Japanese living donor liver transplantation criteria for hepatocellular carcinoma: nationwide cohort study.

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

Recent trends and new developments in liver transplantation.

Liver transplantation (LT) has been an established treatment for end-staged liver disease for acute, chronic, metabolic diseases and liver cancer. Advanced surgical techniques, refined indications and contraindications for LT, improvements of donor selection, prognostic scorings system and immunosuppressive regimens have contributed to the improved outcomes of liver transplantation. The etiologies of cirrhosis have been shifting from viral hepatitis to metabolic associated fatty liver disease. New indications include peripheral or mass forming bile duct cancer, metastases from bowel cancers or neuroendocrine tumors. Resection and partial liver segments 2-3 transplantation with delayed total hepatectomy has been performed to the limited cases, which was the explored technique of auxiliary partial orthotopic LT. Minimally invasive donor hepatectomy (laparoscopic or robotic) has been increasingly done. In this review are described the recent pressing topics in LT.

Diagnostic accuracy of preoperative adhesion mapping by ultrasonography for laparoscopic surgery in patients with past abdominal surgery with special reference to loose adhesion.

PURPOSE: Endoscopic surgery is widely accepted for both elective and emergent abdominal surgery. This study was performed to assess the accuracy of preoperative adhesion mapping by abdominal ultrasonography (US). METHODS: Intra-abdominal intestinal adhesions on the abdominal wall in 50 patients with a history of abdominal surgery were prospectively assessed by the visceral slide test with US before laparoscopic surgery from 2019 to 2022. Adhesion was assessed in six separate abdominal zones during US. Actual adhesion on the abdominal wall was confirmed during laparoscopic surgery. RESULTS: The sliding distances in upper right, upper central, upper left, lower right, lower central, and lower left zones in patients with versus without intestinal adhesion were 4.4 versus 1.4 cm (P = .004), 3.4 versus 2.5 cm, 4.3 versus 1.3 cm (P = .011), 3.1 versus 1.5 cm (P = .0014), 3.3 versus 1.1 cm (P = .013), and 3.4 versus 0.8 cm (P = .0061), respectively. Receiver operating characteristic analysis revealed the optimal value of sliding distance as 2.5 cm and the area under the curve as 0.86. The specificity of US assessment of adhesion was lower in the central zone than in lateral zones. Loose adhesion mostly seen around the scar was attributed to either filmy tissue or omental adhesion, leading to visceral sliding during US. CONCLUSION: This study revealed the reason for insufficient accuracy of preoperative US assessment of intestinal adhesion around the scar area because of loose adhesion. The upper lateral area might be optimal for first port insertion.

Tumor-associated macrophages: The key player in hepatoblastoma microenvironment and the promising therapeutic target.

The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated macrophages (TAMs) are considered the core component. The crosstalk between TAMs and HB cells markedly influences tumor behavior. TAM-derived factors are involved in tumor proliferation and vascular invasion. On the other hand, HB cell secretome attracts, stimulates, and reprograms TAMs to be immunosuppressive in favor of tumor invasion, rather than their innate role in combating tumor growth, such crosstalk sometimes forms bidirectional feedback loops, making the tumor more virulent and resistant to routine therapeutics. Consequently, TAMs are the common denominator of most suggested HB immunotherapeutic strategies. Macrophage immune checkpoint inhibitors, macrophage-mediated antibody-dependent cellular phagocytosis, and the novel chimeric antigen receptor macrophage therapy (CAR Mφ) are currently under trial. In this review, we will summarize the significance of TAMs and their potential role as a therapeutic target in HB.

Advanced Cholangiocarcinoma With High Tumor Mutation Burden Achieving Complete Response to Immune Check Point Inhibitor.

BACKGROUND/AIM: Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial survival benefit for patients with advanced malignancies. CASE REPORT: A female patient in her 60s showed a stenosis of the afferent loop of the small intestine because of circumferential metastatic tumor 14 months after curative surgery for hilar cholangiocarcinoma. Chemotherapy with gemcitabine plus cisplatin was administered for 18 months. An oncopanel examination was performed during chemotherapy, and a high tumor mutation burden was revealed. At 38 months after surgery, a new recurrent tumor, 2.7 cm in size, was observed in the abdominal wall, which was histologically proven to be metastatic adenocarcinoma. Atezolizumab was administered. After three cycles of treatment, treatment was switched to pembrolizumab because of its acceptance by healthcare insurance. The recurrent tumors in the abdominal wall and small intestine disappeared 6 months after the administration of immune checkpoint inhibitor, and the patient has continued pembrolizumab, surviving for 76 months after surgery without any clinical evidence of tumor. CONCLUSION: Immune checkpoint blockade successfully prolonged the survival of a patient with advanced hilar cholangiocarcinoma with high tumor mutation burden, although the optimal number of mutations for such a successful response needs to be clarified.

Donor Complications Following Living Donor Hepatectomy: 17-Year Experience of a Single Team in One Institution of Japan.

OBJECTIVES: Donor safety is paramount in living donor liver transplantation. However, there remains a risk of postoperative complications for some donors. Here, we provide a comprehensive assessment of donor morbidity by a single team with 17 years of experience at a single center. MATERIALS AND METHODS: We retrospectively reviewed 453 donor hepatectomies of living donor liver transplants at Kumamoto University from August 2000 to March 2017. Posterior segment graft cases were excluded in this study. RESULTS: The donors were classified by graft type as follows: right lobe (n = 173), left lobe (n = 149), and left lateral segment (n = 131). The overall complication rate was 29.8%, and the severe complication (Clavien-Dindo grade IIIa or higher) rate was 9.1%. The most frequent complication was bile leakage, with an overall incidence of 13.9% and severe incidence of 4.6%. Among the 3 types of graft, there were no significant differences in bile leakage with any Clavien-Dindo grade. However, upper gastrointestinal complications, such as a duodenal ulcer and gastric stasis, were related to left lobe donation. CONCLUSIONS: There were no significant differences in the incidence of postoperative donor complications, except upper gastrointestinal complications, among the 3 types of graft.

Effects of the COVID-19 pandemic on short-term postoperative outcomes for colorectal perforation: A nationwide study in Japan based on the National Clinical Database.

Aim: Possible negative effects of the COVID-19 pandemic on short-term postoperative outcomes for colorectal perforation in Japan were examined in this study. Methods: The National Clinical Database (NCD) is a large-scale database including more than 95% of surgical cases in Japan. We analyzed 13 107 cases of colorectal perforation from 2019 to 2021. National data were analyzed, and subgroup analyses were conducted for subjects in prefectures with high infection levels (HILs) and metropolitan areas (Tokyo Met. and Osaka Pref.). Postoperative 30-day mortality, surgical mortality, and postoperative complications (Clavien-Dindo grade ≥3) were examined. Months were considered to have significantly high or low mortality or complication rates, if the 95% confidence interval (CI) of the standardized mortality (morbidity) ratio (SMR) does not contain 1. Results: In the NCD, postoperative 30-day mortality occurred in 1371 subjects (10.5%), surgical mortality in 1805 (13.8%), and postoperative complications in 3950 (30.1%). Significantly higher SMRs were found for 30-day mortality in November 2020 (14.6%, 1.39 [95% CI: 1.04-1.83]) and February 2021 (14.6%, 1.48 [95% CI: 1.10-1.96]), and for postoperative complications in June 2020 (37.3%, 1.28 [95% CI: 1.08-1.52]) and November 2020 (36.4%, 1.21 [95% CI: 1.01-1.44]). The SMRs for surgical mortality were not significantly high in any month. In prefectures with HILs and large metropolitan areas, there were few months with significantly higher SMRs. Conclusions: The COVID-19 pandemic had limited negative effects on postoperative outcomes in patients with colorectal perforation. These findings suggest that the emergency system for colorectal perforation in Japan was generally maintained during the pandemic.

A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure.

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.

Excess mortality in COVID-19-affected solid organ transplant recipients across the pandemic.

The excess mortality of coronavirus disease 2019 (COVID-19) solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOCs): Waves 1 to 3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1632 COVID-19-confirmed SOTRs included 1170 kidney, 408 liver, 25 lung, 20 heart, 1 small intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOCs transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1-12.5), 4.0 (1.5-10.6), 3.0 (1.3-6.7), 8.8 (5.3-14.5), and 21.9 (5.5-87.6) for Waves 1 to 3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount.

Combined Neutrophil-to-Lymphocyte Ratio Score Is Associated With Chemotherapeutic Response and Predicts Prognosis in Patients With Advanced Pancreatic Cancer.

BACKGROUND/AIM: Neutrophil-to-lymphocyte ratio (NLR) is a prognostic indicator for several malignancies, including pancreatic cancer. We developed a novel combined NLR score (cNLRS) based on baseline NLR and change in NLR after chemotherapy (ΔNLR), and examined its prognostic value and role in chemotherapeutic response in patients with advanced pancreatic cancer. PATIENTS AND METHODS: This study retrospectively assessed 210 advanced pancreatic cancer patients receiving chemotherapy between 2010 and 2021. The cNLRS was developed and its association with chemotherapeutic response and prognosis was investigated. RESULTS: The cNLRS consisted of baseline NLR ≥2.5 and ΔNLR ≥0, both of which were remained as independent poor predictors of prognosis adjusting for other traditional clinicopathological features. A high cNLRS served as an independent prognostic factor of reduced overall survival. Of note, the cNLRS was significantly associated with disease control rate and treatment duration not only in 1st line treatment but also in 2nd line treatment. CONCLUSION: The cNLRS established as a useful prognostic biomarker might be associated with chemotherapeutic response and could predict survival in advanced patients with pancreatic ductal adenocarcinoma treated with chemotherapy.

IL-32 production from lung adenocarcinoma cells is potentially involved in immunosuppressive microenvironment.

Interleukin 32 (IL-32) is a proinflammatory cytokine secreted from several kinds of cancer cells. In the present study, we investigated the significance of IL-32 in lung adenocarcinoma by immunohistochemistry and bioinformatics analysis. IL-32 was positive in cancer cells of 21 cases (9.2%) of total 228 cases. Increased IL-32 gene expression was linked to worse clinical course in TCGA analysis, however, IL-32 expression in immunohistochemistry was not associated to clinical course in our cohort. It was also found that high IL-32 expression was seen in cases with increased lymphocyte infiltration. In vitro studies indicated that IFN-γ induced gene expression of IL-32 and PD1-ligands in lung adenocarcinoma cell lines. IL-32, especially IL-32ß, also induced overexpression of PD1-ligands in human monocyte-derived macrophages. Additionally, Cancer-cell-derived IL-32 was elevated by stimulation with anticancer agents. In conclusion, IL-32 potentially induced by inflammatory conditions and anticancer therapy and contribute to immune escape of cancer cells via development the immunosuppressive microenvironment. IL-32 might be a target molecule for anti-cancer therapy.

Impact of the COVID-19 pandemic on the number and short-term outcomes in hepatectomy for hepatocellular carcinoma: Results from the Japanese National Clinical Database, 2018-2021.

AIM: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the allocation of medical resources, including cancer screening, diagnosis, and treatment. We aimed to investigate the effects of the pandemic on morbidity and mortality following hepatectomy for hepatocellular carcinoma (HCC). METHODS: We identified patients who underwent hepatectomy for HCC between 2018 and 2021 from the Japanese National Clinical Database (NCD). The number of surgical cases, the use of intensive care units, and the incidence of morbidity were assessed. The standardized morbidity / mortality ratio (SMR) was used to evaluate the rates of morbidity (bile leakage and pneumonia) and mortality in each month, which compares the observed incidence to the expected incidence calculated by the NCD's risk calculator. RESULTS: The study included a total of 10 647 cases. The number of patients undergoing hepatectomy for HCC gradually decreased. The proportion of patients aged 80 years or older increased and that of cases with T1 stage decreased. The proportion of patients who were admitted to the intensive care unit did not change between the pre- and postpandemic period. The mean actual incidence rates of bile leakage, pneumonia, 30-day mortality, and surgical mortality were 9.2%, 2.3%, 1.4%, and 2.1%, respectively. The SMR for the mortalities and morbidities in each month did not increase mostly throughout the COVID-19 pandemic. CONCLUSIONS: The present study showed the decreasing number of resected cases for HCC, while the surgical safety for hepatectomy was enough to be maintained by managing medical resources in Japan.

The expression analysis of SerpinB9 in hepatoblastoma microenvironment.

PURPOSE: In this research, we analyzed the expression of serpinB9 in hepatoblastoma and investigated the factors which enhance its expression. METHOD: SerpinB9 expression in hepatoblastoma cell lines and macrophages co-cultured with each other or stimulated by anticancer agents was examined using RT-qPCR and western blotting. Immunohistochemistry for SerpinB9 in hepatoblastoma specimens was performed. Single-cell RNA-sequence data for hepatoblastoma from an online database were analyzed to investigate which types of cells express SerpinB9. RESULT: HepG2, a hepatoblastoma cell line, exhibited increased expression of SerpinB9 when indirectly co-cultured with macrophages. Immunohistochemistry for the specimens demonstrated that serpinB9 is positive not in hepatoblastoma cells but in macrophages. Single-cell RNA sequence analysis in tissues from hepatoblastoma patients showed that macrophages expressed SerpinB9 more than tumor cells did. Co-culture of macrophages with hepatoblastoma cell lines led to the enhanced expression of SerpinB9 in both macrophages and cell lines. Anticancer agents induced an elevation of SerpinB9 in hepatoblastomas cell lines. CONCLUSION: In hepatoblastoma, SerpinB9 is thought to be more highly expressed in macrophages and enhanced by interaction with hepatoblastoma cell.

The First Successful Living Donor Liver Transplantation for Acute-on-Chronic Liver Failure Caused by Severe Acute Necrotizing Pancreatitis: A Case Report.

Liver transplantation (LT) is the only life-saving option when acute-on-chronic liver failure (ACLF) does not improve with conservative therapy. Acute pancreatitis (AP) can cause chronic liver disease progression to ACLF. However, deceased donor LT for patients with AP has had mixed results, and no consensus has been established regarding the indication for LT. We report the first successful living donor LT (LDLT) for ACLF caused by severe AP. The 38-year-old patient with alcoholic liver disease was transferred to our institute with worsening refractory ascites. During the pretransplant workup, she developed severe acute necrotizing pancreatitis, resulting in grade 3 ACLF. The patient's clinical course was further complicated by high levels of donor-specific antibodies and immune thrombocytopenia. The AP gradually improved after intensive care combined with artificial liver support. The patient successfully underwent urgent LDLT with upfront splenectomy and desensitization therapy, including plasm exchange, high-dose intravenous immunoglobulin, and anti-thymocyte globulin. No infection or recurrence of AP was observed postoperatively. We conclude that LDLT is a feasible option for ACLF patients caused by severe AP if a deceased donor is not readily available.

Impact of COVID-19 pandemic on short-term outcomes after low anterior resection in patients with rectal cancer: Analysis of data from the Japanese National Clinical Database.

Aim: The Coronavirus Disease 2019 (COVID-19) pandemic affected the allocation of various medical resources to several areas, including intensive care units (ICUs). However, currently, its impact on the short-term postoperative outcomes of gastrointestinal cancer surgeries remains unclear. We aimed to evaluate the impact of the pandemic on the incidence of complications occurring after low anterior resection in patients with rectal cancer in Japan. Methods: Data from the Japanese National Clinical Database between 2018 and 2021 were retrospectively examined. The primary outcome of the study was the postoperative morbidity and mortality rates before and after COVID-19 pandemic. Moreover, the postoperative ICU admission rate was assessed. Morbidity and mortality rates were also assessed using a standardized morbidity/mortality ratio (SMR, the ratio of the actual number of incidences to the expected number of incidences calculated by the risk calculator). Results: This study included 74 181 patients, including 43 663 (58.9%) from COVID-19 epidemic areas. The mean actual incidences of anastomotic leakage (AL) and pneumonia during the study period were 9.2% and 0.9%, respectively. The SMRs of these complications did not increase during the pandemic but those of AL declined gradually. The mean 30-day mortality and operative mortality rates were 0.3% and 0.5%, respectively. Moreover, SMRs did not change significantly in the pandemic or regional epidemic status. The ICU admission rate temporarily decreased, especially in the epidemic areas. Conclusion: Although the pandemic temporarily decreased the ICU admission rate, its impact on short-term outcomes following low anterior resection in patients with rectal cancer was insignificant in Japan.

Feasible living donor liver transplantation for patients on chronic hemodialysis: a multicenter study in East Asian countries.

PURPOSES: End-stage liver and kidney disease is an indication for simultaneous liver and kidney transplantation. However, in countries where deceased donor transplantation is not well established, living donor liver transplantation (LDLT) is a realistic option for patients on hemodialysis (HD). We investigated the outcomes of LDLT for patients on HD. METHODS: We conducted a retrospective multicenter survey of patients on chronic HD who underwent LDLT in East Asian countries. The characteristics of donors and recipients and the short and long-term outcomes were analyzed. RESULTS: Between 2001 and 2021, 45 patients on HD underwent LDLT and 11 of these patients also underwent kidney transplantation (KT). The overall survival rate at 5 years of the 34 patients who underwent only LDLT was 44.5%. Multivariate analysis identified a low graft recipient weight ratio (< 1%) (p = 0.048) and long HD duration (≥ 10 years) (p = 0.046) as independent predictors of poor overall survival. The major complication was posttransplant bleeding, which occurred in12 patients (35%). CONCLUSION: It is important to establish the indications for LDLT, taking into consideration graft size and HD duration in candidate patients on HD.

Overexpression of SerpinB9 in non-seminomatous germ cell tumors.

Serpinb9 is an inhibitor of granzyme B and is potentially involved in the immune escape of tumor cells. In the present study, bioinformatics analysis using open databases suggested that SerpinB9 is overexpressed in testicular embryonal carcinoma. Immunohistological analysis was performed on 28 cases of testicular germ cell tumors to investigate the relationship between SerpinB9 expression in testicular germ cell tumors and the tumor immune environment. SerpinB9 was significantly upregulated in the non-seminoma group and inversely correlated with the number of tumor-infiltrating CD8-positive cells. In addition, yolk sac tumors were characterized by the loss of human leukocyte antigen-class I expression. These findings suggest that SerpinB9 contributes to the immune escape of testicular germ cell tumors. Targeting therapy for SerpinB9 might therefore be useful in immunotherapy for testicular germ cell tumors resistant to immune checkpoint inhibitors.

Impact of the coronavirus disease 2019 pandemic on 20 representative surgical procedures in Japan based on the National Clinical Database: annual surveillance of 2021 by the Japan Surgical Society.

PURPOSE: The volume of surgical services has significantly reduced globally due to the coronavirus disease 2019 (COVID-19) pandemic. This study evaluated the level of recovery in terms of the number of operations performed in Japan in 2021, based on nationwide periodic surveillance. METHODS: Information on the weekly and annual volumes of 20 representative procedures in 6 surgical subspecialties in 2021 was extracted from the National Clinical Database. Statistical data for 2018 and 2019 (pre-pandemic era) were compared with those for 2020. Data on waves of infection, peak period, and high-prevalence areas (13 of 47 prefectures) were analyzed individually. RESULTS: The volumes of the 10 procedures, including gastrectomy, hepatectomy, valve replacement and valve plasty, coronary artery bypass grafting, infrarenal abdominal aorta replacement, ventricular septal defect closure, lung lobectomy, inguinal hernia repair (age < 16 years old), and appendectomy (age < 16 years old), did not reach 95% of that in the pre-pandemic era. The most striking decline in the surgical volume of these 10 procedures was observed during the peak period of wave 5 in high-prevalence areas. CONCLUSION: This near-complete enumeration survey identified the polarization of 20 representative procedures in terms of resumption of surgical service after the pandemic.