Background & Aims: The use of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention-to-treat (ITT) outcomes in the peri-transplant setting are currently based on small and heterogenous single-center reports. Methods: This first multiregional US study (2016-2023) included 117 consecutive patients with HCC assessed for liver transplantation (LT) and treated preoperatively with ICIs. ITT and survival analyses were conducted with evaluation of post-LT rejection rates. Results: In total, 86 (73.5%) patients exceeded Milan criteria (MC) and 65 (75.6%) were successfully downstaged within a median of 5.6 months; 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) who were initially beyond but were downstaged. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included being beyond MC (p <0.001), alpha-fetoprotein doubling from baseline (p = 0.014) and radiographic responses (p <0.001). The 3-year ITT survival rate was 71.1% (73.5% within MC vs. 69.7% beyond MC, p = 0.329), with a 3-year post-LT survival rate of 85%. Post-LT rejection occurred in seven patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. Conclusions: The first multicenter evaluation of patients with HCC receiving ICIs pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of alpha-fetoprotein levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. (c) 2024 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

614 Background: Liver transplantation (LT) offers a 5-year survival exceeding 70% for selected patients with hepatocellular carcinoma (HCC). Immune checkpoint inhibitors (ICIs) may be used to downstage or bridge to transplantation. This study aims to evaluate the safety of ICIs prior to LT. Methods: Multicenter retrospective study, involving 9 centers, included adults who received ICIs and, subsequent LT, between 2019 and 2023. The ICI cohort was matched by age, sex, liver diseases and transplant date (1:3) with a similar cohort of HCC transplanted patients that did not receive ICIs. Results: The ICI cohort included 45 patients (Table part 1). The most common underlying liver diseases were viral. 15.5% of patients had macrovascular invasion and, 62.2% multifocal disease. The most commonly used ICI was nivolumab (75.6%), followed by atezolizumab-bevacizumab (17.8%). The median follow up was 32.5 months (17.4 - 47.6). The median ICI duration was 147 days (129.5-276.5), with a median interval of 58 days (22–193) between the last ICI dose and LT. There were 8 (17.8%) cases of graft rejection, 2 steroid-resistant leading to 1 graft failure. There were 4 (8%) HCC recurrences. During follow-up there were 6 deaths, 2 related to HCC recurrence and 4 non liver related. When compared with 135 non-ICI cohort patients, there were no differences within the groups (Table part 2). Importantly, we found no significant differences in crude rejection rates (p=0.5). Conclusions: Our study suggest that ICI treatment prior to LT is safe. ICI rejection primarily occurs in the acute post-transplant period (within 3 months), with a low risk of death due to graft failure. Further clinical trials are needed. Part 1: ICI cohort descriptive analysis. N (%); Median (IQR); Part 2: Comparison between cohorts. N (%); Mean (SD). (part 1) ICI-cohort n=45 General data Male 38 (84.4) Age 61.2 (7.6) Etiology of liver diseases Hepatitis C 17 (37.8)Hepatitis B 6 (13.3)MASLD 6 (13.3)Viral +Alcohol 5 (11.1)Alcohol 3 (6.7)Autoimmune 3 (6.7)Other 3 (6.7)Combined viral 2 (4.4) Largest tumor (mm) 39 (22) Macrovascular invasion 7 (15.5) Multifocal 28 (62.2) Locoregional therapy 36 (80.0) Number of locoregional therapies 2 (2) Immunotherapy Nivolumab 34 (75.6) Atezolizumab/bevacizumab 8 (17.8) Pembrolizumab 1 (2.2) Nivolumab+pembrolizumab 1 (2.2) PD1 inhibitor clinical trial 1 (2.2) Days of ICI treatment 147 (203) Radiological tumor response ICI No 17 (37.8) Transplant Deceased donor 43 (95.6) Washout period (days) 58 (171) Induction therapy (anti-thymoglobulin) 8 (17.8) Outcomes Rejection Biopsy proven 8 (17.8) 8 (100) Time to rejection (days) 43 (102) Graft failure Rejection 2 (4.4)1 (2.2) HCC recurrence 4 (8) Deaths 6 (13.3) Follow up Since transplant (months) 32.5 (30.2) (part 2) ICI-cohort (n=45) Non-ICI cohort (n= 135) P Post transplant rejection rate 8 (17.8) 32 (23.7) 0.53 Time to rejection (days) 180.1 (SD 218) 62.2 (SD 62.8) 0.25 Overall deaths 6 (13.3) 10 (7.4) 0.36

Background: In the current “sickest first” allocation policy for limited deceased liver grafts, identifying patients “too sick to transplant” before transplantation is crucial to optimize outcomes. This study aimed to predict futile outcomes following deceased donor liver transplantation (DDLT) in patients with Model for End-Stage Liver Disease-Sodium (MELD-Na) scores ≥30. Methods: This international multicenter study was conducted as part of the International Society of Liver Surgeons. We collected data from patients with a MELD-Na score ≥30 who underwent DDLT. A total of 994 patients were enrolled between 2010–2021, including 654 from the Republic of Korea, 224 from the US, and 116 from other regions. Futility was defined as death within three months or during the hospital stay following a DDLT. After exclusion, 160 (16.6%) patients were classified into a futile group and 803 (83.4%) into a non-futile group. Results: The MELD-Na scores collected at three time points (listing, matching, and transplantation) were comparable between the groups (P = 0.442, P = 0.180, and P = 0.554, respectively). Regarding concomitant organ failure factors, the futile group showed a higher incidence of organ dysfunction across all measured parameters, including the use of mechanical ventilators, continuous renal replacement therapy (CRRT), pneumonia, bacteremia, and vasopressor use (all P<0.01). Independent risk factors for futile outcome were recipient age (≥65 years), body mass index (<18.5 kg/m 2 ), mechanical ventilator use, CRRT (≥1 week), and prolonged ICU stay before transplantation (≥2 weeks). The futility rate was 53.3% in patients with ≥3 risk factors (P<0.001). We developed a nomogram to predict futility after DDLT based on multivariate regression analysis, which showed a better predictive power than previous models. Conclusions: The risk factors and new nomogram, which adequately reflect concomitant organ failure before liver transplantation, could effectively predict the risk of futile outcomes after DDLT and contribute to decision-making regarding transplantation eligibility in clinical practice.

Background & Aims: The combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT). In this study, we investigate the clinical efficacy and the safety profile of pre-transplant administration of atezolizumab and bevacizumab for HCC. Methods: Herein, we performed a prospective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers. Results: Among the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan criteria. Neoadjuvant locoregional therapies along with the administration of atezolizumab plus bevacizumab (median: 5 months; discontinued at least 4 weeks prior to LT) led to an objective response rate of 94% (complete response: 59%), downstaging to within Milan criteria (82%) and a pathological response at explant examination of 88%. Grade 3-4 treatment-related adverse events accounted for 17.6% of cases and were manageable. During the 25-month median follow-up period, two cases of mild (rejection activity index ≤4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss were reported. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively. Conclusions: This study highlights the favorable oncological and survival outcomes associated with atezolizumab and bevacizumab treatment in the pre-LT setting. This immune-based combination was safe in terms of treatment-related adverse events, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages. Impact and Implications:: Studies on the combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma have been limited, despite its potential to enhance anti-tumor responses and downstaging, owing to concerns about its safety profile. Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within Milan criteria, 94% radiological objective response and 88% pathology response, without drop-outs due to treatment-related adverse events or graft loss. The neoadjuvant combination of atezolizumab plus bevacizumab prior to liver transplantation for hepatocellular carcinoma shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment, leading to improved oncological outcomes.

BACKGROUND AND AIMS:Patients with HCC meeting United Network for Organ Sharing (UNOS)-downstaging (DS) criteria have excellent post-liver transplantation (LT) outcomes. Studies on HCC beyond UNOS-DS criteria ("All-Comers" [AC]) have been limited by small sample size and short follow-up time, prompting this analysis. APPROACH AND RESULTS:Three hundred twenty-six patients meeting UNOS-DS and 190 meeting AC criteria from 9 LT centers across 5 UNOS regions were enrolled from 2015 to 2023 and prospectively followed. Competing risk analysis and Kaplan-Meier method were used to evaluate DS and LT outcomes, and Fine-and-Gray and Cox models were used to identify predictors of outcomes. AC and UNOS-DS had similar median alpha-fetoprotein (15 vs. 12 ng/mL; p =0.08), MELD (9 vs. 9; p =0.52), and Child-Pugh (A vs. A; p =0.30). Two years after the first local regional therapy, 82% of UNOS-DS and 66% of AC were successfully downstaged ( p <0.001). In AC, DS rates were 72% for tumor number plus diameter of largest lesion <10, 51% for sum 10-12, and 39% for sum >12 ( p =0.01). Yttrium-90 achieved higher DS success than transarterial chemoembolization in AC (74% vs. 65%; p <0.001). 48% of UNOS-DS and 40% of AC underwent LT ( p =0.10). Five-year post-LT survival was similar between UNOS-DS and AC (74% vs. 72%; p =0.77), although 5-year post-LT recurrence was higher in AC (30% vs. 14%; p =0.02). CONCLUSIONS:Despite higher HCC recurrence and lower intention-to-treat survival in AC, post-LT survival was comparable between UNOS-DS and AC. Yttrium-90 attained higher DS success than transarterial chemoembolization in AC. LT after DS is feasible in AC, though defining an upper limit in tumor burden may be necessary.

HCA resection is crucial to prevent bleeding and malignant transformation. The aim of this study was to enhance the precision of tumor resection in hepatocellular adenoma (HCA) through the combination of intraoperative ultrasound (IOUS) and indocyanine green (ICG) fluorescence imaging. ICG was intravenously injected 24 h before surgery, enabling positive staining of HCA nodules. IOUS guided the parenchymal transection performed using the RoboLap approach. IOUS combined with ICG effectively demarcated lesions, allowing precision surgery while sparing healthy liver tissue. Intraoperative frozen examination further validated the potential of ICG to identify previously undetected lesions. The study showed promising advantages of ICG in HCA resections, potentially reducing the risk of recurrence and malignant transformation. The combined robotic and laparoscopic approach improved the feasibility of parenchymal-sparing surgery, offering a cautious assessment of HCA lesions.

INTRODUCTION:Incidental Gallbladder Cancer (IGBC) following cholecystectomy constitutes a significant portion of gallbladder cancer diagnoses. Re-exploration is advocated to optimize disease clearance and enhance survival rates. The consistent association of residual disease (RD) with inferior oncologic outcomes prompts a critical examination of re-resection's role as a modifying factor in the natural history of IGBC. METHODS:All patients diagnosed with gallbladder cancer between 2012 and 2022 were included. An elastic net regularized regression model was employed to profile high-risk predictors of RD within the IGBC group. Survival outcomes were assessed based on resection margins and RD. RESULTS:Among the 181 patients undergoing re-exploration for IGBC, 133 (73.5 %) harbored RD, while 48 (26.5 %) showed no evidence. The elastic net model, utilizing a selected λ = 0.029, identified six coefficients associated with the risk of RD: aspiration from cholecystectomy (0.141), hepatic tumor origin (1.852), time to re-exploration >8 weeks (1.879), positive margin status (2.575), higher T stage (1.473), and poorly differentiated tumors (2.241). Furthermore, the study revealed a median overall survival of 44 months (CI 38-60) for IGBC patients with no evidence of RD, compared to 31 months (23-42) for those with RD (p < 0.001). CONCLUSION:Re-resection revealed a high incidence of RD (73.5 %), significantly correlating with poorer survival outcomes. The preoperative identification of high-risk features provides a reliable biological disease profile. This aids in strategic preselection of patients who may benefit from re-resection, underscoring the need to consolidate outcomes with tailored chemotherapy for those with unfavorable characteristics.

Background Surgery for intrahepatic cholangiocarcinoma (iCCA) is jeopardized by significant risk of early recurrence (≤ 6 months). The aim of the present study is to analyze the oncological benefit provided by laparoscopic over open approach for iCCA in patients with high risk of very early recurrence (VER). Materials and Methods A total of 532 liver resections (LR) were performed for iCCA [265 by minimally invasive surgery (MIS) and 267 with open approach, matched through a 1:1 propensity score] and stratified using the postoperative prediction model of VER. Outcomes were compared between open and laparoscopic approaches, specifically evaluating oncological benefit. Results The percentage of patients with high risk of VER was similar (32.7% in the laparoscopic group and 35.3% in the open group, pNS). The number of retrieved nodes as well as the rate and depth of negative resection margins were comparable between laparoscopic and open. The surgery-adjuvant treatment interval was shorter in laparoscopic patients in the overall series, as well in the subgroup of high risk of VER. The rate of patients starting adjuvant treatments within 2 months from surgery was higher in laparoscopic group compared with open group. In VER high-risk group both disease-free survival (DFS) and overall survival (OS) were significantly improved in MIS compared with open group ( p = 0.032 and p = 0.026, respectively). Conclusions In patients with high risk of VER, laparoscopy translates into an advantage in terms of recurrence-free survival, likely related to lower biological impact of surgery, together with a shorter interval between surgery and start of adjuvant treatments, even allowing for a higher number of patients to start adjuvant therapies within 2 months from resection.

Background: Economic impact of robotic liver surgery (RLS) is still a debated issue due to the heterogeneity of liver resections considered and the lack of a rigorous methodology. Therefore, the aim of this study is to perform a time-driven activity-based costing (TD-ABC) comparing the costs of RLS, laparoscopic liver surgery (LLS) and open liver surgery (OLS) in the context of complex liver resections and to compare short term perioperative outcomes. Methods: The institutional databases of two Italian high volume hepatobiliary centres were retrospectively reviewed from February 2021 to April 2022. Patients submitted to major hepatectomies or postero-superior liver resections were selected and divided into three groups according to the approach scheduled (RLS, LLS and OLS) and compared. Major contributors of perioperative expenses were calculated using the TD-ABC model and accurately quantifying each unit resource consumed per patient and the time spent performing each activity. A primary intention-to-treat analysis (ITT-A) including conversions in the RLS and LLS groups was performed. Results: Forty-seven RLS, 101 LLS and 124 OLS were collected. LLS and RLS showed reduced blood loss, morbidity, mortality and hospital stay compared with open. A trend towards reduced conversion rate in RLS compared to LLS was registered. Total costs associated with RLS were estimated at 10,637 vs. 9,543 for LLS and vs. 13,960 for OLS. The higher intraoperative costs associated with RLS (+153.3% vs. OLS and +148.2% vs. LLS, P<0.001), primarily related to surgical equipment expenses, were slightly offset by the postoperative savings (-56.0% vs. OLS and -29.4% vs. LLS, P<0.001) resulting from significantly reduced hospital stays. Conclusions: RLS offers economic advantages over OLS, as initial higher costs are offset by better perioperative outcomes. The evolving robotic marketplace is expected to drive down RLS costs, promoting widespread adoption in minimally invasive procedures. Despite its higher costs than LLS, RLS's ability to enhance minimally invasive feasibility makes it a preferred choice for complex cases, reducing the need for conversions.

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape for advanced hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has demonstrated efficacy, establishing a new standard of care for advanced HCC. Neoadjuvant studies have shown promising results with high response rates, increasing research into ICIs' role. In the peri-operative setting, in addition to adjuvant and neo-adjuvant therapies, strategies for "downstaging" and "bridging" patients to liver transplantation (LT) are being investigated, broadening the eligible candidate pool. Furthermore, therapeutic advances have reshaped conversion strategies for hepatic resection, with emerging evidence indicating a role for adjuvant immunotherapy in patients at high risk of postoperative recurrence. In LT, concerns have arisen over the potential conflict between immunosuppression needs and the immune-enhancing effects of ICIs, with reports of severe rejection. However, liver-specific factors may lessen rejection risks, prompting exploration into the safety of pre-transplant ICI administration. Moreover, ongoing trials must prioritise patient selection and vigilant management protocols. Despite the remarkable progress in immunotherapy, the intricate molecular interactions within the tumour microenvironment and their implications on oncogenic pathways remain incompletely understood. This highlights the need for specialised expertise to effectively integrate immunotherapy into the surgical management of HCC. Key challenges include ensuring safety, optimising oncological outcomes, managing the risk of graft rejection in transplant recipients, and refining patient selection criteria. In this review, we aim to provide a comprehensive overview of the evolving role of immunotherapy in the surgical management of HCC, discussing the rationale for its application in both pre- and post-surgical contexts, leveraging current clinical experience, identifying potential limitations, and envisioning future applications. By integrating existing knowledge and highlighting areas for further investigation, this review seeks to inform clinical practice and guide future research endeavours.

We found the retrospective study by Kawakatsu et al,1 regarding the association between increased intraoperative blood loss (adjusted for body weight, aBL) and the elevated overall risk of developing postoperative complications (estimated through the Comprehensive Complication Index [CCI]), extremely interesting and relevant, specifically when applied to surgery of perihilar cholangiocarcinoma (pCCA). Despite technical and clinical advances, this field of hepatopancreatobiliary (HPB) surgery continues to be burdened by unrestrained surgical risks.2 Lowering postoperative complication rates is a pressing goal to exploit the benefits of the aggressive surgical resection needed. The authors applied a spline regression model to prove the existing association between high aBL and increased CCI and concluded that a primary goal inferior to 10 ml/kg blood losses should be achieved to effectively reduce overall CCI. Several points of interest were raised. First, despite the authors’ utilization of a cubic spline model adjusted for several pre- and intraoperative risk factors associated with an elevated risk of postoperative complications (i.e., type of hepatectomy, necessity for vascular resection), the real intraoperative surgical complexity may be underestimated by relying on a model controlled through a selection of predetermined variables. Factors encompassing complex anatomy and vascular involvement, macroscopic nodal involvement, prior surgical interventions, coexisting medical conditions or comorbidities, and obesity have the potential to elevate a seemingly easily affordable surgical scenario into an extremely challenging procedure.3 Additionally, the complexity of the surgical intervention can also be a function of the disease’s oncological burden. As the disease advances, technical challenges may escalate, adding another layer of intricacy to the surgical approach. Therefore, intraoperative aBL could be considered an epiphenomenon of intraoperative clinical and technical complexity, with postoperative complications being linked to overall surgical complexity rather than aBL. Second, no details of intraoperative management of transfusions are reported. The administration of packed red blood cells, fresh frozen plasma, platelets, or cryoprecipitate is essential to maintain adequate hemostasis, correct abnormal coagulation, and ensure sufficient tissue perfusion and oxygenation. Nevertheless, a restricted application of packed red blood cell transfusions has been recommended, for major surgical resections, due to its association with heightened postoperative morbidity. On the other hand, the influence of fresh frozen plasma and platelets on postoperative complications continues to be a subject of ongoing debate.4,5 Considering that over 85% of the overall cohort failed to meet the primary objective of maintaining aBL below 10 ml/kg, it would be interesting to understand the intraoperative transfusion management of these patients. Over the years, preoperative scores have been developed to predict the risk of blood transfusion and identify those who could benefit from preoperative blood conservation strategies. These scores help stratify patients’ risks and standardize perioperative transfusion management protocols.6 Specifically, detailing the incidence of intraoperative transfusions and the type of red blood cells or hemo-derivatives transfusions administered would provide valuable insights. To date, the potential correlation between intraoperative transfusions and postoperative complications, as well as the extent of this association, remains unclear. Third, the study cohort encompasses all patients undergoing major hepatectomy for pCCA in an Eastern high-volume tertiary referral center specialized in HPB surgery and biliary tract malignancies. However, even within this carefully selected patient cohort, almost 40% experienced aBL exceeding 20 ml/kg. Several studies have highlighted significant differences in postoperative outcomes between Eastern and Western centers, with Western centers reporting higher rates of postoperative morbidity and mortality.7 In a surgical field where there are already notable differences among centers worldwide, achieving such a strict aBL cutoff, which is challenging to obtain even in an advanced center, would be difficult. Before implementing strict protocols for aBL, it is necessary to improve and standardize preoperative management protocols.8 Within preoperative optimization strategies for pCCA, precise assessment and improvement of the preoperative coagulation profile, along with patients’ stratification using preoperative transfusion risk scores, can be an essential tool in reducing aBL and transfusion needs. An overall standardized and effective optimization of preoperative care could serve as a pivotal approach to better prepare and stratify patients for surgery, potentially resulting in less technically demanding procedures. Finally, we would like to compliment the authors for a thorough analysis of intraoperative aBL which led to an empirical determination of optimal target ranges for aBL to be referenced and pursued.

Background:Definition of textbook outcome (TO), defined as a single indicator combining the most advantageous short-term outcomes, is still lacking for perihilar cholangiocarcinoma (PHC). The primary endpoint of the present study is to analyze the rate of achievement of a disease-specific TO for PHC within a high volume tertiary referral centre. Secondary endpoints are to identify predictive factors of TO-achievement and to analyze the impact of achieving TO on long-term results.Methods:Between 2010 and 2022, a total of 237 patients undergoing combined liver and biliary resection for PHC at tertiary referral centre were included. Disease-specific TO were defined as: no 90-day mortality, no postoperative complications, no readmission, no intraoperative transfusions and resection margins. A logistic regression model was developed to identify predictors associated with TO-achievement. Kaplan-Meier curves were designed to determine TO's impact on survival.Results:TO was achieved in 60 (25.3%) patients. At multivariate logistic regression, preoperative biliary drainage [odds ratio (OR) 2.90 (1.13-3.40), P=0.026], high prognostic nutritional index [OR 7.11 (6.71-9.43), P=0.007[ and minimally invasive approach [OR 3.57 (2.31-3.62), P=0.013] were identified as independent predictors of TO. High ASA score [OR 0.38 (0.17-0.82), P=0.013] decreased the odds of TO. A significant improvement in both overall survival and disease-free survival was associated to TO fulfilment.Conclusion:Since the achievement of TO correlates with better disease-free and overall survival, every effort should be made to ameliorate modifiable aspects prior to surery: management within referral centres with dedicated experience in biliary tract cancer and preoperative optimization protocol may positively contribute to improve postoperative outcomes, increasing the chance to obtain TO. Moreover, the implementation of advanced minimally invasive programs plays as well.

Hepatic resection combined with intraoperative ablation has been described as a technical solution potentially widening the resectability rate of patients with colorectal liver metastases (CRLM). Nevertheless, the perioperative and oncological benefit provided by this combined approach remains unclear. We hypothesized that textbook outcome (TO), which is a composite measure achieved for patients for whom some desired health indicators are met, may help to refine the indications of this approach. Patients submitted to hepatectomy with curative intent in combination with radiofrequency ablation or microwave ablation for CRLM ≤ 3 cm in two tertiary referral centers were included. TO was defined according to a recent definition for liver surgery based on a Delphi process including also the achievement of complete radiological response of the ablated lesion/s at 4 weeks. Between 2015 and 2022, 112 patients were enrolled. Among them, 63 (56.2

Background & Aims: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. Methods: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. Results: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. Conclusions: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.

The term “failure to rescue” (FTR) has been recently introduced in the field of hepato-biliary surgery to label cases in which major postoperative complications lead to postoperative fatality. Perihilar cholangiocarcinoma (PHC) surgery has consistently high postoperative morbidity and mortality rates in which factors associated with FTR are yet to be discovered. The primary endpoint of this study is to compare the Rescue with the FTR cohort referencing patients’ characteristics and management protocols applied. A cohort of 224 consecutive patients undergoing surgery for PHC, between 2010 and 2021, was enrolled. Perioperative variables were analyzed according to the severity of major postoperative complications (Clavien ≥ 3a). Kaplan–Meier survival analyses were performed to determine complications’ impact on survival. Major complications were reported in 86 cases (38

BACKGROUND:Aggressive surgical resection in locally advanced hepatopancreatobiliary (HPB) malignancies is frequently advocated as the only potentially curative treatment. In recent years, advances in chemotherapy regimens and surgical techniques have led to improved oncologic outcomes and overall survival, by increasing the rates of radical (R0) resections. Vascular resections are increasingly reported to further increase disease clearance rates. Within this perspective, the issue of vascular reconstruction has raised growing interest, drawing particular attention to vascular substitutes and surgical techniques for reconstruction.CASE PRESENTATION:A case of extrahepatic cholangiocarcinoma with high clinical suspicion of vascular infiltration of the portal trunk at preoperative assessment is reported. An autologous interposition graft, harvested from diaphragmatic peritoneum, was chosen as a vascular substitute leading to successful portal trunk reconstruction and overcoming all possible drawbacks associated with cadaveric and artificial grafts reconstructions.CONCLUSION:This solution was strategic to ensure complete oncologic clearance averting the risk of positive margins (R1) at final pathology.

Background: Infiltrated margins of resection (R1) and lymph node invasion are dominant negative predictors of survival in patients with a resectable perihilar cholangiocarcinoma. Less clear is whether survival predictors stratify differently between R0 (tumor-free margins) and R1 patients and whether the prognosis of the latter patients is influenced by the pattern of neoplastic infiltration (ie, radial versus longitudinal infiltration). We retrospectively evaluated a series of reported resected perihilar chol-angiocarcinoma to obtain insights on the predictive power of these histologic features. Methods: The study includes 264 patients with perihilar cholangiocarcinoma treated between 2004 and 2019 in our center and followed up for >18 months. There were 176 patients with R0 (66.6%) and 88 patients with R1 (33.3%), 31 with radial infiltration only, 30 with longitudinal infiltration only, and 27 with both infiltration patterns. In all patients, the criteria for resection was the absence of metastatic involvement (ie, distant organ metastases, liver metastases, and lymph node metastases beyond the hepatoduodenal ligament). Histopathologic specimens of the resected tumors were centrally reviewed by a pathologist unaware of the clinical outcomes.Results: Three-and 5-year long-term survival were significantly better in R0 (respectively) compared to R1 patients (55% and 42% vs 42% and 18%, respectively, P < .05). In R1 patients with radial infiltration only and those with radial thorn longitudinal infiltration, both disease-free and overall survival were worse than those with longitudinal infiltration only (median disease-free survival of 18 and 23 months, respectively, P < .05, median overall survival of 33 and 39 months, respectively, P < .05). At multivariable analysis, nodal status, side of hepatectomy, grading, and presence of radial margin infiltration were associated with long-term outcome.Conclusion: Radial infiltration of resection margins enhances the negative prognostic value of R1 margins in perihilar cholangiocarcinoma patients and should specifically be accounted for in the prediction of the outcome of adjuvant therapy.& COPY; 2023 Elsevier Inc. All rights reserved.

The correlation between technical feasibility and short-term clinical advantage provided by laparoscopic over open technique for major hepatectomies is unclear. This monocentric retrospective study investigates the possible differences in the benefit provided by minimally invasive approach between left and right hepatectomy, deepening the concept of differential benefit in the setting of anatomical major resections. All hemihepatectomies performed from January 2004 to December 2021 were identified in the institutional database. A propensity score method was used to match minimal invasive (MILS) and open pairs in the left hemihepatectomies (LH) and right hemihepatectomies (RH) groups with a 1:1 ratio to adjust any potential selection bias. The differential benefit for left and right hepatectomy provided by laparoscopic over open technique was evaluated in a pure analysis (i.e., including cases converted to open) and a risk-adjusted analysis (i.e., after excluding open conversion from the laparoscopic series). The analysis of the risk-adjusted differential benefit demonstrated better result of the MILS in the RH group than in the LH group, in terms of blood loss (∆ blood loss − 150 and − 350, respectively; differential benefit: 200 mL, p < 0.05), morbidity (∆ rate of morbidity − 11.3

Purpose: Among liver hypertrophy technics, liver venous deprivation (LVD) has been recently introduced as an effective procedure to combine simultaneous portal inflow and hepatic outflow abrogation, raising growing clinical interest. The aim of this study is to investigate the role of LVD for preoperative optimization of future liver remnant (FLR) in perihilar cholangiocarcinoma (PHC), especially when compared with portal vein embolization (PVE). Methods: Between January 2013 and July 2022, all patients diagnosed with PHC and scheduled for preoperative optimization of FTR, through radiological hypertrophy techniques, prior to liver resection, were included. FTR volumetric assessment was evaluated at two distinct timepoints to track the progression of both early (T1, 10 days post-procedural) and late (T2, 21 days post-procedural) efficacy indicators. Post-procedural outcomes, including functional and volumetric analyses, were compared between the LVD and the PVE cohorts. Results: A total of 12 patients underwent LVD while 19 underwent PVE. No significant differences in either post-procedural or post-operative complications were found. Post-procedural FLR function, calculated with (99m) Tc-Mebrofenin hepatobiliary scintigraphy, and kinetic growth rate, at both timepoints, were greater in the LVD cohort (3.12 ± 0.55%/min/m2 vs. 2.46 ± 0.64%/min/m2, p = 0.041; 27.32 ± 16.86%/week (T1) vs. 15.71 ± 9.82%/week (T1) p < 0.001; 17.19 ± 9.88%/week (T2) vs. 9.89 ± 14.62%/week (T2) p = 0.034) when compared with the PVE cohort. Post-procedural FTR volumes were similar for both hypertrophy techniques. Conclusions: LVD is an effective procedure to effectively optimize FLR before liver resection for PHC. The faster growth rate combined with the improved FLR function, when compared to PVE alone, could maximize surgical outcomes by lowering post-hepatectomy liver failure rates.