腫瘤を認めた。拡大肝左葉切除術と尾状葉切除術を施行した。病理診断では中・低分化型肝細胞癌で、脈管侵襲や肝内転移は認めなかった。手術標本ではプログラム細胞死リガンド-1の高発現とCD8陽性T細胞の存在を認め、腫瘍浸潤性マクロファージが多数観察された。切除4ヵ月後、造影CTで13個の再発結節を認めた。切除不能な肝細胞癌の再発と診断し、系統的な化学療法を行うことにした。一次治療としてレンバチニブを約2年間投与し、肝内腫瘍の縮小を認めた。しかし、経過観察の造影CTで新たな病変、肝胃腸間膜リンパ節腫脹、腹膜播種を認めた。高頻度マイクロサテライト不安定性(MSI-high)が検出されたため、ペムブロリズマブ(200mg、3週ごと)の投与を開始した。約8ヵ月間で11サイクルのペムブロリズマブ療法を施行した結果、肝胃腸間膜リンパ節腫脹と腹膜播種径は縮小したが、その後に再び増加した。三次治療としてソラフェニブを投与したところ、病変は一旦縮小したが、皮疹(グレード3)を認めたため、治療を中止した。さらに、四次治療としてカボザンチニブを8ヵ月間投与した。その結果、腫瘍とリンパ節腫脹が縮小した。MSI-highの肝細胞癌に対してマルチキナーゼ阻害剤が有効であった。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

Recurrence of hepatocellular carcinoma (HCC) after living donor liver transplant (LDLT) is an essential factor defining prognosis, and surgical resection is the only curative treatment. However, the factors that define whether surgical resection is possible remain unclear. Here, we compared resectable and unresectable HCC recurrence cases after LDLT and examined factors that determine whether surgical resection is possible. Resectable (n = 17) and unresectable (n = 14) groups among 264 patients who underwent LDLT for HCC from January 1999 to March 2020 were compared and examined for recurrence type, prognosis, and clinicopathologic factors. Overall survival after LDLT (median, 8.5 vs 1.7 years, P < .01) was significantly longer in the resectable group. In univariate analysis, female recipient rate, lymphocyte to monocyte ratio (LMR) ≥2.75, and tumor size ≤5.0 cm were significantly higher in the resectable group. Younger donors, lower Model for End-Stage Liver Disease scores, lower graft volume, and lower graft volume to standard liver volume ratio were evident in the resectable group. In multivariate analysis, female recipient rate (P = .0034) and LMR ≥2.75 (P = .0203) were independent predictive factors for resectable HCC recurrence after LDLT. Female recipient and LMR ≥2.75 before transplant could predict the surgically resectable type of HCC recurrence after LDLT.

DOI： 10.1016/j.transproceed.2022.09.031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplant International  

The recipient muscle status is closely associated with postoperative poor survival in recipients of living donor liver transplantation (LDLT). However, it is uncertain whether LDLT donor muscle quality and quantity affect graft quality. Hence, we analyzed the correlation between donor muscle status and graft function. We measured the skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) of 380 LDLT donors. We examined the correlation between donor SMI or IMAC and graft mortality, the occurrence rates of small-for-size graft (SFSG) syndrome, and 6-month graft survival rates. The donor SMI had no effect on the occurrence of SFSG syndrome and graft survival, while a high IMAC in both male and female donors was significantly correlated with the rate of SFSG syndrome [high vs low: (male donors) 15.8% vs. 2.5%, p = 0.0003; (female donors) 12.8% vs. 3.1%, p = 0.0234] and 6-month graft survival rates [(male donors) 87.7% vs 95.9%, p = 0.02; (female donors) 83.0% vs. 99.0%, p < 0.0001]. Multivariate analysis revealed that a high donor IMAC (HR; 5.42, CI; 2.13–13.8, p = 0.0004) was an independent risk factor for 6-month graft survival, and the donor IMAC is useful for donor selection for high-risk recipients.

DOI： 10.3389/ti.2022.10723

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Publisher：南江堂  

DOI： 10.15106/j_geka84_1362

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

Although there have been a few liver transplantations (LTs) between identical twins, to our knowledge hepatic damage after LT in an immunosuppressant-free patient has not been reported. Autoimmune liver disease recurrence after LT is also a postoperative problem. In this follow-up to our previous report, we present the case of a 57-year-old man with acute liver failure who underwent living donor liver transplantation (LDLT) from an identical twin. Six months after LDLT, the patient was free from immunosuppressive medication and showed good liver function. However, 1 year after LDLT, he developed liver damage and was diagnosed with autoimmune hepatitis by liver biopsy. His liver function was improved with steroid pulse therapy and the resumption of immunosuppressive medications. Even after LDLT from an identical twin, careful management is required for patients to remain free of immunosuppressive medications, considering the background liver disease.

DOI： 10.1016/j.transproceed.2022.09.022

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞肝硬変を伴う肝癌患者は,蛋白質・エネルギー栄養障害を合併するため周術期合併症発生リスクが高く,術前栄養評価を行うことがきわめて重要である.新たな評価法として血液細胞成分や炎症反応指標,サルコペニアによる評価の有用性が近年明らかとなった.従来の栄養療法に加えてL-カルニチンやω-3脂肪酸を併用して栄養状態の改善を図ることで,術後合併症の予防,さらには予後の改善が期待できる.

Language：Japanese   Publisher：日本消化器病学会-九州支部  

Language：Japanese   Publisher：日本消化器病学会-九州支部  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Targeted Oncology  

Background: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear. Objective: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC. Patients and Methods: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed. Results: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007). Conclusions: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN.

DOI： 10.1007/s11523-022-00921-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Clinical Oncology  

Background: There is little evidence concerning survival after surgery in patients with hepatocellular carcinoma who have received lenvatinib treatment. The aim of this study was to evaluate whether post-lenvatinib surgical treatment in patients with hepatocellular carcinoma improves overall survival. Methods: The cohort of this retrospective study comprised 55 patients with hepatocellular carcinoma who had undergone lenvatinib treatment. We classified them into two groups according to post-lenvatinib surgical treatment status and compared clinicopathologic factors and prognosis between the two groups with the aim of identifying predictors of overall survival. Results: The median duration of lenvatinib administration was 5.8 months (range, 0.4–24.0 months). Twelve of the 55 patients underwent surgery after receiving lenvatinib. There was no significant difference in assessed clinicopathological factors between patients who did and did not undergo surgery after being treated with lenvatinib. Multivariate analysis revealed that older age was associated with a significantly worse overall survival (hazard ratio: 2.332; 95% confidence interval 1.062–5.168; P = 0.0369) and that surgery after treatment with lenvatinib achieved better overall survival than other forms of treatment (hazard ratio: 0.121; 95% confidence interval 0.016–0.901; P = 0.0393). Conclusions: Surgical treatment after lenvatinib administration may be a useful therapeutic option for select patients with hepatocellular carcinoma.

DOI： 10.1007/s10147-022-02229-2

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Congenital portosystemic shunt is an infrequent abnormal connection between the portal vascular system and the systemic circulation. Portosystemic shunts are common findings in patients with cirrhosis, causing gastroesophageal varices, hepatic encephalopathy, and others. However, there is no consensus or literature describing how to manage asymptomatic patients with portosystemic shunts and normal liver. CASE PRESENTATION: The patient was a 39-year-old female who underwent donor right hepatectomy for living donor liver transplantation. The patient was healthy by nature, however, developed hepatic encephalopathy after the surgery due to a development of portosystemic shunt. Portosystemic shunt stole portal blood flow, and imaging modalities revealed narrowing of the portal trunk, representing prolonged depletion of portal blood flow. Balloon-occluded retrograde transvenous obliteration (B-RTO) was performed for occlusion of the portosystemic shunt. B-RTO increased portal blood flow, and hepatic encephalopathy with hyperammonemia was successfully resolved without the outbreak of any other symptom of portal hypertension. CONCLUSIONS: A congenital portosystemic shunt itself is not a contraindication for donor hepatectomy, but perioperative endovascular shunts occlusion or intraoperative ligature of these shunts should be considered.

DOI： 10.1186/s40792-022-01533-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Surgical Case Reports  

The case is a 78-year-old female. A giant liver cyst was pointed out by abdominal echo from 7 years ago, but because the size of the cyst tended to increase, it was decided to operate taking into account the risk of the cyst rupturing. Laparoscopic surgery was started, and the cyst contents did not fluorescent when observed by the indocyanine green (ICG) fluorescence method. Laparoscopic liver cyst fenestration was performed using the ICG fluorescence method, paying attention to the damage to the bile duct excluded by the cyst. The opened cyst was filled with the greater omentum. In this report, we describe that the ICG fluorescence method can evaluate the presence or absence of bile leakage from the hepatic dissection and the running of the bile duct on the inner wall of the cyst, and is considered to contribute to safer laparoscopic liver cyst fenestration.

DOI： 10.1093/jscr/rjac479

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Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   Publisher：Hepatology Communications  

The quality and size of liver grafts are critical factors that influence living-donor liver transplantation (LDLT) function and safety. However, the biomarkers used for predicting graft quality are lacking. In this study, we sought to identify unique graft quality markers, aside from donor age, by using the livers of non-human primates. Hepatic gene microarray expression data from young and elderly cynomolgus macaques revealed a total of 271 genes with significantly increased expression in the elderly. These candidate genes were then narrowed down to six through bioinformatics analyses. The expression patterns of these candidate genes in human donor liver tissues were subsequently examined. Importantly, we found that grafts exhibiting up-regulated expression of these six candidate genes were associated with an increased incidence of liver graft failure. Multivariable analysis further revealed that up-regulated expression of LRRN2 (encoding leucine-rich repeat protein, neuronal 2) in donor liver tissue served as an independent risk factor for graft failure (odds ratio 4.50, confidence interval 2.08–9.72). Stratification based on graft expression of LRRN2 and donor age was also significantly associated with 6-month graft survival rates. Conclusion: Up-regulated LRRN2 expression of liver graft is significantly correlated with graft failure in LDLT. In addition, combination of graft LRRN2 expression and donor age may represent a promising marker for predicting LDLT graft quality.

DOI： 10.1002/hep4.2033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Liver transplantation (LT) is the only curative therapy for decompensated liver cirrhosis. For recipients of living donor LT (LDLT), restoration of liver function after transplantation is highly dependent on liver regenerative capacity, which requires large amounts of intracellular energy. Mitochondrial metabolism provides a stable supply of adenosine 5′-triphosphate (ATP) for liver regeneration. Mitophagy is a selective process in which damaged, non-functional mitochondria are degraded and replaced with new functional mitochondria. We investigated the relationship between expression of Syntaxin17 (STX17), a key protein in mitophagy regulation, in donor livers and graft survival. Methods: We examined STX17 expression in grafts from 143 LDLT donors who underwent right lobe resection and investigated the relationship between STX17 expression and graft function. We investigated the correlations among STX17 expression, mitochondrial membrane potential and cell proliferation, using a STX17-knockdown hepatocyte cell line. Results: Recipients transplanted with low STX17-expression grafts had significantly lower graft survival rates than recipients transplanted with high STX17-expression grafts (88.9% vs. 100%, p < 0.01). Multivariate analysis showed that low STX17 expression (HR: 10.7, CI: 1.29–88.0, p < 0.05) and the absence of splenectomy (HR: 6.27, CI: 1.59–24.8, p < 0.01) were independent predictive factors for small-for-size graft syndrome, which is the severe complication in LDLT. In the vitro experiments, the percentage of depolarized damaged mitochondria was increased in the STX17-knockdown hepatocyte cell line, suggesting decreased mitophagy and ATP synthesis. Cell proliferation was significantly decreased in the STX17-knockdown hepatocyte cell line. Conclusion: STX17 contributes to mitophagy and maintenance of mitochondrial function in hepatocytes and may be a predictor of graft dysfunction in LDLT patients.

DOI： 10.1111/hepr.13809

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Language：English   Publisher：(一社)日本外科学会  

症例は39歳女性で、生体移植のためにドナー肝切除を施行された。合併症はなく、術前MD-CTでは残肝容積は429mL(40.5%)を示し、先天性門脈体循環シャントの拡張が認められた。シャント径は9cmに及び、左胃静脈(LGV)から左腎静脈(LRV)への流入を認めたが、臨床検査所見に異常はなかった。術中所見では肝臓の外観は正常であり、手術時間は320分、推定出血量は245mLで術後経過は良好であった。しかし、術後9日目、活動量低下と記憶障害をきたし、軽度脳症と全身性血中アンモニア高値が検出された。MD-CTでは明らかな門脈血栓はみられなかったが、門脈幹の狭小化と門脈血流の低下を認め、先天性門脈体循環シャントへの盗血が疑われた。さらに、プロトロンビン時間-国際標準化比(PT-INR)とD-ダイマーの上昇が確認されたことから、門脈血流不良による門脈微小血栓の存在が示唆された。このため、右大腿静脈アプローチによるバルーン閉塞下逆行性経静脈的塞栓術(B-RTO)を行うこととし、門脈圧を13mmHgに設定してLGV-LRVシャントを閉塞した。術後、肝性脳症と高アンモニア血症の改善が得られ、PT-INRも正常化しB-RTO施行後9日目に退院となった。6ヵ月後のMD-CTでは門脈幹の拡大と残肝の再生促進が得られていた。

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Annals of Gastroenterological Surgery  

Aim: This study aimed to clarify the clinical effects of the indocyanine green (ICG)-fluorescence imaging (FI) technique for determination of liver transection lines during laparoscopic partial liver resection for liver tumors. Methods: This was a retrospective study including 112 patients who underwent laparoscopic partial liver resection for liver tumors. These enrolled patients were divided into an ICG-FI group (n = 55) and a non-ICG-FI group (n = 57) according to the availability of the ICG-FI. The clinicopathological characteristics of patients between two groups were compared before and after propensity score matching. Results: The ICG-FI and non-ICG-FI groups differed at baseline in terms of ICG retention rate at 15 min. After propensity score matching, two comparable groups of 32 patients each were obtained. The negativity rated of the pathological surgical margins were comparable between the two groups before and after propensity score matching. However, the surgical margins were significantly wider in the ICG-FI group before and after propensity score matching (P =.039 and P =.047, respectively). Conclusion: The ICG-fluorescence imaging technique may offer clinical benefits in terms of a secure surgical margin in laparoscopic partial liver resection.

DOI： 10.1002/ags3.12563

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular and Clinical Oncology  

The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarci-noma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.

DOI： 10.3892/mco.2022.2564

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Transplantation  

Aim: Recently, new diagnostic criteria for acute-on-chronic liver failure (ACLF) were established in Japan. However, there is little evidence regarding the feasibility of classifying patients undergoing living-donor liver transplantation (LDLT). The aim was to re-evaluate the impact of these new diagnostic criteria on ACLF and the severity classification of patients undergoing LDLT. Methods: We collected data of 82 recipients who underwent LDLT for liver failure between 1997 and 2020 and reviewed it retrospectively. Results: Of the 82 patients with liver failure, 31 (37.8%) were diagnosed with ACLF; Grade 0 (n = 6), Grade 1 (n = 7), Grade 2 (n = 9), and Grade 3 (n = 9). There was no substantial difference in overall survival (OS) and the occurrence of postoperative complications between liver failure patients with and without ACLF. The OS after LDLT was significantly different among the four groups of ACLF patients (P =.036). Interestingly, ACLF Grade 3 patients had substantially lower OS compared to other ACLF groups even after LDLT (P =.006; 5-year OS rates, 33.3% vs. 85.9%). Conclusion: Proper use of the new diagnostic criteria for ACLF in Japan demonstrated that the presence and severity of ACLF, especially the presence of multiple organ failures, leads to morbidity and mortality even in an LDLT setting. Considering that the patients with ACLF Grade 3 do not have the favorable outcomes of LDLT, deceased-donor liver transplantation usage, or LDLT before reaching the severity of Grade 3 may be suitable for further research.

DOI： 10.1111/ctr.14739

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Language：Japanese   Publisher：金原出版(株)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid-derived 2-like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib-induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib-induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor-4 (FGFR4) or Nrf2 and overexpressing-Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system X<inf>c</inf>⁻ (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing-FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2-silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2-overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low-FGFR4 expression than in those with high-FGFR4 expression. Patients with FGFR4-positive HCC displayed significantly longer progression-free survival than those with FGFR4-negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.

DOI： 10.1111/cas.15378

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Authorship：Corresponding author   Language：English   Publisher：John Wiley & Sons Australia, Ltd  

肝細胞癌において、チロシンキナーゼ阻害剤レンバチニブによる細胞毒性のメカニズムや核因子赤芽球2関連因子2(Nrf2)の関与を検討した。肝細胞癌由来のHep3BおよびHuH7細胞にて、レンバチニブはシステムXc(xCT)とグルタチオンペルオキシダーゼ4(GPX4)の発現を抑制した。xCTとGPX4のシスチン取り込み活性を阻害すると、脂質活性酸素種(ROS)が蓄積された。FGFR4をサイレンシングすると、xCTとGPX4の発現が抑制され、脂質ROSレベルが増加した。Nrf2をサイレンシングした肝細胞癌細胞は、レンバチニブに対して感受性を示し、脂質ROSレベルが亢進した。Nrf2を発現する肝細胞癌細胞では、レンバチニブに対して抵抗性を示し、脂質ROSレベルは低かった。FGFR4が低発現の再発肝細胞癌病変に対するレンバチニブの有効性はFGFR4が高発現している病変に比べて有意に低かった。FGFR4陽性肝細胞癌の患者では、FGFR4陰性肝細胞癌の患者よりも無増悪生存期間が有意に長かった。レンバチニブは、FGFR4を阻害することによってフェロプトーシスを誘導した。以上より、Nrf2は肝細胞癌のレンバチニブに対する感受性に関与していた。

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Jgh Open  

Background and Aim: Sarcopenia has received much attention as a poor prognostic factor in various fields, and has also been reported to worsen prognosis in patients with hepatocellular carcinoma (HCC) treated with sorafenib or lenvatinib (LEN). Atezolizumab/bevacizumab (ATZ/BEV) is recommended as first-line drug therapy for unresectable-HCC, but the effect of sarcopenia on patients treated with ATZ/BEV is unknown. Methods: We enrolled 98 patients treated with ATZ/BEV or LEN. Computed tomography performed before the initiation of drug therapy was used to diagnose sarcopenia in accordance with the criteria proposed by the Japanese Society of Hepatology. Patients were divided into two groups based on the presence or absence of sarcopenia in each regimen, and patient characteristics, adverse events, and prognosis were compared. Results: In ATZ/BEV therapy, 57.1% of patients had sarcopenia. The sarcopenia group had significantly more women (P = 0.0125) and more macroscopic vascular invasion (P = 0.0270). Sarcopenia had no significant effect on progression-free survival (PFS) and overall survival (OS). In LEN therapy, 63.4% of patients had sarcopenia. The sarcopenia group was significantly older (P = 0.0064) and had a higher number of women (P = 0.0003), a higher neutrophil–lymphocyte ratio (P = 0.0222), worse albumin–bilirubin grade (P = 0.0087), and worse best response (P = 0.0255). PFS (P = 0.0091) and OS (P = 0.0006) were worse in the sarcopenia group. In multivariate analysis, age (P = 0.0362), lymphocyte–monocyte ratio (P = 0.0365), and sarcopenia (P = 0.0268) were independent prognostic factors for OS. Conclusion: In ATZ/BEV therapy, sarcopenia does not determine prognosis, and therapeutic efficacy can be expected even in cases of sarcopenia.

DOI： 10.1002/jgh3.12777

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Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

<p>肝細胞癌に対する肝移植の保険適用が新日本基準（5-5-500基準内あるいはミラノ基準内）に拡大された．本邦の肝細胞癌治療アルゴリズムでは，肝移植はChild-Pugh C症例で新基準内に留まっているものに推奨されている．このため肝予備能が許容される限り，肝切除，焼灼療法，塞栓療法，肝動注，薬物療法などが行われ，肝機能不良となった症例に肝移植が施行される．肝細胞癌に対してチロシンキナーゼ阻害剤や免疫チェックポイント阻害剤が使用可能となり，肝移植前のdown stageあるいは移植後の補助療法・再発後の治療に，これらの薬物療法を使用した報告が見られるようになった．これらの報告とわれわれの経験を概説する．</p>

DOI： 10.11405/nisshoshi.119.432

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CiNii Research

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(一財)日本消化器病学会  

肝細胞癌に対する肝移植の保険適用が新日本基準(5-5-500基準内あるいはミラノ基準内)に拡大された.本邦の肝細胞癌治療アルゴリズムでは,肝移植はChild-Pugh C症例で新基準内に留まっているものに推奨されている.このため肝予備能が許容される限り,肝切除,焼灼療法,塞栓療法,肝動注,薬物療法などが行われ,肝機能不良となった症例に肝移植が施行される.肝細胞癌に対してチロシンキナーゼ阻害剤や免疫チェックポイント阻害剤が使用可能となり,肝移植前のdown stageあるいは移植後の補助療法・再発後の治療に,これらの薬物療法を使用した報告が見られるようになった.これらの報告とわれわれの経験を概説する.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Medical Association / The Japanese Associaiton of Medical Sciences  

<p><b>Introduction:</b> This study aimed to validate whether preoperative sarcopenia can predict long-term outcomes in patients with hepatocellular carcinoma (HCC) and identify the associations between sarcopenia and polyunsaturated fatty acids (PUFAs).</p><p><b>Methods:</b> This large, retrospective study included 353 patients who underwent hepatic resection for HCC and preoperative computed tomography scans. Skeletal muscle mass was measured at the third lumbar vertebrae. The cutoff value for sarcopenia followed the Japan Society of Hepatology's assessment criteria for sarcopenia.</p><p><b>Results:</b> Ninety-three patients (26.3%) with preoperative sarcopenia were enrolled. These patients had a significantly lower body mass index (p < 0.0001) and serum albumin level (p = 0.0070) as well as a higher rate of advanced-stage cancer (p = 0.0062) than those without sarcopenia. Patients with sarcopenia had significantly shorter overall survival than the other patients before (p = 0.0001) and after (p = 0.0415) propensity score matching. The sarcopenia group was significantly associated with low levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which were categorized based on omega-3 PUFAs, compared with those in the non-sarcopenia group (p = 0.0030 and p = 0.0135).</p><p><b>Conclusions:</b> We demonstrated an association between sarcopenia and the long-term prognosis in patients with HCC. Low EPA and DHA levels were associated with preoperative sarcopenia. Further prospective studies are needed to investigate whether nutritional support using omega-3 PUFAs can prevent and manage skeletal muscle mass depletion.</p>

DOI： 10.31662/jmaj.2022-0037

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CiNii Research

Language：Japanese   Publisher：(株)アークメディア  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Background: Early recurrence (ER) of hepatocellular carcinoma (HCC) (within 1 year after resection) is known to be a poor prognostic factor. The aim was to identify the risk factors associated with ER after HCC resection. Methods: Data were analyzed retrospectively from patients who underwent primary resection for HCC from two hospitals. For cross-validation, HCC resection cases were divided into the training and testing cohort. The clinicopathological factors between the ER and non-ER groups and factors for predicting ER and prognosis after HCC resection were compared. Results: Out of 173 patients in the training dataset, 33 patients had ER and the ER group showed larger tumor size, more intrahepatic metastasis (IM), and a higher ratio of serum des-gamma-carboxy prothrombin (DCP) to tumor volume (TV) (DCP/TV) than the non-ER group. Out of 203 patients in the testing dataset, 30 patients had ER and the ER group demonstrated larger tumor size, more IM, and higher serum alpha-fetoprotein, AFP/TV, DCP/TV, AFP/tumor maximum diameter (TMD), and DCP/TMD than the non-ER group. The patients were divided into high and low DCP/TV groups and high serum DCP/TV was associated with unfavorable overall survival in the training and testing dataset. Multivariate analysis confirmed that high serum DCP/TV and IM were independently associated with ER. Conclusion: Preoperative high serum DCP/TV may be useful for stratifying patients at risk of early HCC recurrence after curative resection.

DOI： 10.1111/hepr.13750

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Communications  

We examined phosphorylated nuclear factor erythroid 2–related factor 2 (P-NRF2) expression in surgically resected primary hepatocellular carcinoma (HCC) and investigated the association of P-NRF2 expression with clinicopathological features and patient outcome. We also evaluated the relationship among NRF2, cancer metabolism, and programmed death ligand 1 (PD-L1) expression. In this retrospective study, immunohistochemical staining of P-NRF2 was performed on the samples of 335 patients who underwent hepatic resection for HCC. Tomography/computed tomography using fluorine-18 fluorodeoxyglucose was performed, and HCC cell lines after NRF2 knockdown were analyzed by array. We also analyzed the expression of PD-L1 after hypoxia inducible factor 1α (HIF1A) knockdown in NRF2-overexpressing HCC cell lines. Samples from 121 patients (36.1%) were positive for P-NRF2. Positive P-NRF2 expression was significantly associated with high alpha-fetoprotein (AFP) expression, a high rate of poor differentiation, and microscopic intrahepatic metastasis. In addition, positive P-NRF2 expression was an independent predictor for recurrence-free survival and overall survival. NRF2 regulated glucose transporter 1, hexokinase 2, pyruvate kinase isoenzymes L/R, and phosphoglycerate kinase 1 expression and was related to the maximum standardized uptake value. PD-L1 protein expression levels were increased through hypoxia-inducible factor 1α after NRF2 overexpression in HCC cells. Conclusions: Our large cohort study revealed that P-NRF2 expression in cancer cells was associated with clinical outcome in HCC. Additionally, we found that NRF2 was located upstream of cancer metabolism and tumor immunity.

DOI： 10.1002/hep4.1838

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

単発肝細胞癌に対して治癒的肝切除を受けた日本人患者の早期再発(ER)に関連する危険因子を後方視的に検討した。2つの病院で肝細胞癌に対して一次切除を受けた患者をトレーニングコホートとテストコホートに分けた。トレーニングコホート173例中33例がERを経験し、ER群は非ER群に比べて、腫瘍サイズが大きく、肝内転移(IM)が多く、血清デス-ガンマ-カルボキシプロトロンビン(DCP)の腫瘍体積(TV)に対する比率(DCP/TV)が高かった。テストコホート203例のうち、30例がERを経験し、ER群は非ER群に比べて、腫瘍サイズが大きく、IMが多く、血清αフェトプロテイン(AFP)、AFP/TV、DCP/TV、AFP/腫瘍最大径(TMD)、DCP/TMDが高かった。トレーニングとテストコホートの患者を高いDCP/TV群と低いDCP/TV群に分けて比較したところ、高いDCP/TVは全生存率低下と関連していた。多変量解析では、高いDCP/TVとIMが独立してERと関連していた。以上より、術前の高いDCP/TVは、治癒的切除後の早期肝細胞癌再発のリスクを有する患者の層別化に有用である可能性が示唆された。

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purposes: Lenvatinib (LEN) is a molecular-target drug, used for unresectable hepatocellular carcinoma (HCC). It is associated with adverse events (AEs), including hypertension, proteinuria, fatigue, and anorexia, which may force dose reduction or discontinuation. Ninjin’yoeito (NYT) is a Chinese–Japanese herbal compound that can effectively treat fatigue and anorexia, and which has been used for chronic liver diseases. NYT reduces AEs and improves the liver function in patients treated with sorafenib but its effect on LEN is unclear. Methods: The present study included 46 patients (male, n = 32; female, n = 14) who received LEN for HCC at our hospital. Their median age was 70 years (range 36–88 years), and their median body weight was 61.5 kg (range 38.4–97.0 kg). Patients were divided into two groups, depending on whether they received NYT medication. Their AEs and liver function were examined one month after starting LEN. Results: The NYT group suffered less fatigue (63.6% vs. 11.4%, P = 0.0014) and showed elevated aspartate aminotransferase levels (45.5% vs. 14.3%, P = 0.0433) in comparison to the non-NYT group. The non-NYT group also showed a significantly exacerbated albumin-bilirubin (ALBI) grade (P = 0.0342) and ALBI score (average change: + 0.232, P = 0.0001) at 1 month in comparison to baseline. Conclusion: NYT apparently suppressed LEN-induced fatigue and helped maintain liver function in patients with HCC.

DOI： 10.1007/s00595-021-02358-7

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Authorship：Corresponding author   Language：English   Publisher：シュプリンガー・ジャパン(株)  

レンバチニブ(LEN)を投与された肝細胞癌(HCC)患者に対する人参養栄湯(NYT)の有効性を検討した。LENを投与されたHCC患者46例をNYT投与群35例(男性24例、女性11例、年齢中央値70歳)と非投与群11例(男性8例、女性3例、年齢中央値68歳)に分類し、LEN投与開始1ヵ月後における有害事象(AE)の発現と肝機能を評価した。LENは体重60kg未満の患者には8mg/日、60kg以上の患者には12mg/日を投与し、NYTは3gを1日3回投与した。AEの全発現率に関してNYT投与群と非投与群の間に有意差はみられなかったが、疲労、AST上昇はNYT投与群の方が有意に少なかった。グレード3以上のAEの発現率に群間差はなかった。また、肝機能を表すアルブミン-ビリルビン(ALBI)グレードの増悪を呈したのはNYT投与群が20.0%、非投与群が63.6%と有意差がみられ、NYT投与群のうち2ヵ月後にも投与を継続していた31例において、ALBIスコアに有意な変化は認められなかった。LENを投与されているHCC患者に対するNYT投与によって、有害事象としての疲労の軽減が得られ、肝機能も維持されることが示された。

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oncology Letters  

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8+ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8+ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8+ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8+ T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8+ T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSChighCD8+ T-cellLow, 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSChighCD8+ T-cellLow, 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8+ T-cell status enabled further classification of patients based on their outcomes.

DOI： 10.3892/ol.2022.13213

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Publisher：Pancreas  

DOI： 10.1097/MPA.0000000000001976

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

We examined the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incident cases, over 24 years. Data of 20,547 HCC patients (1996–2019) were analyzed in this prospective study. We divided the study period into four 6-yearly quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV + hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). The incident cases of HCC per quarter of the study period were 4311 (21.0%), 5505 (26.8%), 5776 (28.1%), and 4955 (24.1%), sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients < 60 years, 60–69 years, 70–79 years, and ≥ 80 years were 3711 (18.1%), 6652 (32.4%), 7448 (36.2%), and 2736 (13.3%), respectively. The average age of newly-diagnosed patients increased in each quarter. HCC was associated with HBV, HBV + HCV, and HCV infections and non-BC in 2997 (14.6%), 187 (0.9%), and 12,019 (58.5%), and 5344 (26.0%) cases, respectively. The number of HCV-associated cases decreased in each quarter, while that of non-BC-associated cases increased. HCC incident cases tend to increase in the elderly and in non-BC patients; in contrast, HCC incident cases due to HCV tend to decrease.

DOI： 10.1038/s41598-022-05444-z

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research  

Background/Aim: Mac2-binding protein glycosylation isomer (M2BPGi) is a non-invasive marker for assessing liver fibrosis. This was a retrospective study investigating whether M2BPGi predicts recurrence of hepatocellular carcinoma (HCC) after hepatectomy in patients with HCC who achieved a sustained virological response (SVR). Patients and Methods: We retrospectively reviewed the clinicopathological factors from 60 patients who underwent hepatectomy for HCC after achieving a SVR. We divided all patients into high M2BPGi and low M2BPGi groups and analyzed the clinicopathological and surgical outcomes. Results: High M2BPGi (>1.54, n=23) was significantly associated with lower serum albumin, higher ICGR15, higher Fib-4 index, large blood loss, and worse recurrence-free survival compared to low M2BPGi (≤1.54, n=37). Multivariate analysis identified high M2BPGi and large tumor size as being associated with reduced recurrence-free survival. Multivariate analysis identified lower serum albumin, larger tumor size and higher DCP as associated with reduced overall survival. There was no difference regarding recurrence pattern. Conclusion: Preoperative M2BPGi is a useful biomarker for HCC recurrence after hepatectomy for SVR-HCC.

DOI： 10.21873/anticanres.15479

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.pan.2021.08.003

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DOI： 10.1007/s10147-021-01985-x

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DOI： 10.1002/jgh3.12588

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DOI： 10.1007/s10147-021-01962-4

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DOI： 10.1245/s10434-020-09339-z

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DOI： 10.1097/SLA.0000000000005001

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DOI： 10.1016/j.transproceed.2021.02.020

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DOI： 10.1245/s10434-021-10209-5

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DOI： 10.1007/s00595-021-02305-6

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DOI： 10.1007/s00423-021-02103-1

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DOI： 10.1002/ags3.12412

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DOI： 10.1111/hepr.13667

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DOI： 10.1038/s41379-020-00702-9

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DOI： 10.1007/s00595-021-02276-8

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DOI： 10.1002/hep4.1659

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DOI： 10.1002/cam4.3519

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DOI： 10.1038/s41598-021-85186-6

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DOI： 10.1002/hep4.1643

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DOI： 10.1016/j.ejso.2020.08.002

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DOI： 10.1016/j.jhep.2020.08.017

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DOI： 10.1155/2021/8813410

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DOI： 10.1111/hepr.13607

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DOI： 10.1007/s00280-020-04178-x

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DOI： 10.1002/ags3.12412

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DOI： 10.1016/j.pan.2020.07.011

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DOI： 10.6002/ect.2020.0041

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: Inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are reportedly predictive of the long-term outcomes of several cancers. We evaluated their correlations with the post-surgical long-term outcomes of patients with mass-forming (MF) intrahepatic cholangiocarcinoma (ICC). Methods: The subjects of this study were 52 patients who underwent hepatic resection for MF-ICC at our hospital. We measured the cutoff values of NLR, LMR and PLR, using receiver operating characteristic curves, and compared the survival rates of patients with high vs. those with low values. We also evaluated a prognostic scoring system based on significant inflammatory biomarkers. Results: The cutoff values for NLR, LMR, and PLR were 1.93, 4.78, and 98, respectively. The high-NLR and low-LMR groups had significantly worse prognoses than the low-NLR and high-LMR groups. We designed a scoring system using the inflammation score (IS) based on NLR and LMR values, stratifying patients into three groups with scores of 0, 1, or 2. The IS was significantly correlated with overall survival (OS), with 5-year survival rates by the IS score of 100% for 0, 61% for 1, and 32% for 2 (P = 0.011). The IS was found to be an independent predictor of OS in multivariate analysis. Conclusions: Our IS scoring system may predict long-term outcomes after surgery for MF-ICC.

DOI： 10.1007/s00595-019-01905-7

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DOI： 10.21037/hbsn.2019.09.14

Language：English   Publishing type：Research paper (scientific journal)  

Background: Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors. Methods: Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively. Results: Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P < 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for post-LDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well. Conclusions: Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component.

DOI： 10.1016/j.hpb.2019.08.008

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The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid-derived 2-like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage-independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β-lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α-fetoprotein, and des-γ-carboxy-prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P =.0073) and was an independent risk factor for poor prognosis (P =.0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage-independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy.

DOI： 10.1111/cas.14320

Language：English   Publishing type：Research paper (scientific journal)  

Extrahepatic malignancy is a relative contraindication for liver transplant in many countries. Nevertheless, the indications for living-donor liver transplantation (LDLT) for such patients vary by institution. Our aim was to reevaluate the indications for LDLT in patients with extrahepatic malignancy. We retrospectively reviewed data for 609 patients who underwent adult LDLT from May 1997 to January 2018 and analyzed patients with a history of extrahepatic malignancies or concurrent malignancies. Fourteen patients had extrahepatic malignancies concurrent with or before LDLT. Malignancies in 9 patients were detected during their systematic screening for LDLT. The mean duration between surgeries was 70 days (range, 20-209 days). Five patients had a history of extrahepatic malignancies before considering LDLT. The estimated 5-year survival rate was 100%. Although the risk and long-term prognosis of patients with extrahepatic malignancy are not well known, such patients can be candidates for LDLT if they undergo curative surgery for the malignancy, and if the prognosis of the malignancy is the same or superior to that of LDLT.

DOI： 10.1016/j.transproceed.2019.12.041

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Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8-hydroxy-deoxyguanosine (8-OHdG) DNA glycosylase (OGG1) enhances the repair of 8-OHdG, which is the primary oxidative stress-induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress-induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8-OHdG expressions in 86 resected HCC specimens. High 8-OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8-OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8-OHdG expression than in those with low 8-OHdG expression. The 8-OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8-OHdG group and the other group. The patients with low OGG1/high 8-OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8-OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8-OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.

DOI： 10.1111/pin.12952

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Background: Osteopenia, loss of bone mineral density (BMD), was recently identified to be independently associated with early marker of deconditioning that precedes sarcopenia in patients with hepatocellular carcinoma (HCC). The aim of this study was to clarify the impact of osteopenia as the risk factor for mortality after living donor liver transplantation (LDLT) compared with already-reported biological markers. Methods: Data were collected retrospectively for all consecutive patients who underwent LDLT for HCC at our institution between January 1998 and December 2015. BMD was evaluated with computed tomographic measurement of pixel density in the midvertebral core of the 11th thoracic vertebra. Data related to clinicopathological parameters and prognosis were analyzed. Results: The median value of BMD was 163.6 Hounsfield units and osteopenia was identified in 103 (53.4%) of the 193 recipients, according to the age-specific formula. In addition to the other tumor burdens, such as tumor numbers ≥5 (HR 2.521, P = 0.027), DCP levels >200 mAU/mL (HR 2.678, P = 0.006), and neutrophil-to-lymphocyte ratio ≥3.01 (HR 2.068, P = 0.025), osteopenia (HR 2.106, P = 0.024) was independent risk factor for mortality by multivariate analysis. Overall survival of the patients who met the two risk factors and more was significantly lower than the others (HR 5.382, P < 0.001). Besides, the calibration plot for the 5-year overall survival using nomogram was predicted very well (C-index 0.746). Conclusions: Preoperative osteopenia was independently associated with post-LDLT mortality among patients with HCC. Moreover, risk score and nomogram with calibration curve were developed to confirm the clinical usefulness of osteopenia for post-LDLT patients.

DOI： 10.1007/s00268-019-05206-5

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Background: The Japan criteria (JC, maximum tumor size within 5 cm, within five tumor nodules, AFP within 500 ng/mL or within Milan criteria) have been applied to cadaveric liver transplantation (LT) for hepatocellular carcinoma (HCC) and will be used for living donor LT (LDLT) in Japan. The aim of this study was to verify the JC in LDLT and to clarify the risk factor of HCC recurrence and mortality after LDLT beyond the JC. Patients and methods: Adult patients who underwent LDLT for end-stage liver disease with HCC until October 2019 were reviewed retrospectively (n = 246). Patients were divided into two groups according to whether they were within JC (n = 203) or beyond JC (n = 43). Recurrence-free or overall survival rates after LDLT were compared. Univariate and multivariate analyses were performed to identify risk factors of HCC recurrence and HCC-related mortality after LDLT for patients beyond the JC. Results: Patients beyond the JC had significantly poorer 5-year recurrence-free (50.3% vs 95.9%, P <.001) or overall (61.7% vs 98.1%, P <.001) survival rates compared with patients within the JC. A multivariate analysis revealed that des-gamma-carboxy prothrombin (DCP) ≥ 300 mAU/mL (hazard ratio 9.36, 95% CI; 2.41-36.4, P =.001) was an independent risk factor for HCC recurrence and HCC-related mortality (hazard ratio 13.8, 95% CI; 1.92-98.6, P =.01) after LDLT in patients beyond the JC. Conclusion: The outcome of LDLT for patients within the JC was favorable. Patients beyond the JC with DCP ≥ 300 mAU/mL might be contraindicated for LDLT.

DOI： 10.1002/ags3.12335

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Introduction: The aim of this study was to clarify the impact of middle hepatic artery reconstruction on the outcomes of duct-to-duct biliary anastomosis after living donor liver transplantation (LDLT) using the left lobe. Materials and Methods: Among 258 patients who underwent LDLT using the left lobe, 216 patients who underwent hepatic artery reconstruction and one hepatic duct reconstruction with duct-to-duct interrupted anastomosis were divided into three groups: Group A (n = 123), one arterial stump with left hepatic artery reconstruction; Group B (n = 32), two arterial stumps with only left hepatic artery reconstruction; and Group C (n = 61), two arterial stumps with reconstruction of the left and middle hepatic arteries. The outcomes after LDLT were compared among the three groups. Results: No hepatic artery complications occurred. Group B had a significantly greater incidence of anastomotic biliary stricture than Group C. A multivariate analysis with Cox regression revealed that being in Group B was the only significant independent risk factor for postoperative anastomotic biliary stricture after LDLT. Conclusions: Middle and left hepatic artery reconstruction is safe in LDLT and may prevent biliary stricture caused by dual hepatic artery reconstruction when the graft has left and middle hepatic artery stumps.

DOI： 10.1111/ctr.13850

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Background: The surgical indication for non-hypervascular hypointense nodules (NHVN) detected incidentally on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) for classical hepatocellular carcinoma (HCC) is unknown. Our aim is to clarify the long-term outcomes in patients with this finding. Methods: We reviewed the cases of 290 HCC patients, including 66 patients with NHVN, who underwent Gd-EOB-MRI prior to hepatectomy, between October 2008 and December 2017 at our center. We divided the patients into three groups: a no-NHVN group, a treated NHVN group, and an untreated NHVN group. Results: There was no significant difference in (RFS) or overall survival (OS) between the no-NHVN and untreated NHVN groups (p = 0.103 and 0.103, respectively). There was no significant difference between these two groups after propensity score matching. Multivariate analyses showed that microscopic intrahepatic metastases and the size of the main classical HCC, the target tumor, were independent prognostic factors of overall survival, but the presence of non-hypervascular hypointense nodules was not. There was no significant difference in RFS or OS between the treated NHVN and untreated NHVN groups (p = 0.158 and 0.109, respectively). Conclusions: Non-hypervascular hypointense nodules detected incidentally on Gd-EOB-MRI associated with targeted hypervascular HCC did not reflect prognosis of HCC after hepatectomy. Surgical procedures for classical enhancing HCC may be performed even if non-hypervascular hypointense nodules adjacent to the targeted HCC cannot be removed completely.

DOI： 10.1245/s10434-020-08419-4

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Aim: There is increasing evidence that inflammation-based prognostic scores are stage-independent predictors of poor outcome in patients with hepatocellular carcinoma (HCC). However, these findings were observed in a small-sized study comparing the prognostic value of these scores for patients after curative resection for HCC. Methods: We retrospectively analyzed 717 consecutive patients with HCC who underwent curative liver resection at Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital. Clinicopathological variables including preoperative inflammation-based prognostic scores, such as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, Controlling Nutritional Status score, prognostic nutritional index (PNI), and Glasgow Prognostic Score were analyzed. The prognostic value of these scores was compared by the time-dependent receiver operating characteristic curve analyses. Results: The integrate area under the curve of PNI, Controlling Nutritional Status score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and Glasgow Prognostic Score were 0.6751, 0.6435, 0.5845, 0.5276, and 0.5351 for overall survival (OS), respectively, and 0.5955, 0.5694, 0.4692, 0.4873, and 0.5272 for disease-free survival, respectively. Multivariate analyses for prognosis factor in HCC patients showed that PNI was an independent predictor of both OS (HR 0.91, P < 0.001) and disease-free survival (HR 0.94, P < 0.001). When the patients were divided into high and low PNI groups, the patients in the low PNI group had significant poorer OS (P < 0.001) and disease-free survival (P < 0.001), even after background factors were matched between these two groups. Conclusions: PNI is superior to Controlling Nutritional Status score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, or Glasgow Prognostic Score as a predictor of OS and recurrence-free survival in patients with HCC who underwent curative hepatic resection.

DOI： 10.1111/hepr.13431

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Management of portal vein thrombosis (PVT), especially advanced PVT involving the superior mesenteric vein (SMV), in living donor liver transplantation (LDLT) is challenging. There were 514 adults who underwent LDLT between 2005 and 2018 included in this retrospective study, and PVT was observed in 67 (13.0%) patients. The LDLT recipients with PVT were characterized by increased portal pressure at laparotomy (26.1 ± 6.0 versus 24.3 ± 5.9 mm Hg; P = 0.03) and at closure (16.8 ± 3.9 versus 15.6 ± 3.6 mm Hg; P = 0.02), increased operative blood loss (14.6 ± 29.7 versus 5.7 ± 6.3 L; P < 0.01), and decreased 1-year graft survival (83.5% versus 92.8%; P = 0.04). Among the 18 patients with atrophic or vanished portal vein on pre-LDLT computed tomography, significant portal atrophy was actually observed only in 1 (5.6%) patient during LDLT surgery. For advanced PVT (n = 7) involving SMV in era 1, we performed nonanatomical inflow reconstruction using interposition grafts, resulting in significant inflow problems in 4 (57.1%) patients. Thus, for the patients with advanced PVT (n = 4) in era 2, we abandoned nonanatomical reconstruction and applied extensive thrombectomy under ultrasound guidance with secure shunt ligation, resulting in no inflow problems and no graft loss. In conclusion, even for advanced PVT involving SMV, extensive thrombectomy under sonogram guidance followed by anatomical inflow reconstruction and shunt ligation is a legitimate strategy in adult LDLT with PVT.

DOI： 10.1002/lt.25623

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. Materials and methods, and results: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. Conclusion: We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival.

DOI： 10.1007/s10147-019-01499-7

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Background: Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel serum glycomarker used to assess liver fibrosis. However, it has been reported that M2BPGi is likely to reflect other factors not limited to liver fibrosis. Methods: We retrospectively analyzed 79 patients with liver tumors who underwent liver resection. M2BPGi was measured within 1 week before operation and almost 1 month after operation. We introduced a value termed the “ΔM2BPGi ratio” (=M2BPGi_{after operation}/M2BPGi_{before operation}), and analyzed factors that influenced the ΔM2BPGi ratio. Results: The median value of the ΔM2BPGi ratio was 1.28 (range, 0.36-5.68). In 64 patients (81.0%), the cutoff index values of M2BPGi were elevated approximately 1 month after operation, especially in patients who experienced post-hepatectomy liver failure (PHLF). Multiple linear regression showed total Pringle time, PHLF grade ≥B, and preoperative value of creatinine were significant predictors of the ΔM2BPGi ratio. The mean values of the ΔM2BPGi ratio were 1.37 ± 0.07, 1.52 ± 0.22, and 2.94 ± 0.30 for PHLF grade 0, grade A, and grade B, respectively, resulting in statistically significant differences by the Kruskal-Wallis test (P = 0.022). Conclusions: Total Pringle time, PHLF grade ≥B, and preoperative creatinine significantly influenced the elevation of M2BPGi almost 1 month after liver resection. This study strongly affirms the previous suggestion that M2BPGi is likely to reflect other factors not limited to liver fibrosis.

DOI： 10.1002/ags3.12271

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Background: Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)–associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment. Materials and methods: PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed. Results: Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8 ⁺ T cells and a higher number of FoxP3 ⁺ cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA. Conclusions: Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.

DOI： 10.1016/j.jss.2019.02.038

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Background/Aim: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. Materials and Methods: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. Results: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. Conclusion: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression.

DOI： 10.21873/anticanres.13465

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Backgrounds: Distal pancreatectomy with en bloc celiac axis resection (DP-CAR) is an extended surgical procedure for patients with locally advanced cancer of the pancreatic body and tail. Recently, the usability of neoadjuvant chemotherapy (NAC) in pancreatic cancer was reported. The purpose of this study was to clarify the impact of NAC on surgical outcomes and prognosis in DP-CAR patients. Methods: This study retrospectively reviewed 20 consecutive patients who underwent DP-CAR at a single institution. Results: Eleven of 20 patients (55.0%) received NAC. Their first regimens were gemcitabine (GEM) plus nab-PTX (n = 7, 63.6%), GEM plus S-1 (n = 3, 27.3%), and GEM (n = 1, 9.1%). Although two patients converted to a second regimen, none abandoned NAC due to adverse effects or could not undergo a planned procedure for disease progression. There were no significant differences in intraoperative variables, morbidity, including pancreatic fistula and delayed gastric emptying, and mortality between patients with and without NAC; however, patients with NAC had a significantly lower proportion of arterial invasion (p = 0.025), lymphatic invasion (p < 0.0001), and vascular invasion (p = 0.035). There were no significant differences in the induction rate of adjuvant chemotherapy (p = 0.201). The recurrence-free survival and overall survival rates in patients with NAC were significantly higher than in patients without NAC (p = 0.041 and p = 0.018, respectively). Conclusion: DP-CAR following NAC was associated with a preferable prognosis and had no negative effect on surgical outcomes. Therefore, NAC in DP-CAR patients might be a beneficial and safe therapeutic strategy.

DOI： 10.1007/s11605-019-04324-8

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Autophagy has a critical role in liver regeneration. However, no studies have demonstrated autophagic flux in the regenerating fatty liver. The aim of this study was to clarify the dynamics of autophagy in the regeneration of the fatty liver. Following 70% partial hepatectomy (PH) in db/db fatty mice, which is a non-alcoholic fatty liver disease (NAFLD) model, we investigated the survival rate and recovery of liver volume. Histological examination of the regenerating liver was examined using electron microscopy. The 7-day survival rate after PH in db/db mice was 20%, which was significantly lower than that in control mice (P<.01). Liver regeneration within 48 h after PH was significantly impaired in db/db mice (P<.05). The number of proliferating cell nuclear antigen (PCNA) positive cells and the expression levels of cell-cycle markers cyclins D, E, and A were lower in db/db mice compared with controls. In the regenerating liver, LC3-II level was higher in db/db mice, but p62 expression was increased and cathepsin D expression, a marker of autophagolysosome proteolysis, was decreased compared with controls. Additionally, electronic microscopy revealed that autophagosomes during liver regeneration in db/db mice were mainly located in lipid droplets. Our findings indicate that the different localization of autophagosomes in db/db mice compared with controls led to impairment of liver regeneration in the fatty liver.

DOI： 10.1080/15476278.2019.1633872

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Background: We studied the prognostic impact of sarcopenia after hepatic resection for intrahepatic cholangiocarcinoma (ICC). Methods: Sixty-one patients who underwent surgery for ICC during 2000–2017 were analyzed retrospectively. Psoas muscle areas were measured on CT scans at the third lumbar vertebra. Areas less than the sex-specific median were deemed low skeletal muscle masses (SMMs). Results: Low-SMM patients were significantly more often older (p = 0.002) than high-SMM patients, had lower serum albumin (p = 0.004), higher serum C-reactive protein (CRP) (p = 0.002), and higher carbohydrate antigen 19-9 (p < 0.001). Five-year overall survival rates were 72.5% and 17.6% and 5-year recurrence-free survival rates were 58.6% and 21.1%, respectively, in high- and low-SMM patients. Multivariable analysis revealed that low SMM predicted unfavorable prognoses. SMM was associated with immune nutritional status (e.g., prognostic nutritional index, Glasgow prognostic score, CRP/albumin ratio). Conclusion: Low SMM was related to worse surgical outcomes in patients with ICC following hepatic resection.

DOI： 10.1016/j.amjsurg.2019.03.010

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Introduction: The aim of this study was to evaluate the effect of hepatic artery (HA) size mismatch anastomosis on outcomes after living-donor liver transplantation (LDLT). Materials and methods: After excluding 128 patients with the exclusion criteria among 233 LDLTs using the right lobe, 104 LDLT patients were divided into two groups: donor HA diameter that was greater than or equal to the recipient HA diameter (D ≥ R group; n = 79), and donor HA diameter that was smaller than the recipient HA diameter (D < R group; n = 25). Results: Hepatic artery-related complications occurred in only one patient (HA thrombosis; 1.0%) who was in the D < R group. The reconstructed HA flow in the D ≥ R group was significantly greater than that in the D < R group (P = 0.015). There was a higher incidence of anastomotic biliary stricture in the D < R group (32.0%) compared with the D ≥ R group (13.9%, P = 0.022) after LDLT. A multivariate analysis with Cox regression revealed that the HA anastomosis of the D < R group and hepaticojejunostomy were significant independent risk factors for postoperative anastomotic biliary stenosis. Conclusions: Hepatic artery anastomosis with a donor HA diameter smaller than that of the recipient HA might be an independent risk factor for postoperative biliary stenosis after LDLT using the right lobe.

DOI： 10.1111/ctr.13444

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/lt.25339

Language：English   Publishing type：Research paper (scientific journal)  

Chimeric mice with humanized liver were first established by transplanting primary human hepatocytes (PHHs) isolated from a Japanese 27-year-old donor into complementary DNA-urokinase-type plasminogen activator/severe combined immunodeficiency mice. The PHHs from the Japanese donor increased more than 100-fold in the mouse liver, and human hepatocytes purified from the chimeric mouse liver (hcPHs) were successfully transplanted into second-passaged mice. These PHHs and hcPHs can produce human albumin and preserve many liver-specific enzyme genes, which are important for liver function. Interestingly, hepatitis B virus can be infected with these chimeric mice; hepatitis B viral DNA and hepatitis B surface antigen levels were detectable. In conclusion, hcPHs can be an ideal cell source for analysis of human hepatocytes.

DOI： 10.1016/j.transproceed.2018.06.035

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Background/Aim: Computed tomography (CT) has recently been applied to measure bone mineral density (BMD). However, the definition of osteopenia, which means depletion of BMD, using CT remains controversial. The aim of this study was to establish formulae to calculate standard BMD. Patients and Methods: Fifty healthy donors for liver transplantation underwent CT. BMD was measured as crosssectional average pixel density (Hounsfield units) only in trabecular-bone at Th11 bottom. Validation was performed on another 50 healthy donors to check the accuracy of formulae for standard BMD. Results: Measured BMD was significantly correlated with age in both males and females (p<0.0001). The formulae to calculate standard BMD were 308.82-2.49 × Age in males and 311.84-2.41 × Age in females. Estimated BMD was significantly correlated with measured BMD in males and females (p<0.0001). Conclusion: Osteopenia can be defined by the difference between measured data and calculated data using our new formula based on each age.

DOI： 10.21873/anticanres.13009

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Recent studies revealed that systemic inflammation was correlated with poorer prognosis in various cancers. We investigated the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). We retrospectively analyzed the records of 216 patients who underwent LDLT for HCC. Patients were divided into high (n = 126) and low (n = 90) LMR groups. Their clinicopathological parameters and survival times were compared. To determine the mechanisms of the change in the LMR, we performed immunohistochemical analyses of CD3 and CD68 expression. A low LMR was significantly associated with a high Model for End-Stage Liver Disease score; a high Child-Pugh score; elevation of alpha-fetoprotein, des-gamma-carboxyprothrombin, and neutrophil-to-lymphocyte ratio; larger tumor size; more tumors; and poorer prognosis. A low LMR was associated with poor prognosis and represented an independent prognostic factor, particularly among patients beyond the Milan criteria. The ratio of CD3-positive to CD68-positive cells was significantly lower in the low-LMR group. In conclusion, our results show that the LMR was an independent predictor of survival of patients with HCC beyond the Milan criteria who underwent LDLT. The LMR reflected the immune status of the tumor microenvironment.

DOI： 10.1002/lt.25204

Language：English   Publishing type：Research paper (scientific journal)  

Background: The Controlling Nutritional Status (CONUT) score is an objective tool that is widely used to assess the nutritional status in patients, including those with cancer. The relationship between the CONUT score and prognosis in patients who have undergone hepatic resection has not been evaluated in a multi-institutional study. Methods: Data were retrospectively collected for 2461 consecutive patients with hepatocellular carcinoma (HCC) who had undergone hepatic resection with curative intent at 13 institutions between January 2004 and December 2015. Patients were assigned to two groups: preoperative CONUT scores ≤ 3 (low CONUT score) and ≥ 4 (high CONUT score). Clinicopathological characteristics, surgical outcomes, and long-term survival were compared using propensity score matching analysis. Results: Of the 2461 patients, 540 (21.9%) had high (≥ 4) and 1921 (78.1%) had low (≤ 3) preoperative CONUT scores. Overall, a high CONUT score was significantly associated with older age, female sex, low body mass index, low serum albumin, high serum total bilirubin, low lymphocyte count, low serum cholesterol, shorter prothrombin time, higher indocyanine green retention test at 15 min, Child–Pugh B (vs. A), liver cirrhosis, minor resection, shorter operation time, massive blood loss, blood transfusion, and postoperative complications. After propensity score matching, a higher CONUT score was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS) using multivariate analysis. Conclusions: This retrospective, multi-institutional analysis showed that, in patients who undergo curative hepatectomy for HCC, the preoperative CONUT score is predictive of worse OS and RFS, even after propensity score matching analysis.

DOI： 10.1245/s10434-018-6672-6

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Background/Aim: This study’s aim was to investigate the safety and effectiveness of asunaprevir and daclatasvir treatment for recurrent hepatitis C virus (HCV) infection in transplant recipients. The study cohort comprised 14 transplant recipients with recurrent hepatitis C who were receiving asunaprevir and daclatasvir. Patients and Methods: Serum concentrations of asunaprevir and daclatasvir, their therapeutic effects, trough concentrations/dose ratios of tacrolimus, and adverse effects were evaluated. Results: Hepatitis C virus was still undetectable in 12 (85.7%) out of 14 patients 12 weeks after completing treatment. One week after starting treatment, asunaprevir concentrations were significantly higher in patients with baseline albumin concentrations ≤3.6 g/dl than in those with baseline albumin concentrations >3.6 g/dl. No marked fluctuations were identified in tacrolimus trough concentrations/dose ratios during the 24 weeks of therapy. Conclusion: Full doses of asunaprevir and daclatasvir-based treatment can be safely and effectively administered to liver transplant recipients for recurrent HCV genotype 1b after living donor liver transplantation (LDLT) with little effect on blood concentrations of tacrolimus.

DOI： 10.21873/anticanres.12885

Language：English   Publishing type：Research paper (scientific journal)  

Background Although risk factors for the long-term mortality of liver transplantation are well described, there is a lack of detailed study regarding these factors for adult living donor liver transplantation (LDLT). Methods We retrospectively analyzed 528 adult LDLT recipients in our hospital. The risk factors were analyzed for overall deaths more than 5 years post-LDLT. Results Over the 20-year follow-up, 137 patients died. Patient survival at 1, 3, 5, and 10 years post-LDLT was 87.8%, 81.8%, 79.4%, and 72.8%, respectively. The independent risk factors for more than 5 years post-LDLT overall death were hepatocellular carcinoma recurrence (hazard ratio [HR], 38.9; P < 0.001), lymphoid de novo malignancy (HR, 47.2; P = 0.001), primary sclerosing cholangitis as primary diagnosis (HR, 11.5; P < 0.001), chronic rejection (HR, 6.93; P = 0.006), acute rejection (HR, 2.96; P = 0.017), and bile duct stenosis (HR, 2.30; P = 0.045). Conclusions Not only malignancies and rejection but also bile duct stenosis and primary sclerosing cholangitis had significant impacts on late period post-LDLT mortality.

DOI： 10.1097/TP.0000000000002324

Language：English   Publishing type：Research paper (scientific journal)  

Aim The clinical impact of pathological classification based on architectural pattern in hepatocellular carcinoma (HCC) remains elusive in spite of its well-known and common feature. Methods The prognostic impact of pathological classification was examined with prospective database. Three hundred and eighty HCC patients who underwent curative hepatectomy as an initial treatment in Kumamoto University were enrolled as a test cohort. The outcome was confirmed with a validation cohort in Kyushu University. Results Macrotrabecular (macro-T) subtype (n = 38) and compact subtype (n = 43) showed similar biological and prognostic features. Both showed higher AFP level and worse overall survival than microrabecular (micro-T) subtype (n = 266). Multivariate analysis for overall survival revealed that DCP 40, multiple tumor and macro-T/compact subtype were associated with poor overall survival (risk ratio = 2.2, 1.6 and 1.6; p = 0.002, 0.020, and 0.047, respectively). Of note, 32% of macro-T/compact subtype showed early recurrence within 1 year, which showed substantially low (5%) 5 year overall survival, whereas 16% of micro-T/PG subtype did. Twenty-one percent of macro-T/compact subtype showed multiple intrahepatic metastases ( 4) or distant metastases, which resulted in non-curative treatment, whereas 5% of micro-T/PG subtype did. In validation cohort, macro-T/compact subtype was an independent predictor of worse overall survival. Conclusion Macro-T/compact subtype is biologically discriminated from micro-T and PG subtypes due to its aggressive features and poor prognosis after curative treatment. Additional treatment with curative hepatectomy on Macro-T/compact subtype should be discussed because of high possibility of systemic residual cancer cell.

DOI： 10.1371/journal.pone.0203856

Language：English   Publishing type：Research paper (scientific journal)  

Background: The prognosis of hepatocellular carcinoma (HCC) with portal hypertension (PH) is very poor. Splenomegaly is considered important evidence of PH. Our aim was to clarify the prognostic value of splenic volume (SV) and the effect of splenectomy on the prognosis of HCC within the Milan criteria after curative hepatectomy. Methods: In this single-center retrospective study, we reviewed 160 patients with HCC that met the Milan criteria, including 138 who had undergone hepatectomy and 22 who had undergone hepatectomy and splenectomy between July 2004 and December 2010. SV was measured by three-dimensional computed tomography and patients allocated to three groups (high SV ≥300 mL; low OpenSPiltSPi300 mL; and splenectomy) to compare post-hepatectomy survival rates. Results: Multivariate analyses showed that SV is an independent prognostic factor for overall and disease-free survival. The overall survival rates at 5 years in the high SV, low SV, and splenectomy groups were 39, 75, and 88%, respectively. The overall survival rate in the high SV group was significantly worse than in the low SV and splenectomy groups (P OpenSPiltSPi 0.001). There was no significant difference between the low SV and splenectomy groups (P = 0.831). Conclusions: High SV is an independent predictor of post-hepatectomy HCC recurrence and overall survival. There is no significant difference in prognosis between low SV and splenectomy groups, even though the latter had high SV. Combined splenectomy with hepatectomy for HCC and PH may improve prognosis and be an appropriate alternative when liver transplantation cannot be performed.

DOI： 10.1007/s00268-017-4232-z

Language：English   Publishing type：Research paper (scientific journal)  

Aim: Liver ischemia–reperfusion (I/R) injury is a severe complication of liver surgery. However, the responsible molecular mechanism remains unclear. High-mobility group box 1 (HMGB1) is released from the nuclei of cells and behaves as a damage-associated molecular pattern. The aim of this study is to reveal the roles of HMGB1 and the effects of recombinant thrombomodulin (rTM) in I/R liver injury. Methods: Rats underwent partial hepatic ischemia followed by reperfusion, and changes in HMGB1 were assessed. Recombinant thrombomodulin was used as an inhibitor of HMGB1. Results: In rats with I/R injury, the HMGB1 level significantly decreased in the liver tissue and significantly increased in the serum after surgery (P < 0.001 for both). No difference in the HMGB1 level in the hepatocytes was observed between the rTM(−) group and rTM(+) group after surgery. Conversely, the serum HMGB1 level was significantly lower in the rTM(+) group than the rTM(−) group after surgery (P < 0.001). The levels of tumor necrosis factor-α and interleukin-6 in the liver tissue 24 h after surgery were significantly lower in the rTM(+) group than the rTM(−) group (P < 0.001). The plasma alanine aminotransferase level at 24 h after surgery of the rTM(+) group was significantly decreased after surgery compared with that of the rTM(−) group (P < 0.001). The necrotic area of the liver tissue 24 h after surgery was significantly smaller in the rTM(+) group than the rTM(−) group (P < 0.001). Conclusions: Recombinant thrombomodulin can serve as a treatment for I/R liver injury by inhibiting HMGB1.

DOI： 10.1111/hepr.13005

Language：English   Publishing type：Research paper (scientific journal)  

Aim: We aimed to evaluate the effect of antibody to hepatitis B core antigen (HBcAb) positivity on clinical outcomes after hepatic resection in hepatocellular carcinoma (HCC) patients with negative hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non-B, non-C HCC (NBNC-HCC), or with HCV-related HCC. Methods: Two hundred and sixty-three patients who underwent hepatic resection for HCC and measurements of HBsAg, HCVAb, and HBcAb were enrolled in this study. Results: The percentages of HBcAb positivity were 52.3% (n = 57) and 56.9% (n = 66) in patients with NBNC- and HCV-related HCC, respectively. The proportion of multiple NBNC-HCCs was significantly greater in patients with HBcAb positivity compared to HBcAb negativity (P = 0.028). There were no significant differences in the recurrence-free and overall survival rates between NBNC-HCC patients with HBcAb positivity versus negativity (P = 0.461 and P = 0.190, respectively). Furthermore, for HCV-related HCC patients, there were no significant differences in the baseline factors between patients with positive versus negative HBcAb. The proportion of patients with HBcAb-positive HCV-related HCC who underwent anatomical resection of the liver was significantly greater than that of HBcAb-negative patients, whereas the recurrence-free and overall survival rates were not significantly different (P = 0.158 and P = 0.191, respectively). Conclusion: In our study, the presence of HBcAb had no impact on surgical outcomes after hepatic resection in patients with NBNB- and HCV-related HCC. Occult HBV infection might be associated with hepatocarcinogenesis in patients with NBNC-related HCC.

DOI： 10.1111/hepr.12939

Language：English   Publishing type：Research paper (scientific journal)  

Background: Laparoscopic gastric devascularization(Lap GDS) and splenectomy (SPL) for gastric varices is technically challenging because of highly developed collateral vessels and bleeding tendency. We investigated the feasibility of customization of Lap GDS and SPL based on CT vascular anatomy. Methods: We analyzed 61 cirrhotic patients with gastric varices who underwent Lap GDS and SPL between 2006 and 2014. Lap GDS was customized according to the afferent feeding veins (left gastric vein (LGV) and/or posterior gastric vein (PGV)/short gastric vein (SGV)) and efferent drainage veins (gastrorenal shunt and/or gastrophrenic shunt, or numerous retroperitoneal veins) based on CT imaging. Results: Thirty-four patients with efferent drainage veins suitable for balloon-occluded retrograde transvenous obliteration (B-RTO) underwent B-RTO instead of surgical GDS, with subsequent Lap SPL. Among 27 patients with gastric varices unsuitable for B-RTO, 15 patients with PGV/SGV underwent Lap GDS of the greater curvature and SPL, and 12 patients with LGV or LGV/PGV/SGV underwent Lap GDS of the greater and lesser curvature and SPL. The mean operation time was 294 min and mean blood loss was 198 g. There was no mortality or severe morbidity. Gastric varices were eradicated in all 61 patients, with no bleeding or recurrence during a mean follow-up of 55.9 months. The cumulative 3-, 5-, and 7-year survival rates were 92, 82, and 64%, respectively. Conclusions: Lap GDS and SPL customized based on CT vascular anatomy is a safe and effective procedure for treating gastric varices.

DOI： 10.1007/s00464-017-5646-2

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The aims of this study were to clarify the relationship of gait speed, hand grip strength, and skeletal muscle mass with complications after hepatic resection and to identify risk factors for complications in patients who underwent hepatic resection. Methods: We evaluated the risk factors for complications after hepatic resection in 154 consecutive patients. Preoperative factors included gait speed, hand grip strength, and skeletal muscle mass. The gait speed and hand grip strength of patients were measured by physical therapists, and skeletal muscle mass was measured by computed tomography. Multivariate logistic regression analyses using preoperative factors were performed to assess predictors of the development of complications after hepatic resection. Results: Thirty-three patients (21.4%) developed complications after hepatic resection. These patients had a significantly lower serum albumin level (p = 0.015), slower gait speed (p = 0.007), higher rate of hepatic resection ≥ 2 Couinaud segments (p = 0.014), and lower rate of laparoscopic hepatic resection (p = 0.017) than patients without complications. Multivariate analysis revealed that a gait speed ≤ 1.10 m/s and a serum albumin level of ≤ 4.0 g/dl were independent risk factors for complications after hepatic resection. Conclusions: Slow gait speed and low serum albumin level are significant risk factors for complications after hepatic resection. These data will be helpful for perioperative patient management.

DOI： 10.1007/s11605-018-3993-5

Language：English   Publishing type：Research paper (scientific journal)  

Background: Liver transplantation has been established as the optimal treatment for hepatocellular carcinoma in cirrhotic patients, but hepatic resection is also effective in patients with well-preserved liver function. Determining the suitable surgical treatment for patients with Child–Pugh class B cirrhosis is a more difficult challenge.Methods: We retrospectively compared the results of hepatic resection and living donor liver transplantation for hepatocellular carcinoma in 137 patients with Child–Pugh class B cirrhosis. The procedures were performed at Kyushu University Hospital from April 2014 through October 2016. Results: Patients who underwent hepatic resection were significantly older and had better liver function, larger tumor size, smaller number of tumors, and less surgical stress compared with patients who underwent living donor liver transplantation. The overall survival rate and the recurrence-free survival rate in patients with transplantation were significantly better than that in patients with resection. The multivariate analysis showed that recurrent hepatocellular carcinoma and microvascular invasion were significant prognostic factors for both overall and recurrence-free survival in the hepatic resection group. In the group with protein induced by vitamin K absence or antagonist-II ≥300 mAU/mL, both the overall survival curve and the recurrence-free survival curve in patients with living donor liver transplantation were not significantly different from those in patients with hepatic resection. Conclusions: Living donor liver transplantation for hepatocellular carcinoma in patients with Child–Pugh class B cirrhosis was favorable under the condition of protein induced by vitamin K absence or antagonist-II <300 mAU/mL in selected recipients and donors. Hepatic resection for recurrent hepatocellular carcinoma and excessive blood loss should be avoided in patients with Child–Pugh class B cirrhosis.

DOI： 10.1007/s00268-018-4493-1

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.13975

Language：English   Publishing type：Research paper (scientific journal)  

Background Expanding patient selection beyond the Milan criteria in living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) has long been a matter for debate. We have used the Kyushu University Criteria – maximum tumor diameter <5 cm or des-γ-carboxy prothrombin <300 mAU/ml – in LDLT for HCC since June 2007. The aim of the present study was to present the results of our prospective patient selection by Kyushu University Criteria and to confirm whether or not our criteria were justified. Methods The entire study period was divided into the pre-Kyushu era (July 1999–May 2007) and the Kyushu era (June 2007–November 2014). Eighty-nine and 90 patients underwent LDLT for HCC in the pre-Kyushu era and the Kyushu era, respectively. Results In the pre-Kyushu era, there were significant differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients. In the Kyushu era, however, the differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients disappeared. The 5-year overall patient survival in the Kyushu era was 89.4%. Conclusion Our selection criteria enabled a considerable number of beyond-Milan patients to undergo LDLT without jeopardizing the recurrence-free, and disease-specific, and overall patient survival.

DOI： 10.1016/j.hpb.2017.08.004

Language：English   Publishing type：Research paper (scientific journal)  

Background Sarcopenia is an independent predictor of death after living-donor liver transplantation (LDLT). However, the ability of the Asian Working Group for Sarcopenia criteria for sarcopenia (defined as reduced skeletal muscle mass plus low muscle strength) to predict surgical outcomes in patients who have undergone LDLT has not been determined. Methods This study prospectively enrolled 366 patients who underwent LDLT at Kyushu University Hospital. Skeletal muscle area (determined by computed tomography), hand-grip strength, and gait speed were measured in 102 patients before LDLT. We investigated the relationship between sarcopenia and surgical outcomes after LDLT performed in three time periods. Results The number of patients with lower skeletal muscle area has increased to 52.9% in recent years. The incidence of sarcopenia according to the Asian Working Group for Sarcopenia criteria was 23.5% (24/102). Patients with sarcopenia (defined by skeletal muscle area and functional parameters) had significantly lower skeletal muscle area and weaker hand-grip strength than did those without sarcopenia. Compared with non-sarcopenic patients, patients with sarcopenia also had significantly worse liver function, greater estimated blood loss, greater incidence of postoperative complications of Clavien-Dindo grade IV or greater (including amount of ascites on postoperative day 14, total bilirubin on postoperative day 14, and postoperative sepsis), and longer postoperative hospital stay. Multiple logistic regression analysis revealed sarcopenia as a significant predictor of 6-month mortality. Conclusions The combination of skeletal muscle mass and function can predict surgical outcomes in LDLT patients.

DOI： 10.1016/j.transproceed.2017.09.017