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Background: Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies., Patients and Methods: We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes., Results: The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months., Conclusion: The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease., (© 2024. Society of Surgical Oncology.)

Chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC), continue to be a global health burden with a rise in incidence and mortality, necessitating a need for the discovery of novel biomarkers for HCC detection. This study aimed to identify novel non-invasive biomarkers for these different liver disease states. We performed untargeted metabolomics in plasma (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 34) and saliva samples (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 22) to test for significant metabolite associations with each disease state. Additionally, we identified enriched biochemical pathways and analyzed correlations of metabolites between, and within, the two biofluids. We identified two salivary metabolites and 28 plasma metabolites significantly associated with at least one liver disease state. No metabolites were significantly correlated between biofluids, but we did identify numerous metabolites correlated within saliva and plasma, respectively. Pathway analysis revealed significant pathways enriched within plasma metabolites for several disease states. Our work provides a detailed analysis of the altered metabolome at various stages of liver disease while providing some context to altered pathways and relationships between metabolites.

Background: Liver transplantation (LT) is the treatment of choice for end-stage liver disease and certain malignancies such as hepatocellular carcinoma (HCC). Data on the surgical management of de novo or recurrent tumors that develop in the transplanted allograft are limited. This study aimed to investigate the perioperative and long-term outcomes for patients undergoing hepatic resection for de novo or recurrent tumors after liver transplantation., Methods: The study enrolled adult and pediatric patients from 12 centers across North America who underwent hepatic resection for the treatment of a solid tumor after LT. Perioperative outcomes were assessed as well as recurrence free survival (RFS) and overall survival (OS) for those undergoing resection for HCC., Results: Between 2003 and 2023, 54 patients underwent hepatic resection of solid tumors after LT. For 50 patients (92.6 %), resection of malignant lesions was performed. The most common lesion was HCC (n = 35, 64.8 %), followed by cholangiocarcinoma (n = 6, 11.1 %) and colorectal liver metastases (n = 6, 11.1 %). The majority of the 35 patients underwent resection of HCC did not receive any preoperative therapy (82.9 %) or adjuvant therapy (71.4 %), with resection their only treatment method for HCC. During a median follow-up period of 50.7 months, the median RFS was 21.5 months, and the median OS was 49.6 months., Conclusion: Hepatic resection following OLT is safe and associated with morbidity and mortality rates that are comparable to those reported for patients undergoing resection in native livers. Hepatic resection as the primary and often only treatment modality for HCC following LT is associated with acceptable RFS and OS and should be considered in well selected patients., (© 2024. Society of Surgical Oncology.)

Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002-2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1-3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings., Methods: In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort., Results: Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88)., Conclusion: BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Evaluate outcome of left-lobe graft (LLG) first combined with purely laparoscopic donor hemihepatectomy (PLDH) as a strategy to minimize donor risk., Background: An LLG first approach and a PLDH are 2 methods used to reduce surgical stress for donors in adult living donor liver transplantation (LDLT). But the risk associated with application LLG first combined with PLDH is not known., Methods: From 2012 to 2023, 186 adult LDLTs were performed with hemiliver grafts, procured by open surgery in 95 and PLDH in 91 cases. LLGs were considered first when graft-to-recipient weight ratio ≥0.6%. Following a 4-month adoption process, all donor hepatectomies, since December 2019, were performed laparoscopically., Results: There was one intraoperative conversion to open (1%). Mean operative times were similar in laparoscopic and open cases (366 vs 371 minutes). PLDH provided shorter hospital stays, lower blood loss, and lower peak aspartate aminotransferase. Peak bilirubin was lower in LLG donors compared with right-lobe graft donors (1.4 vs 2.4 mg/dL, P < 0.01), and PLDH further improved the bilirubin levels in LLG donors (1.2 vs 1.6 mg/dL, P < 0.01). PLDH also afforded a low rate of early complications (Clavien-Dindo grade ≥ II, 8% vs 22%, P = 0.007) and late complications, including incisional hernia (0% vs 13.7%, P < 0.001), compared with open cases. LLG was more likely to have a single duct than a right-lobe graft (89% vs 60%, P < 0.01). Importantly, with the aggressive use of LLG in 47% of adult LDLT, favorable graft survival was achieved without any differences between the type of graft and surgical approach., Conclusions: The LLG first with PLDH approach minimizes surgical stress for donors in adult LDLT without compromising recipient outcomes. This strategy can lighten the burden for living donors, which could help expand the donor pool., Competing Interests: C.H.D.K. has consulted for, received compensation for serving as a fiduciary from, or received royalties from the following companies, Medtronic plc, Integra Lifesciences Corporation, and Fujifilm. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs)., Background: The clinical implications of mut BRAF status in CRLMs are largely unknown., Methods: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management., Results: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis., Conclusions: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Colorectal cancer is a leading cause of cancer-related death worldwide. Metastatic liver disease develops in 50% of cases and drives patient outcomes. Although the ideal treatment for colorectal cancer liver metastases (CRLM) is resection, only a third of patients are suitable for this approach. Reports of liver transplantation in selected patients with unresectable CRLM have shown encouraging results compared to conventional forms of therapy. No study to date has examined the utility of liquid biopsy circulating tumor DNA (ctDNA) for evaluation of residual disease in this cohort of patients. We report a small series of liver transplantation in patients with CRLM in whom ctDNA was assessed peri-operatively., Methods: Five patients underwent liver transplantation for unresectable CRLM or liver failure following CRLM treatment from 2018 to 2022. Clinical data, cross-sectional imaging, and serum biomarkers including peri-operative ctDNA were reviewed from electronic medical records., Results: All patients are alive without radiologic evidence of disease at time of this publication. Median time of follow-up was 32 months (IQR 6.6-40 months). ctDNA was assessed before (4 patients) and after transplant (6 patients). One patient experienced a pulmonary recurrence that was resected, for whom pre-recurrence ctDNA was not available; the remaining patients have not experienced recurrence. Four patients are without evidence of ctDNA following transplant, and two demonstrate persistent ctDNA positivity post-transplant. Three of four patients with positive pre-transplant ctDNA remain ctDNA-negative post-transplant., Conclusions: Liver transplantation for liver-confined unresectable CRLM is emerging as a valid surgical option in selected patients. The significance of liquid biopsy in this population remains elusive due to lack of data. The clearance of ctDNA after transplant in these patients with metastatic disease and despite their immunosuppression is notable. The significance and usefulness of liquid biopsy in patient selection, surveillance, and as an indication for treatment warrant further investigation., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: Current success in transplant oncology for select liver tumors, such as hepatocellular carcinoma, has ignited international interest in liver transplantation (LT) as a therapeutic option for nonresectable colorectal liver metastases (CRLM). In the United States, the CRLM LT experience is limited to reports from a handful of centers. This study was designed to summarize donor, recipient, and transplant center characteristics and posttransplant outcomes for the indication of CRLM., Methods: Adult, primary LT patients listed between December 2017 and March 2022 were identified by using United Network Organ Sharing database. LT for CRLM was identified from variables: "DIAG&#95;OSTXT"; "DGN&#95;OSTXT&#95;TCR"; "DGN2&#95;OSTXT&#95;TCR"; and "MALIG&#95;TY&#95;OSTXT.", Results: During this study period, 64 patients were listed, and 46 received LT for CRLM in 15 centers. Of 46 patients who underwent LT for CRLM, 26 patients (56.5%) received LTs using living donor LT (LDLT), and 20 patients received LT using deceased donor (DDLT) (43.5%). The median laboratory MELD-Na score at the time of listing was statistically similar between the LDLT and DDLT groups (8 vs. 9, P = 0.14). This persisted at the time of LT (8 vs. 12, P = 0.06). The 1-, 2-, and 3-year, disease-free, survival rates were 75.1, 53.7, and 53.7%. Overall survival rates were 89.0, 60.4, and 60.4%, respectively., Conclusions: This first comprehensive U.S. analysis of LT for CRLM suggests a burgeoning interest in high-volume U.S. transplant centers. Strategies to optimize patient selection are limited by the scarce oncologic history provided in UNOS data, warranting a separate registry to study LT in CRLM., (© 2023. Society of Surgical Oncology.)

Background: Advances in surgical and medical technology over the years has made liver transplantation possible for older and higher risk patients. Despite rigorous preoperative cardiac testing, cardiovascular events remain a major cause of death after orthotopic liver transplantation (OLT). However, there are little data on the outcomes of OLT in patients with preexisting coronary artery disease (CAD). This study aimed to compare all-cause and cardiovascular mortality of patients with and without history of CAD undergoing OLT., Methods: Six hundred ninety-three adult patients with cirrhosis underwent liver transplantation between July 2013 and December 2018 (female n = 243, male n = 450; median age 59)., Results: During the study period of 5 y (median follow-up, 24.1 mo), 92 of 693 patients (13.3%) died. All-cause mortality in the CAD group was significantly higher than in the non-CAD group (26.7% versus 9.6%; P <0.01). Cardiovascular events accounted for 52.5% of deaths (n = 21) in patients with CAD compared with 36.5% (n = 19) in non-CAD patients. At 6 mo, patients with combined nonalcoholic steatohepatitis (NASH)/CAD had significantly worse survival than those with CAD or NASH alone ( P <0.01). After 6 mo, patients with CAD alone had similar survival to those with combined NASH/CAD., Conclusions: Patients with preexisting CAD before liver transplantation are at higher risk of death from any cause, specifically cardiovascular-related death. This risk increases with coexisting NASH. The presence of NASH and CAD at the time of liver transplant should prompt the initiation of aggressive risk factor modification for patients with CAD., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients., (Copyright © 2022 American Association for the Study of Liver Diseases.)

Background: Although interest in expanding the application of minimally invasive liver resection (MILR) is high the world over, most of the extensive experience in MILR has been reported from Far East Asia and Europe and its adoption in North America is limited. The aim of this study was to review the experience of MILR in a single North American institute over a 15-year period, highlighting both the obstacles encountered and strategies adopted to overcome the stagnation in its uptake., Methods: This study included 500 MILR cases between 2006 and 2020. Patient demographics, disease characteristics, surgical technique, and perioperative outcomes are summarized. The major hepatectomy rate and conversion rate were assessed according to case numbers (first 100, 101-300, and 301-500 cases) to assess chronological trends., Results: Of 500, 402 MILRs were done by pure laparoscopic (80.4%), 67 were hand assisted (13.4%), and 31 were robotic (6.2%). The majority (64%) of cases were performed for malignancy (n = 320; 100 Hepatocellular carcinoma, 153 Colorectal metastases, 27 Intrahepatic cholangiocarcinoma, and others, 40, 64%). A total of 71 cases were converted to open (14.2%). The annual case number gradually increased over the first few years; however, case numbers stayed around 30 between 2009 and 2017. In this period, despite accumulating MILR experience, open conversion rates increased despite no change in major hepatectomy rate. After this period of long-term stagnation, we introduced crucial changes in team composition and laparoscopic instrumentation. Our MILR case number and major hepatectomy rate thereafter increased significantly without increasing conversion or complication rates., Conclusion: Our recovery from long-term stagnation by instituting key changes as detailed in this study could be used as a guidepost for programs that are contemplating transitioning their MILR program from minor to advanced resections. Establishing a formal MILR training model through proper mentorship/proctorship and building a dedicated MILR team would be imperative to this strategy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: In patients with resectable colorectal cancer liver metastases (CRLM), the choice of surgical technique and resection margin are the only variables that are under the surgeon's direct control and may influence oncologic outcomes. There is currently no consensus on the optimal margin width., Objective: To determine the optimal margin width in CRLM by using artificial intelligence-based techniques developed by the Massachusetts Institute of Technology and to assess whether optimal margin width should be individualized based on patient characteristics., Design, Setting, and Participants: The internal cohort of the study included patients who underwent curative-intent surgery for KRAS-variant CRLM between January 1, 2000, and December 31, 2017, at Johns Hopkins Hospital, Baltimore, Maryland, Memorial Sloan Kettering Cancer Center, New York, New York, and Charité-University of Berlin, Berlin, Germany. Patients from institutions in France, Norway, the US, Austria, Argentina, and Japan were retrospectively identified from institutional databases and formed the external cohort of the study. Data were analyzed from April 15, 2019, to November 11, 2021., Exposures: Hepatectomy., Main Outcomes and Measures: Patients with KRAS-variant CRLM who underwent surgery between 2000 and 2017 at 3 tertiary centers formed the internal cohort (training and testing). In the training cohort, an artificial intelligence-based technique called optimal policy trees (OPTs) was used by building on random forest (RF) predictive models to infer the margin width associated with the maximal decrease in death probability for a given patient (ie, optimal margin width). The RF component was validated by calculating its area under the curve (AUC) in the testing cohort, whereas the OPT component was validated by a game theory-based approach called Shapley additive explanations (SHAP). Patients from international institutions formed an external validation cohort, and a new RF model was trained to externally validate the OPT-based optimal margin values., Results: This cohort study included a total of 1843 patients (internal cohort, 965; external cohort, 878). The internal cohort included 386 patients (median [IQR] age, 58.3 [49.0-68.7] years; 200 men [51.8%]) with KRAS-variant tumors. The AUC of the RF counterfactual model was 0.76 in both the internal training and testing cohorts, which is the highest ever reported. The recommended optimal margin widths for patient subgroups A, B, C, and D were 6, 7, 12, and 7 mm, respectively. The SHAP analysis largely confirmed this by suggesting 6 to 7 mm for subgroup A, 7 mm for subgroup B, 7 to 8 mm for subgroup C, and 7 mm for subgroup D. The external cohort included 375 patients (median [IQR] age, 61.0 [53.0-70.0] years; 218 men [58.1%]) with KRAS-variant tumors. The new RF model had an AUC of 0.78, which allowed for a reliable external validation of the OPT-based optimal margin. The external validation was successful as it confirmed the association of the optimal margin width of 7 mm with a considerable prolongation of survival in the external cohort., Conclusions and Relevance: This cohort study used artificial intelligence-based methodologies to provide a possible resolution to the long-standing debate on optimal margin width in CRLM.

Background: Laparoscopic liver resection (LLR) involves a difficult learning curve, for which multiple difficulty scores have been proposed to assist with safe adaptation. The IWATE Criteria is a 4-level difficulty score shown to correlate with conversion to open surgery, estimated blood loss (EBL), and operative time in Japanese and French cohorts. We set out to validate the IWATE Criteria in a North American cohort, describe the evolution of our LLR program, and analyze the IWATE Criteria's ability to predict conversion to open surgery., Methods: Patients that underwent LLR between January 2006 and December 2019 were selected from a prospectively maintained database. Difficulty outcomes, including conversion to open surgery, EBL, operative time, and post-operative complications were analyzed according to IWATE difficulty level, both overall and between chronological eras. The IWATE Criteria's ability to predict conversion to open surgery was assessed with a receiver operating characteristic (ROC) analysis., Results: A total of 426 patients met inclusion criteria. Operative time, EBL, and conversion to open surgery increased in concordance with low to advanced IWATE difficulty. ROC analysis for conversion to open surgery demonstrated an overall area under the curve (AUC) of 0.694. Predictive performance was superior during the first two eras, with AUCs of 0.771 and 0.775; predictive value decreased as the LLR program gained experience, with AUCs of 0.708 and 0.551 for eras three and four., Conclusions: This study validated the IWATE Criteria in a North American population distinct from previous Japanese and French cohorts, based on its correlation with operative time, EBL, and conversion to open surgery. The IWATE Criteria may be of utility for identification of LLR cases appropriate for surgeon experience, as well as determination of laparoscopic feasibility. Interval difficulty score recalibration may be warranted as surgeon perception of difficulty evolves., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sustained virological response (SVR) to the treatment of recurrent HCV in liver transplant recipients has excellent clinical outcomes; however, little is known about the effects on allograft histology. The study aimed to assess the histology of the allograft liver. In this single-center, retrospective cohort study, patients with recurrent hepatitis C (HCV) in allograft liver who were cured with antiviral therapy between 2010 and 2016 were identified. Biopsies were reviewed by two liver pathologists blinded to the treatment and SVR status. Paired analysis was performed to compare pre- and post-treatment histological features. Of the 62 patients analyzed, 22 patients received PEGylated interferon/ribavirin (IFN) therapy, while 40 patients received direct-acting antiviral agents (DAA). The mean age was 57 years, 24% were female, and 79% were Caucasian. RNA in situ hybridization testing for HCV and HEV was negative in all the tested patients. Significant reduction in the inflammatory grade of post-treatment biopsy specimens was noted in all subjects (n = 57; p < 0.001) and in the IFN group (n = 21; p = 0.001) but not in the DAA group (p = 0.093). Of all subjects, 21% had worsening stage, 31% had improvement, and 48% had no change in stage. Of the treatment groups, 27% in the IFN and 17% in the DAA groups had worsening stage; however, the results were not statistically significant in all subjects or by treatment modality. Persistent inflammatory infiltrates and fibrosis was noted in allograft tissue of patients cured with DAA. Significant improvement in grade was noted in the IFN group, without a significant change in stage., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Rates of withdrawal of life-sustaining treatment are higher among critically ill pediatric patients compared to adults. Therefore, livers from pediatric donation after circulatory death (pDCD) could improve graft organ shortage and waiting time for listed patients. As knowledge on the utilization of pDCD is limited, this study used US national registry data (2002-2017) to estimate the prognostic impact of pDCD in both adult and pediatric liver transplant (LT)., Methods: In adult LT, the short-term (1-year) and long-term (overall) graft survival (GS) between pDCD and adult donation after circulatory death (aDCD) grafts was compared. In pediatric LT, the short- and long-term prognostic outcomes of pDCD were compared with other type of grafts (brain dead, split, and living donor)., Results: Of 80 843 LTs in the study, 8967 (11.1%) were from pediatric donors. Among these, only 443 were pDCD, which were utilized mainly in adult recipients (91.9%). In adult recipients, short- and long-term GS did not differ significantly between pDCD and aDCD grafts (hazard ratio = 0.82 in short term and 0.73 in long term, both P > 0.05, respectively). Even "very young" (≤12 y) pDCD grafts had similar GS to aDCD grafts, although the rate of graft loss from vascular complications was higher in the former (14.0% versus 3.6%, P < 0.01). In pediatric recipients, pDCD grafts showed similar GS with other graft types whereas waiting time for DCD livers was significantly shorter (36.5 d versus 53.0 d, P < 0.01)., Conclusions: Given the comparable survival seen to aDCDs, this data show that there is still much scope to improve the utilization of pDCD liver grafts., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The use of livers from donation after circulatory death (DCD) is historically characterized by increased rates of biliary complications and inferior short-term graft survival (GS) compared to donation after brain death (DBD) allografts. This study aimed to evaluate the dynamic prognostic impact of DCD livers to reveal whether they remain an adverse factor even after patients survive a certain period following liver transplant (LT). This study used 74 961 LT patients including 4065 DCD LT in the scientific registry of transplant recipients from 2002-2017. The actual, 1 and 3-year conditional hazard ratio (HR) of 1-year GS in DCD LT were calculated using a conditional version of Cox regression model. The actual 1-, 3-, and 5-year GS of DCD LT recipients were 83.3%, 73.3%, and 66.3%, which were significantly worse than those of DBD (all P < 0.01). Actual, 1-, and 3-year conditional HR of 1-year GS in DCD compared to DBD livers were 1.87, 1.49, and 1.39, respectively. Graft loss analyses showed that those lost to biliary related complications were significantly higher in the DCD group even 3 years after LT. National registry data demonstrate the protracted higher risks inherent to DCD liver grafts in comparison to their DBD counterparts, despite survival through the early period after LT. These findings underscore the importance of judicious DCD graft selection at individual center level to minimize the risk of long-term biliary complications., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Introduction: Two novel clinical risk scores (CRS) that incorporate KRAS mutation status were developed: modified CRS (mCRS) and GAME score. However, they have not been tested in large national and international cohorts. The aim of this study was to validate the prognostic discrimination utility and determine the clinical usefulness of the two novel CRS., Methods: Patients undergoing hepatectomy for CRLM (2000-2018) in 10 centers were included. The discriminatory abilities of mCRS, GAME, and Fong CRS were evaluated using Harrell's C-index and Akaike's Information Criterion., Results: In the entire cohort, the C-index of the GAME score (0.61) was significantly higher than those of Fong score (0.57) and mCRS (0.54), while the C-Index of mCRS was significantly lower than that of Fong score. When we compared the models in the various geographical regions, the C-index of GAME score was significantly higher than that of mCRS in North America, Europe, and South America. The AIC of Fong score, mCRS, and GAME score were 14 405, 14 447, and 14 319, respectively., Conclusion: In conclusion, using the largest and most heterogenous population of CRLM patients with known KRAS status, this independent, external validation demonstrated that the GAME score outperforms both the traditional Fong score and mCRS., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status., Background: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors., Methods: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status., Results: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38)., Conclusions: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Neuroendocrine tumor (NET) metastasis localized to the liver is an accepted indication for liver transplantation as such tumors have a low biological aggressiveness in terms of malignancy and are slow growing., Recent Findings: The long-term results are comparable with and in some cases even better than those of transplantations performed for primary liver cancer. However, compared with nonmalignant conditions, neuroendocrine liver metastasis (NELM) may result in an inferior outcome of transplantation. In the face of the scarcity of donated organs and recent improved results of non-surgical treatment for NELM, controversy over patient selection and timing for liver transplantation continues., Summary: In this review, we provide an overview of the diagnostic work-up and selection criteria of patients with NELM being considered for liver transplantation. Thereafter, we provide a critical analysis of the reported outcomes of OLT., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Objectives: Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established., Methods: Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature., Results: A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs., Conclusion: The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores., (© 2021 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Surgical resection of hepatic metastases remains the only potentially curative treatment option for patients with colorectal liver metastases (CRLM). Widely adopted prognostic tools may oversimplify the impact of model parameters relative to long-term outcomes., Methods: Patients with CRLM who underwent a hepatectomy between 2001 and 2018 were identified in an international, multi-institutional database. Bootstrap resampling methodology used in tandem with multivariable mixed-effects logistic regression analysis was applied to construct a prediction model that was validated and compared with scores proposed by Fong and Vauthey., Results: Among 1406 patients who underwent hepatic resection of CRLM, 842 (59.9%) had recurrence. The full model (based on age, sex, primary tumor location, T stage, receipt of chemotherapy before hepatectomy, lymph node metastases, number of metastatic lesions in the liver, size of the largest hepatic metastases, carcinoembryonic antigen [CEA] level and KRAS status) had good discriminative ability to predict 1-year (area under the receiver operating curve [AUC], 0.693; 95% confidence interval [CI], 0.684-0.704), 3-year (AUC, 0.669; 95% CI, 0.661-0.677), and 5-year (AUC, 0.669; 95% CI, 0.661-0.679) risk of recurrence. Studies analyzing validation cohorts demonstrated similar model performance, with excellent model accuracy. In contrast, the AUCs for the Fong and Vauthey scores to predict 1-year recurrence were only 0.527 (95% CI, 0.514-0.538) and 0.525 (95% CI, 0.514-0.533), respectively. Similar trends were noted for 3- and 5-year recurrence., Conclusion: The proposed clinical score, derived via machine learning, which included clinical characteristics and morphologic data, as well as information on KRAS status, accurately predicted recurrence after CRLM resection with good discrimination and prognostic ability.

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSCs in the peripheral blood of patients with other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), and colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). The investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions, suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of The Cancer Genome Atlas dataset demonstrated that a high MDSC score in HCC patients is associated with poor disease outcome. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, these cells may represent suitable targets for effective immunotherapy approaches.

Background: Although KRAS mutation status is known to affect the prognosis of patients with colorectal liver metastasis, the hierarchical association between other prognostic factors and KRAS status is not fully understood., Methods: Patients who underwent a hepatectomy for colorectal liver metastasis were identified in a multi-institutional international database. A classification and regression tree model was constructed to investigate the hierarchical association between prognostic factors and overall survival relative to KRAS status., Results: Among 1,123 patients, 29.9% (n = 336) had a KRAS mutation. Among wtKRAS patients, the classification and regression tree model identified presence of metastatic lymph nodes as the most important prognostic factor, whereas among mtKRAS patients, carcinoembryonic antigen level was identified as the most important prognostic factor. Among patients with wtKRAS, the highest 5-year overall survival (68.5%) was noted among patients with node negative primary colorectal cancer, solitary colorectal liver metastases, size <4.3 cm. In contrast, among patients with mtKRAS colorectal liver metastases, the highest 5-year overall survival (57.5%) was observed among patients with carcinoembryonic antigen <6 mg/mL. The classification and regression tree model had higher prognostic accuracy than the Fong score (wtKRAS [Akaike's Information Criterion]: classification and regression tree model 3334 vs Fong score 3341; mtKRAS [Akaike's Information Criterion]: classification and regression tree model 1356 vs Fong score 1396)., Conclusion: Machine learning methodology outperformed the traditional Fong clinical risk score and identified different factors, based on KRAS mutational status, as predictors of long-term prognosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted., (© 2019 by the American Association for the Study of Liver Diseases.)

Objective: The objective of this retrospective study was to characterize the neutrophil to lymphocyte ratio (NLR) on the waitlist and determine its prognostic utility in liver transplantation (LT) for hepatocellular carcinoma (HCC) with special focus on longitudinal data. Biomarkers such as pre-operative NLR have been suggested to predict poor oncological outcomes for patients with HCC seeking LT. NLR's utility is thought to be related to tumor biology. However, recent studies have demonstrated that a high NLR conveys worse outcomes in non-HCC cirrhotics. This study investigated the relationship between NLR, liver function, tumor factors and patient prognosis., Methods: Patients with HCC undergoing LT were identified between 2002 and 2014 (n = 422). Variables of interest were collected longitudinally from time of listing until LT. The prognostic utility of NLR was assessed using Kaplan-Meier and Cox Proportional Hazard regression. Associations between NLR and MELD-Na, AFP, and tumor morphology were also assessed., Results: NLR demonstrated a positive correlation with MELD-Na at LT (R2 = 0.125, P < 0.001) and had parallel trends over time. The lowest NLR quartile had a median MELD-Na of 9 while the highest had a median MELD-Na of 19. There were minimal differences in AFP, tumor morphology, and rates of vascular invasion between quartiles. NLR was a statistically significant predictor of OS (HR = 1.64, P = 0.017) and recurrence (HR = 1.59, P = 0.016) even after controlling for important tumor factors. However, NLR lost its statistical significance when MELD-Na was added to the Cox regression model (OS: HR = 1.46, P = 0.098) (recurrence: HR = 1.40, P = 0.115)., Conclusions: NLR is a highly volatile marker on the waitlist that demonstrates a significant correlation and collinearity with MELD-Na temporally and at the time of LT. These characteristics of NLR bring into question its utility as a predictive marker in HCC patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Portal vein thrombosis (PVT) does not preclude liver transplantation (LT), but poor portal vein (PV) flow after LT remains a predictor of poor outcomes. Given the physiologic tendency of the hepatic artery (HA) to compensate for low PV flow via vasodilation, we investigated whether adequate HA flow would have a favorable prognostic impact among patients with low PV flow following LT., Methods: This study included 163 patients with PVT who underwent LT between 2004 and 2015. PV and HA flow were categorized into quartiles, and their association with 1-year graft survival (GS) and biliary complication rates was assessed. For both the HA and the PV, patients at the lowest two quartiles were categorized as having low flow and the remainder as having high flow., Results: The median MELD score was 22 and 1-year GS was 87.3%. As expected, GS paralleled PV flow with patients at the lowest flow quartile faring the worst. In combination of PV and HA flows, high HA flow was associated with improved 1-year GS among patients with low PV flow (P = .03). Similar findings were observed with respect to biliary complication rates., Conclusions: Sufficient HA flow may compensate for poor PV flow. Consequently, meticulous HA reconstruction may be central to achieving optimal outcomes in PVT cases., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Investigation into right and left-sided primary colon liver metastasis (CLM) has revealed differences in the tumor biology and prognosis. This indicates that preoperative and operative factors may affect outcomes of right-sided primary CLM differently than left. This retrospective analysis investigated the effects of resection margin stratified by left and right-sided primary CLM on overall survival (OS) for patients undergoing hepatectomy., Methods: A total of 732 patients undergoing hepatic resection for CLM at the Cleveland Clinic and Johns Hopkins were identified between 2002 and 2016. Clinically significant variables were analyzed using Cox proportional hazard regression. The cohort was then divided into patients with right and left-sided CLM and analyzed separately using Kaplan Meier analysis and Cox proportional hazard regression., Results: Cox proportional hazard regression showed that left-sided CLM with an R0 margin was a statistically significant predictor of OS even after controlling for other important factors (HR = 0.629, P = 0.024) but right-sided CLM with R0 margin was not (HR = 0.788, P = 0.245). Kaplan-Meier analysis demonstrated that patients with a left-sided CLM and R0 margin had the best prognosis (P = 0.037)., Conclusion: Surgical margin is an important prognostic factor for left-sided primary CLM but tumor biology may override surgical technique for right-sided CLM., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis., Background: CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery., Methods: CS analysis was performed in 1099 patients of an international, multi-institutional cohort. Three-year CS (CS3) estimates at the "xth" year after surgery were calculated as follows: CS3 = CS (x + 3)/CS (x). The standardized difference (d) between CS3 rates was used to estimate the changing prognostic power of selected variables over time. A d < 0.1 indicated very small differences between groups, 0.1 ≤ d < 0.3 indicated small differences, 0.3 ≤ d < 0.5 indicated moderate differences, and d ≥ 0.5 indicated strong differences., Results: According to OS estimates calculated at the time of surgery, the presence of BRAF and KRAS mutations, R1 margin status, resected extrahepatic disease, patient age, primary tumor lymph node metastasis, tumor number, and carcinoembryonic antigen levels independently predicted worse survival. However, when temporal changes in the prognostic impact of these variables were considered using CS3 estimates, BRAF mutation dominated prognosis during the first year (d = 0.48), whereas surgeon-related variables (ie, surgical margin and resected extrahepatic disease) determined prognosis thereafter (d ≥ 0.5). Traditional clinicopathologic factors affected survival constantly, but only to a moderate degree (0.3 ≤ d < 0.5)., Conclusions: The impact of genetic, surgery-related, and clinicopathologic factors on OS and CS3 changed dramatically over time. Specifically, BRAF mutation status dominated prognosis in the first year, whereas positive surgical margins and resected extrahepatic disease determined prognosis thereafter.

A recent study using US national registry data reported, using Cox proportional hazards (PH) models, that split-liver transplantation (SLT) has improved over time and is no more hazardous than whole-liver transplantation (WLT). However, the study methods violated the PH assumption, which is the fundamental assumption of Cox modeling. As a result, the reported hazard ratios (HRs) are biased and unreliable. This study aimed to investigate whether the risk of graft survival (GS) in SLT has really improved over time, ensuring attention to the PH assumption. This study included 80,998 adult deceased donor liver transplantation (LT) (1998-2015) from the Scientific Registry Transplant Recipient. The study period was divided into 3 time periods: era 1 (January 1998 to February 2002), era 2 (March 2002 to December 2008), and era 3 (January 2009 to December 2015). The PH assumption was tested using Schoenfeld's test, and where the HR of SLT violated the assumption, changes in risk for SLT over time from transplant were assessed. SLT was performed in 1098 (1.4%) patients, whereas WLT was used in 79,900 patients. In the Cox PH analysis, the P values of Schoenfeld's global tests were <0.05 in all eras, which is consistent with deviation from proportionality. Assessing HRs of SLT with a time-varying effect, multiple Cox models were conducted for post-LT intervals. The HR curves plotted according to time from transplant were higher in the early period and then decreased at approximately 1 year and continued to decrease in all eras. For 1-year GS, the HRs of SLT were 1.92 in era 1, 1.52 in era 2, and 1.47 in era 3 (all P < 0.05). In conclusion, the risk of SLT has a time-varying effect and is highest in the early post-LT period. The risk of SLT is underestimated if it is evaluated by overall GS. SLT was still hazardous if the PH assumption was considered, although it became safer over time., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Biliary mucinous cystic neoplasms are rare parenchymal neoplasms with a considerable malignant potential. Due to a lack of diagnostic imaging criteria, histopathologic evaluation remains the definitive method of diagnosis. Resection is the treatment of choice. Here, the authors present a case of biliary mucinous neoplasm in a 39-year-old female with the associated radiographic and histopathologic findings.

Portal vein thrombosis (PVT) is commonly encountered during liver transplantation (LT). Depending on the grade of thrombosis, varied management strategies are indicated. The aims of this study are to clarify the contemporary role of renoportal anastomosis (RPA) in patients with splanchnic vein thrombosis (SVT) undergoing LT and to systematically analyze all reported cases of RPA. A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement guidelines. The study was limited to studies reported in English between January 1997 and May 2017. Only retrospective single center studies were included in the analysis. A total of 66 patients with SVT were reported to have undergone RPA during LT. Transient renal dysfunction was reported in 12 patients (18.1%), variceal hemorrhage in 2 patients (3%), early portal vein (PV) re-thrombosis in 2 patients (3%), chronic renal dysfunction in 2 patients (3%), and late PV re-thrombosis in 1 patient (1.5%). The overall patient and graft survival were each 80%. This analysis illustrates the decades-long evolution of a technique practiced across the field of transplantation. Postoperative complications and graft survival appear to be encouraging, even in the setting of SVT., (© 2018 Steunstichting ESOT.)

Patients with hepatocellular carcinoma (HCC) are screened at presentation for appropriateness of liver transplantation (LT) using morphometric criteria, which poorly specifies risk. Morphology is the crux of measuring tumor response to locoregional therapy (LRT) using modified Response Evaluation Criteria in Solid Tumors (mRECIST). This study investigated the utility of following a continuous risk score (hazard associated with liver transplantation in hepatocellular carcinoma; HALTHCC) to longitudinally assess risk. This multicenter, retrospective study from 2002 to 2014 enrolled 419 patients listed for LT for HCC. One cohort had LRT while waiting (n = 351), compared to the control group (n = 68) without LRT. Imaging studies (n = 2,085) were collated to laboratory data to calculate HALTHCC, MORAL, Metroticket 2.0, and alpha fetoprotein (AFP) score longitudinally. Cox proportional hazards evaluated associations of HALTHCC and peri-LRT changes with intention-to-treat (ITT) survival (considering dropout or post-LT mortality), and utility was assessed with Harrell's C-index. HALTHCC better predicted ITT outcome (LT = 309; dropout = 110) when assessed closer to delisting (P < 0.0001), maximally just before delisting (C-index, 0.742 [0.643-0.790]). Delta-HALTHCC post-LRT was more sensitive to changes in risk than mRECIST. HALTHCC score and peri-LRT percentage change were independently associated with ITT mortality (hazard ratio = 1.105 [1.045-1.169] per point and 1.014 [1.004-1.024] per percent, respectively)., Conclusions: HALTHCC is superior in assessing tumor risk in candidates awaiting LT, and its utility increases over time. Peri-LRT relative change in HALTHCC outperforms mRECIST in stratifying risk of dropout, mortality, and recurrence post-LT. With improving estimates of post-LT outcomes, it is reasonable to consider allocation using HALTHCC and not just waiting time. Furthermore, this study supports a shift in perspective, from listing to allocation, to better utilize precious donor organs. (Hepatology 2018)., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: While several prognostic models have been developed to predict long-term outcomes in resectable intrahepatic cholangiocarcinoma (ICC), their prognostic discrimination remains limited. The addition of tumor markers might improve the prognostic power of the classification schemas proposed by the AJCC 8th edition and the Liver Cancer Study Group of Japan (LCSGJ)., Methods: The prognostic discrimination of the AJCC and the LCSGJ were compared before and after the addition of CA 19-9 and CEA, using Harrell's C-index, net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) in an international, multi-institutional cohort., Results: Eight hundred and five surgically treated patients with ICC that met the inclusion criteria were identified. On multivariable analysis, CEA5 ng/mL, 100IU/mL CA 19-9< 500IU/mL and CA 19-9500 IU/mL were associated with worse overall survival. The C-index of the AJCC and the LCSGJ improved from 0.540 to 0.626 and 0.553 to 0.626, respectively following incorporation of CA 19-9 and CEA. The NRI and IDI metrics confirmed the superiority of the modified AJCC and LCSGJ, compared to the original versions., Conclusion: The inclusion of preoperative CA 19-9 and CEA in the AJCC and LCSGJ staging schemas may improve prognostic discrimination among surgically treated patients with ICC., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Importance: BRAF mutations are reportedly associated with aggressive tumor biology. However, in contrast with primary colorectal cancer, the association of V600E and non-V600E BRAF mutations with survival and recurrence after resection of colorectal liver metastases (CRLM) has not been well studied., Objective: To investigate the prognostic association of BRAF mutations with survival and recurrence independently and compared with other prognostic determinants, such as KRAS mutations., Design, Setting, and Participants: In this cohort study, all patients who underwent resection for CRLM with curative intent from January 1, 2000, through December 31, 2016, at the institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had data on BRAF and KRAS mutational status were retrospectively identified. Multivariate Cox proportional hazards regression models were used to assess long-term outcomes., Interventions: Hepatectomy in patients with CRLM., Main Outcomes and Measures: The association of V600E and non-V600E BRAF mutations with disease-free survival (DFS) and overall survival (OS)., Results: Of 853 patients who met inclusion criteria (510 men [59.8%] and 343 women [40.2%]; mean [SD] age, 60.2 [12.4] years), 849 were included in the study analyses. Forty-three (5.1%) had a mutated (mut) BRAF/wild-type (wt) KRAS (V600E and non-V600E) genotype; 480 (56.5%), a wtBRAF/wtKRAS genotype; and 326 (38.4%), a wtBRAF/mutKRAS genotype. Compared with the wtBRAF/wtKRAS genotype group, patients with a mutBRAF/wtKRAS genotype more frequently were female (27 [62.8%] vs 169 [35.2%]) and 65 years or older (22 [51.2%] vs 176 [36.9%]), had right-sided primary tumors (27 [62.8%] vs 83 [17.4%]), and presented with a metachronous liver metastasis (28 [64.3%] vs 229 [46.8%]). On multivariable analysis, V600E but not non-V600E BRAF mutation was associated with worse OS (hazard ratio [HR], 2.76; 95% CI, 1.74-4.37; P < .001) and DFS (HR, 2.04; 95% CI, 1.30-3.20; P = .002). The V600E BRAF mutation had a stronger association with OS and DFS than the KRAS mutations (β for OS, 10.15 vs 2.94; β for DFS, 7.14 vs 2.27)., Conclusions and Relevance: The presence of the V600E BRAF mutation was associated with worse prognosis and increased risk of recurrence. The V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort.

Background: While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described., Case Series: We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection., Conclusion: The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Accurate prediction of prognosis for patients with intrahepatic cholangiocarcinoma (ICC) remains a challenge. We sought to define a preoperative risk tool to predict long-term survival after resection of ICC., Study Design: Patients who underwent hepatectomy for ICC at 1 of 16 major hepatobiliary centers between 1990 and 2015 were identified. Clinicopathologic data were analyzed and a prognostic model was developed based on the regression β-coefficients on data in training set. The model was subsequently assessed using a validation set., Results: Among 538 patients, most patients had a solitary tumor (median tumor number 1; interquartile range 1 to 2) and median tumor size was 5.7 cm (interquartile range 4.0 to 8.0 cm). Median and 5-year overall survival was 39.0 months and 39.0%, respectively. On multivariable analyses, preoperative factors associated with long-term survival included tumor size (hazard ratio [HR] 1.12; 95% CI 1.06 to 1.18), natural logarithm carbohydrate antigen 19-9 level (HR 1.33; 95% CI 1.22 to 1.45), albumin level (HR 0.76; 95% CI 0.55 to 0.99), and neutrophil to lymphocyte ratio (HR 1.05; 95% CI 1.02 to 1.09). A weighted composite prognostic score was constructed based on these factors: [9 + (1.12 × tumor size) + (2.81 × natural logarithm carbohydrate antigen 19-9) + (0.50 × neutrophil to lymphocyte ratio) + (-2.79 × albumin)]. The model demonstrated good performance in the testing (area under the curve 0.696) and validation (0.691) datasets. The model performed better than both the T categories (area under the curve 0.532) and the cumulative stage classifications in the American Joint Committee on Cancer staging manual, 8th edition (area under the curve 0.559). When assessing risk of death within 1 year of operation, a risk score ≥25 had a positive predictive value of 59.8% compared with a positive predictive value of 35.3% for American Joint Committee on Cancer staging manual, 8th edition T4 disease and 31.8% for stage IIIB disease., Conclusions: Postsurgical long-term outcomes could be predicted using a composite weighted scoring system based on preoperative clinical parameters. The preoperative risk model can be used to inform patient to provider conversations and expectations before operation., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Hepatic artery thrombosis after liver transplantation is a devastating complication associated with ischemic cholangiopathy that can occur even after successful revascularization. This study explores long-term outcomes after hepatic artery thrombosis in adult liver transplantation recipients, focusing on the probability, risk factors, and resolution of ischemic cholangiopathy., Methods: A retrospective chart review of 1,783 consecutive adult liver transplantations performed between 1995 and 2014 identified 44 cases of hepatic artery thrombosis (2.6%); 10 patients underwent immediate retransplantation, and 34 patients received nontransplant treatments, involving revascularization (n = 19) or expectant nonrevascularization management (n = 15)., Results: The 1-year graft survival after nontransplant treatment was favorable (82%); however, 16 of the 34 patients who received a nontransplant treatment developed ischemic cholangiopathy and required long-term biliary intervention. A Cox regression model showed that increased serum transaminase and bilirubin levels at the time of hepatic artery thrombosis diagnosis, but not nonrevascularization treatment versus revascularization, were risk factors for the development of ischemic cholangiopathy. Ischemic cholangiopathy in revascularized grafts was less extensive with a greater likelihood of resolution within 5-years than that in nonrevascularized grafts (100% vs 17%). Most liver abscesses without signs of liver failure also were reversible. Salvage retransplantation after a nontransplant treatment was performed in 8 patients with a 1-year survival rate equivalent to immediate retransplantation (88% vs 80%)., Conclusion: Selective nontransplant treatments for hepatic artery thrombosis resulted in favorable graft survival. Biliary intervention can resolve liver abscess and ischemic cholangiopathy that developed in revascularized grafts in the long-term; salvage retransplantation should be considered for ischemic cholangiopathy in nonrevascularized grafts because of a poor chance of resolution., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare overall survival and toxicities after yttrium-90 ( 90 Y) radioembolization and chemoembolization with drug-eluting embolics (DEE) in patients with infiltrative hepatocellular carcinoma (HCC)., Materials and Methods: Retrospective review of 50 patients with infiltrative HCC without main portal vein invasion who were treated with 90 Y radioembolization (n = 26) or DEE chemoembolization (n = 24) between March 2007 and August 2012 was completed. Infiltrative tumors were defined by cross-sectional imaging as masses that lacked well-demarcated boundaries, and treatment allocations were made by a multidisciplinary tumor board. Median age was 63 years; median tumor diameter was 9.0 cm; and there were no significant differences between groups in performance status, severity of liver disease, or HCC stage. Toxicities were graded by Common Terminology Criteria for Adverse Events v4.03. Overall survival from treatment was assessed by Kaplan-Meier analysis, with analysis of potential predictors of survival with log-rank test., Results: There was no difference in the average number of procedures performed in each treatment group (DEE, 1.5 ± 1.1; 90 Y, 1.6 ± 0.5; P = .97), and technical success was achieved in all cases. Abdominal pain (73% vs 33%; P = .004) and fever (38% vs 8%; P = .01) were more frequent after DEE chemoembolization. There was no significant difference in median overall survival between treatment groups after treatment (DEE, 9.9 months; 90 Y, 8.1 months; P = .11)., Conclusions: 90 Y radioembolization and DEE chemoembolization provided similar overall survival in the treatment of infiltrative HCC without main portal vein invasion. Abdominal pain and fever were more frequent after DEE chemoembolization., (Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Techniques for laparoscopic liver resection (LLR) have been developed over the past two decades. The aim of this study is to analyze the outcomes and trends of LLR., Methods: 203 patients underwent LLR between 2006 and 2015. Trends in techniques and outcomes were assessed dividing the experience into 2 periods (before and after 2011)., Results: Tumor type was malignant in 62%, and R0 resection was achieved in 87.7%. Procedures included segmentectomy/wedge resection in 64.5%. Techniques included a purely laparoscopic approach in 59.1% and robotic 12.3%. Conversion to open surgery was necessary in 6.4% cases. Mean hospital stay was 3.7 ± 0.2 days. 90-day mortality was 0% and morbidity 20.2%. Pre-coagulation and the robot were used less often, while the performance of resections for posteriorly located tumors increased in the second versus the first period., Conclusion: This study confirms the safety and efficacy of LLR, while describing the evolution of a program regarding patient and technical selection. With building experience, the number of resections performed for posteriorly located tumors have increased, with less reliance on pre-coagulation and the robot.

Background: Tumour morphological criteria for determining the appropriateness of liver transplantation in patients with hepatocellular carcinoma poorly estimate post-transplantation mortality. The aim of this study was to develop and assess the utility of a continuous risk score in predicting overall survival following liver transplantation for hepatocellular carcinoma., Methods: We did a retrospective cohort analysis to develop a continuous multivariable risk score for assessment of overall survival following liver transplantation for hepatocellular carcinoma. We used data from 420 patients with hepatocellular carcinoma who underwent liver transplantation between Jan 1, 2002, and Oct 31, 2014, at the Cleveland Clinic Foundation (CCF), Cleveland, OH, USA. The model we developed (Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma; HALT-HCC) assessed the association of the following previously reported variables of interest with overall survival by use of multivariate Cox regression: MELD-sodium (MELD-Na), tumour burden score (TBS), alpha-fetoprotein (AFP), year of transplantation, underlying cause of cirrhosis, neutrophil-lymphocyte ratio, history of locoregional therapy, and Milan criteria status. Once the risk equation was generated, validation and calibration of risk assessment was done with nationwide data for the same time period from the Scientific Registry of Transplant Recipients (SRTR; n=13 717)., Findings: The risk equation was generated as (1·27 × TBS) + (1·85 × lnAFP) + (0·26 × MELD-Na) and the HALT-HCC score ranged from 2·40 to 46·42 in the CCF cohort. In the validation cohort, prognosis worsened with increasing HALT-HCC score (5-year overall survival of 78·7% [95% CI 76·9-80·4] for quartile 1, 74·5% [72·6-76·2] for quartile 2, 71·8% [70·1-73·5] for quartile 3, and 61·5% [59·6-63·3] for quartile 4; p<0·0001). Multivariate Cox modelling showed that HALT-HCC was significantly associated with overall survival (hazard ratio [HR] 1·06 per point, 95% CI 1·05-1·07), even after adjustment for risk factors not related to hepatocellular carcinoma. Assessment of discrimination revealed a C-index of 0·613 (95% CI 0·602-0·623). Calibration coefficients for linear regressions of observed versus predicted mortality were 1·001 (95% CI 0·998-1·007) at 1 year and 0·982 (0·980-0·987) at 2 years after transplantation. Patients within and outside the Milan criteria showed similar risk of death when stratified by HALT-HCC score. Among the 12 754 patients who met the Milan criteria, 2714 were shown to have poor prognosis after transplantation after stratification by HALT-HCC score with a cutoff of 17; conversely, among the 963 patients who did not meet the Milan criteria, 287 had demonstrably good prognosis., Interpretation: The HALT-HCC score might enable clinicians to accurately assess post-transplantation survival in patients with hepatocellular carcinoma by use of individualised, preoperatively assessed characteristics. However, further studies are needed before adoption., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)