Hepatocyte Growth Factor DNA Aptamer for Prevention of Postoperative Peritoneal Adhesion via Enhancement of Fibrinolysis and Inhibition of Mesothelial Mesenchymal Transition.

Postoperative peritoneal adhesion (PPA) is a prevalent complication of abdominal surgery, posing a significant hindrance to postsurgical recovery. Although several strategies have been developed to alleviate and prevent adhesions, their efficacy remains unsatisfactory. For the first time, we studied the therapeutic effect and mechanism of our recently developed thermally stable oligonucleotide-based mimetics of hepatocyte growth factor (HGF DNA aptamer) to prevent PPA. The HGF DNA aptamer effectively inhibited canonical TGF-ß1 signaling transduction, partially suppressing mesothelial mesenchymal transition. Additionally, the aptamer, respectively, upregulated and downregulated the expression of tissue plasminogen activator and plasminogen activator inhibitor 1, thereby enhancing fibrinolytic activity. As a pleiotropic factor, the HGF DNA aptamer also enhanced the migratory and proliferative capacities of mesothelial cells. Finally, the aptamer demonstrated a higher level of effectiveness in preventing PPAs than the commercially available antiperitoneal adhesion barrier, Seprafilm. Due to its therapeutic benefits, excellent stability, biosafety, cost-effectiveness, and versatility, the HGF DNA aptamer demonstrates promise for preventing PPA in future clinical settings.

Loss of ATRX and DAXX in pancreatic neuroendocrine tumors: Association with recurrence risk, cellular phenotype, and heterogeneity.

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm based on emerging biomarkers, including chromatin-remodeling molecules DAXX/ATRX/H3K36me3, in conjunction with established prognostic factors, such as WHO grade and size. In immunohistochemical analyses, 18 of the 111 (16.2%) primary PanNETs showed DAXX or ATRX loss in a mutually exclusive manner. DAXX/ATRX loss was significantly correlated with higher recurrence risk and better predicted postoperative recurrence than WHO grade. We proposed a novel algorithm for stratifying patients with resectable PanNET into three groups according to recurrence risk: (A) WHO Grade 1 and ≤2 cm (very low-risk); for the others, (B) retained DAXX/ATRX (low-risk) and (C) DAXX/ATRX complete/heterogeneous loss (high-risk). Furthermore, we elucidated the intratumoral heterogeneities of PanNETs. Among cases with DAXX or ATRX loss, nine cases demonstrated heterogeneous loss of expression of DAXX/ATRX/H3K36me3. The majority of cases with DAXX/ATRX loss, either homogeneous or heterogeneous loss, showed uniform α-cell-like phenotype (ARX1+/PDX1-). In cases of metastatic or recurrent tumors, the expression pattern was identical to that observed in at least part of the primary tumor. In some instances, the expression pattern differed among different metastatic or recurrent tumors of the same patient. In summary, we propose a clinically useful and practical algorithm for postoperative recurrence risk stratification in PanNETs, by combining DAXX/ATRX status with WHO grade and size. Moreover, our findings highlighted the frequent spatiotemporal heterogeneity of chromatin-remodeling molecule expression in PanNETs with an α-cell phenotype, offering insights into tumorigenesis.

Evaluation of two-stage hepatectomy using portal vein embolization for colorectal liver metastasis: a retrospective nationwide cohort survey in Japan.

INTRODUCTION: Two-stage hepatectomy (TSH) enables patients to undergo surgery for colorectal liver metastasis (CRLM) which one-stage hepatectomy cannot remove. Although the outcome of TSH has been reported, there is no original report from Japan. The aim of this retrospective study was to evaluate the outcome of TSH in Japanese patients with CRLM. METHODS: We conducted a retrospective cohort study using the nationwide database that included clinical information of 12,519 patients treated with CRLM between 2005 and 2017 in Japan. The primary outcome measure was overall survival. The second outcome measure was progression-free survival. Fisher's exact test, chi-squared test and Mann-Whitney U test were conducted to examine an intergroup difference. Univariate and multivariate analyses were performed using Cox regression model. Survival analysis was performed by Kaplan-Meier method and log-rank test. RESULTS: Of the database, 53 patients undergoing TSH using portal vein embolization (PVE) were identified and analyzed. Their morbidity and in-hospital mortality rate at the second hepatectomy were 26.4% and 0.0%. The mean observation period was 21.8 months. The estimated 1-, 3- and 5-year overall survival rate were 92.5%, 70.8% and 34.7%. Multivariate analyses showed that more than 10 liver nodules significantly increased the mortality risk by 4.2-fold (95%CI 1.224-14.99, P= 0.023). Survival analysis revealed that repeat hepatectomy for disease progression after TSH was superior to chemotherapy in overall survival (mean: 49.6 vs. 18.7, months, P= 0.004). CONCLUSION: In the Japanese cohort, TSH was confirmed to be a safety procedure with acceptable survival outcome. More than 10 liver nodules may be a predictor for unfavorable outcome of patients with CRLM undergoing TSH. Furthermore, repeat hepatectomy can be a salvage treatment for resectable intrahepatic recurrence after TSH.

The Revised Kyoto Criteria and Risk of Malignancy Among Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: The revised Kyoto guidelines have a new catalog of high-risk stigmata and worrisome features for the risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We aimed to validate the stratification system in terms of short- and long-term risks of pancreatic carcinoma. METHODS: We included 3,336 patients diagnosed with IPMNs in 2000-2021 and examined short-term (≤ 6 months) and long-term risks of pancreatic carcinoma diagnosis. We used the multivariable competing-risks proportional hazards regression model to calculate subdistribution hazard ratios for long-term incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In short-term analyses, pancreatic carcinomas were prevalent predominantly in IPMNs with high-risk stigmata (49% vs. 1.3% and 0.05% in IPMNs with worrisome features and no risk factors, respectively). In long-term analyses of worrisome features, the main pancreatic duct diameter of 5-9.9 mm, acute pancreatitis, and IPMN growth rate of 2.5 mm/year were associated with a high incidence with multivariable subdistribution hazard ratios (95% confidence intervals) of 3.46 (2.04-5.89), 5.65 (1.86-17.2), and 3.83 (2.14-6.86), respectively. An increasing number of worrisome features at baseline was associated with a higher prevalence and incidence of pancreatic carcinoma (Ptrend < .001). Patients with 1, 2, and 3-4 worrisome features had multivariable subdistribution hazard ratios (95% confidence intervals) for pancreatic cancer incidence of 1.43 (0.93-2.19), 2.17 (1.17-4.05), and 10.1 (4.20-24.5), respectively (vs. no positive feature). CONCLUSIONS: The revised Kyoto criteria stratify IPMN patients well in terms of the short- and long-term risks of pancreatic carcinoma diagnosis, potentially informing personalized patient management.

A Multicenter Phase 2 Trial Evaluating the Efficacy and Safety of Preoperative Lenvatinib Therapy for Patients with Advanced Hepatocellular Carcinoma (LENS-HCC Trial).

Introduction: The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC. Methods: In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 min as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057). Results: Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months. Conclusions: The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC.

PRKACA/PRKACB Fusions in Pancreatobiliary Intraductal Oncocytic Papillary Neoplasms Including Those With Atypical Morphology: An Analysis of 22 Cases Expanding Morphologic Spectrum.

Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreatobiliary tract are considered a separate entity from intraductal papillary mucinous neoplasms (IPMNs), especially because of the distinct molecular alterations represented by PRKACA or PRKACB fusion. However, IOPNs display a spectrum of cytoarchitectural features. Typically, an IOPN is composed of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent nucleoli, and intraepithelial lumina, while a significant subset shows atypical morphology: lack of the characteristic cytoarchitectural features such as arborizing papillae and prominent nucleoli, or mixture with nononcocytic IPMN-like components within a single lesion. To elucidate the tumorigenesis and morphologic spectrum of IOPNs, we analyzed 22 IOPNs, including those with atypical morphology for PRKACA/PRKACB fusions in each different component separately using fluorescence in situ hybridization. In total, 18 of 22 (82%) cases harbored PRKACA/PRKACB fusions, including 3 of 3 (100%) purely typical IOPNs and 15 of 19 (79%) IOPNs with atypical morphology. In the latter, PRKACA/PRKACB fusions were noted in atypical components as well as typical IOPN components. Notably, gastric-type IPMN-like components in the fusion-positive cases were usually low grade and had scattered neoplastic cells with eosinophilic cytoplasm, a morphologic feature suggestive of an early lesion of IOPN. In summary, most IOPNs with atypical morphology either lack characteristic cytoarchitectural features or exhibit a mixture with nononcocytic IPMN-like components, harbored PRKACA/PRKACB fusion as did typical IOPN components. Our observations expanded the morphologic spectrum of IOPNs. They are expected to be useful for correct diagnosis of this neoplasm.

Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis.

Background: While surufatinib, sunitinib, and everolimus have shown efficacy for advanced neuroendocrine neoplasms (NENs) in randomized controlled trials (RCTs), direct comparisons in a real-world setting remain unexplored. This gap highlights the clinical need to understand their comparative effectiveness and safety within the diverse Chinese population. Addressing this, our study provides insights into the real-world performance of these therapies, aiming to inform treatment selection and improve patient outcomes. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs treated with surufatinib, sunitinib, or everolimus between July 2020 and April 2023. Eligibility criteria focused on histologically confirmed, locally advanced, unresectable, or metastatic NENs, with patients having received at least one month of targeted therapy. We employed inverse probability weighting (IPW) with the propensity score (PS) matching to adjust for the bias of baseline characteristics. The assessment of covariates included age, sex, performance status, primary tumor site, functional status, genetic mutations, tumor differentiation, Ki67 index, tumor grade, metastasis site, and previous therapies. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: The study enrolled 123, 56, and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib, and everolimus, respectively. Before adjusting for confounding factors, surufatinib was used less frequently as a first-line treatment compared to sunitinib and everolimus in pancreatic NENs (pNENs) (11.1% vs. 22.1%, P=0.057). Significant differences were noted in prior treatments and tumor characteristics between surufatinib and everolimus groups in extrapancreatic NENs (epNENs) (P<0.05). Post-IPW, these disparities were resolved (P>0.05). Surufatinib demonstrated superior median PFS (mPFS) in both pancreatic [8.30 vs. 6.33 months, hazard ratio (HR) 0.592, P<0.001] and epNENs (8.73 vs. 3.70 months, HR 0.608, P<0.001) compared to everolimus or sunitinib. Notably, male gender (HR 1.75, P=0.001), functional status (HR 2.09, P=0.01), Ki67 index >20% (HR 12.7, P=0.004), previous somatostatin analogue (SSA) treatment (HR 1.73, P=0.001), germline mutation (HR 5.62, P<0.001), poor differentiation (HR 7.45, P<0.001), liver metastasis (HR 1.72, P=0.001) and multiple treatment lines (HR 1.62 for 2nd line, P=0.04; HR 1.88 for ≥3rd line, P=0.01) were identified as negative prognostic factors for PFS. Conversely, dose adjustment (HR 0.63, P=0.009) and treatment with surufatinib (HR 0.58 for pNEN, P<0.001; HR 0.62 for epNEN, P=0.002) were correlated with longer PFS. Conclusions: In a real-world Chinese cohort, surufatinib significantly outperformed sunitinib and everolimus in prolonging PFS among advanced NEN patients, with identifiable clinical features impacting survival, and conclusions regarding superiority should be interpreted with caution due to the retrospective design. Our findings underscore the need for prospective studies to further validate these results and explore additional predictive biomarkers for personalized treatment strategies.

Resection and reconstruction of the largest abdominal vein system (the inferior vena cava, hepatic, and portal vein): a narrative review.

Background and Objective: As tumors invade major abdominal veins, surgical procedures are transformed from simple and basic to complicated and challenging. In this narrative review, we focus on what is currently known and not known regarding the technical aspects of major abdominal venous resection and its reconstruction, patency, and oncologic benefit in a cross-cutting perspective. Methods: A systematic literature search was performed in PubMed and Semantic Scholar from inception up to October 18, 2023. We reviewed 106 papers by title, abstract, and full text regarding resection or reconstruction of the inferior vena cava, hepatic vein confluence, portal vein (PV), and middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT) in a cross-cutting perspective. Key Content and Findings: The oncologic benefit of aggressive hepatic vein resection with suitable reconstruction against adenocarcinoma remains unclear, and further studies are required to clarify this point. A superior mesenteric/PV resection is now a universal, indispensable, and effective procedure for pancreatic ductal adenocarcinoma. Although many case series using tailor-made autologous venous grafts have been reported, not only size mismatch but also additional surgical incisions and a longer operation time remain obstacles for venous reconstruction. The use of autologous alternative tissue remains only an alternative procedure because the patency rate of customized tubular conduit type to interpose or replace the resected vein is not known. Unlike arterial replacement, venous replacement using synthetic vascular grafts is still rarely reported and there are several inherent limitations except for reconstruction of tributaries of MHV in LDLT. Conclusions: Various approaches to abdominal vein resection and replacement or reconstruction are technically feasible with satisfactory results. Synthetic vascular grafts may be appropriate but have a certain rate of complications.

Three-Dimensional Bio-Printed Tubular Tissue Using Dermal Fibroblast Cells as a New Tissue-Engineered Vascular Graft for Venous Replacement.

The current study was a preliminary evaluation of the feasibility and biologic features of three-dimensionally bio-printed tissue-engineered (3D bio-printed) vascular grafts comprising dermal fibroblast spheroids for venous replacement in rats and swine. The scaffold-free tubular tissue was made by the 3D bio-printer with normal human dermal fibroblasts. The tubular tissues were implanted into the infrarenal inferior vena cava of 4 male F344-rnu/rnu athymic nude rats and the short-term patency and histologic features were analyzed. A larger 3D bio-printed swine dermal fibroblast-derived prototype of tubular tissue was implanted into the right jugular vein of a swine and patency was evaluated at 4 weeks. The short-term patency rate was 100%. Immunohistochemistry analysis showed von Willebrand factor positivity on day 2, with more limited positivity observed on the luminal surface on day 5. Although the cross-sectional area of the wall differed significantly between preimplantation and days 2 and 5, suggesting swelling of the tubular tissue wall (both p < 0.01), the luminal diameter of the tubular tissues was not significantly altered during this period. The 3D bio-printed scaffold-free tubular tissues using human dermal or swine fibroblast spheroids may produce better tissue-engineered vascular grafts for venous replacement in rats or swine.

The Role of Frequent Screening or Diagnostic Testing of Serum Cryptococcal Antigen in Liver Transplant Recipients: A Descriptive Epidemiology.

Background: Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. Methods: This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus, we manually reviewed clinical manifestations, management, and prognosis from the medical records. Results: During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. Conclusions: Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results.

Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer.

OBJECTIVE: To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. SUMMARY BACKGROUND DATA: Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. METHODS: Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. RESULTS: Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). CONCLUSIONS: The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.

The impact of COVID-19 on the diagnosis and treatment of HCC: analysis of a nationwide registry for advanced liver diseases (REAL).

The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Is Repeat Resection for Recurrent Intrahepatic Cholangiocarcinoma Warranted? Outcomes of an International Analysis.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR) remains high, and optimal therapy for recurrent ICC is challenging. Herein, we assess the outcomes of patients undergoing repeat resection for recurrent ICC in a large, international multicenter cohort. PATIENTS AND METHODS: Outcomes of adults from six large hepatobiliary centers in North America, Europe, and Asia with recurrent ICC following primary LR between 2001 and 2015 were analyzed. Cox models determined predictors of post-recurrence survival. RESULTS: Of patients undergoing LR for ICC, 499 developed recurrence. The median time to recurrence was 10 months, and 47% were intrahepatic. Overall 3-year post-recurrence survival rate was 28.6%. In total, 121 patients (25%) underwent repeat resection, including 74 (61%) repeat LRs. Surgically treated patients were more likely to have solitary intrahepatic recurrences and significantly prolonged survival compared with those receiving locoregional or systemic therapy alone with a 3-year post-recurrence survival rate of 47%. Independent predictors of post-recurrence death included time to recurrence < 1 year [HR 1.66 (1.32-2.10), p < 0.001], site of recurrence [HR 1.74 (1.28-2.38), p < 0.001], macrovascular invasion [HR 1.43 (1.05-1.95), p = 0.024], and size of recurrence > 3 cm [HR 1.68 (1.24-2.29), p = 0.001]. Repeat resection was independently associated with decreased post-recurrence death [HR 0.58 0.43-0.78), p < 0.001]. CONCLUSIONS: Repeat resection for recurrent ICC in select patients can result in extended survival. Thus, challenging the paradigm of offering these patients locoregional or chemo/palliative therapy alone as the mainstay of treatment.

Thick silk fibroin vascular graft: A promising tissue-engineered scaffold material for abdominal vein grafts in middle-sized mammals.

Abdominal vein replacement with synthetic tissue-engineered vascular grafts constructed from silk-based scaffold material has not been reported in middle-sized mammals. Fourteen canines that underwent caudal vena cava replacement with a silk fibroin (SF) vascular graft (15 mm long and 8 mm diameter) prepared with natural silk biocompatible thread were allocated to two groups, thin and thick SF groups, based on the graft wall thickness. The short-term patency rate and histologic reactions were compared. The patency rate at 2 weeks after replacement in the thin and thick SF groups was 50% and 88%, respectively (p = 0.04). CD31-positive endothelial cells covered the luminal surface of both groups at 4 weeks. The elastic modulus of the thick SF graft was significantly better than that of the thin SF graft (0.0210 and 0.0007 N/m2, p < 0.01). Roundness of thick SF groups (o = 0.8 mm) was better than thin SF (o = 2.0 mm). There was significant difference between the groups (p = 0.01). SF vascular grafts are a promising tissue-engineered scaffold material for abdominal venous system replacement in middle-sized mammals, with thick-walled grafts being superior to thin-walled grafts.

Update on the Diagnosis and Treatment of Combined Hepatocellular Cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a unique type of liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components within a single tumor. The fifth edition of the World Health Organization classification provides a definition and diagnostic criteria for cHCC-CCA. However, the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment. A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepatocellular carcinoma and cholangiocarcinoma, a mixed enhancement pattern on imaging, and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern. Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diagnosing cHCC-CCA, and comprehensive examination of resection or biopsy specimens is crucial for an accurate diagnosis. Currently, there is no standard treatment for cHCC-CCA, and surgery is the mainstay. Anatomic hepatectomy with lymphadenectomy is among the recommended surgical procedures. The role of liver transplantation in the management of cHCC-CCA is still uncertain. Transarterial chemoembolization may be effective for unresectable cHCC-CCA, particularly for hypervascular tumors. However, the available evidence does not support systemic therapy for advanced cHCC-CCA. The prognosis of cHCC-CCA is generally poor, and there is no established staging system. Further research is needed to better understand the histogenesis and clinical management of cHCC-CCA. This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical characteristics, pathological diagnosis, and management.

Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study.

BACKGROUND: International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. METHODS: An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005-2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. RESULTS: Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). CONCLUSION: This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.

The Effect of Renin-Angiotensin System Inhibitors in Patients Undergoing Pancreatic Cancer Resection.

OBJECTIVES: The local renin-angiotensin system promotes angiogenesis and proliferation via vascular endothelial growth factor or epidermal growth factor receptor expression. In this study, we aimed to evaluate the impact of angiotensin system inhibitors (ASIs) on long-term outcomes in patients undergoing surgical resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: A single institutional retrospective analysis was performed using the medical records of patients who underwent pancreatic resection with curative intent for PDAC between January 2005 and December 2018. Patient characteristics and surgical outcomes were compared between patients taking ASIs and those who are not. RESULTS: A total of 272 patients were included in the study and classified into the ASI group (n = 121) and the non-ASI group (n = 151). The median overall survival times in the ASI group and non-ASI group were 38.0 and 34.0 months ( P = 0.250), and the median recurrence-free survival times were 24.0 and 15.0 months ( P = 0.025), respectively. Multivariate analysis for recurrence-free survival identified the use of ASIs ( P = 0.020), CA19-9 level >500 IU/L ( P = 0.010), positive lymph node metastasis ( P < 0.001), and no adjuvant chemotherapy ( P < 0.001) as independent prognostic factors. CONCLUSIONS: The use of ASI may improve long-term outcomes after surgery for PDAC.

Metallic Stents for Hepatic Venous Outflow Obstruction After Living-Donor Liver Transplantation and their Therapeutic Effects.

BACKGROUND: Living-donor liver transplantation (LDLT) is established as a standard therapy for end-stage liver disease; however, vessel reconstruction is more demanding due to the short length and small size of the available structures compared with deceased-donor whole liver transplantation. Interventional radiology (IR) has become the first-line treatment for vascular complications after LDLT. Hepatic venous outflow obstruction (HVOO) is a life-threatening complication after LDLT. The aim of this study of 592 adult-to-adult LDLT cases was to investigate the safety and efficacy of stent implantation for HVOO after LDLT. METHODS: Records of patients who developed HVOO requiring any treatment were collected with special reference to the metallic stent implantation. There were 232 left-side grafts and 360 right-side grafts. Sixteen cases developed HVOO after LDLT with an incidence rate of 2.7%, 5 with a left liver graft (2%), and 11 with a right-side graft (3%). The IR was attempted for 14 cases; among those, 8 cases were treated by stent implantation. RESULTS: The technical success rate of the initial stent implantation was 100%. The pressure gradient at the stenotic site significantly improved from 12.2 (range, 10.9-20.4 cm H2O) to 3.9 cm H2O (range, 1.4-8.2 cm H2O; P = .03). The volume of the congested graft liver decreased significantly from 1448 (range, 788-2170 mL) to 1265 mL (range, 748-1665 mL; P = .01), and the serum albumin level improved significantly from 3.3 (range, 1.7-3.7 g/dL) to 3.7 g/dL (range, 2.9-4.1 g/dL; P = .02). No procedure-related complication was noted, and the long-term stent patency was 100%. CONCLUSION: Metallic stent implantation for stenotic venous anastomosis after LDLT is a safe and effective treatment.