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To assess the impact of difficult location (based on preoperative computed tomography) of liver metastases from colorectal cancer (LMCRC) on surgical difficulty, and occurrence of severe postoperative complications (POCs).A retrospective single-centre study of 911 consecutive patients with LMCRC who underwent hepatectomy by the open approach between 1998 and 2011, before implementation of laparoscopic surgery to obviate approach selection bias. LMCRC with at least one of the following four features on preoperative imaging: tumor invading the hepatocaval confluence or retro-hepatic inferior vena cava, centrally located (Segments 4,5,8) and10 cm in diameter, abutting the supra-hilar area, or involving the paracaval portion or caudate process of Segment 1; were considered as topographically difficult (top-diff). Independent predictors of surgical difficulty assessed by number of blood units transfused, duration of ischemia, and number of sessions of pedicle clamping during surgery and of severe POCs were identified by multivariate analysis before, and after propensity score matching.Top-diff tumor location independently predicted surgical difficulty. Severe POCs were associated with the tumor location [top-diff vs. topographically non difficult (non top-diff)], preoperative portal vein embolization, and variables related to surgical difficulty.LMCRC in difficult location independently predicts surgical difficulty and severe POCs.

The futility of liver transplantation in elderly recipients remains under debate in the HCV eradication era.The aim was to assess the effect of older age on outcome after liver transplantation. We used the ELTR to study the relationship between recipient age and post-transplant outcome. Young and elderly recipients were compared using a PSM method.A total of 10,172 cases were analysed. Recipient age65 years was identified as an independent risk factor associated with reduced patient survival (HR:1.42 95%CI:1.23-1.65,p 0.001). After PSM, 2124 patients were matched, and the same association was found between elderly recipients and patient survival and graft survival (p 0.001). As hepatocellular carcinoma and alcoholic cirrhosis were independent prognostic factors for patient and graft survival a propensity score-matching was performed for each. Patient and graft survival were significantly worse (p 0.05) in the alcoholic cirrhosis elderly group. However, patient and graft survival in the hepatocellular carcinoma cohort were similar (p 0.05) between groups.Liver transplantation is an acceptable and safe curative option for elderly transplant candidates, with worse long-term outcomes compare to young candidates. The underlying liver disease for liver transplantation has a significant impact on the selection of elderly patients.

Background: Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic Hypothermic Oxygenated Machine Perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. Methods: HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4°C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 hours. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage. Discussion: We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on June 31, 2021, and is ongoing Trial registration: ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

A. Overall survival in derivation (MSKCC) and validation (European) cohorts. B. Recurrence free survival in derivation (MSKCC) and validation (European) cohorts.

mRNA expression and hierarchical clustering of molecular risk score (MRS) genes in colorectal liver metastases in derivation cohort. Genes are indicated on the x-axis, patients on the y-axis.

Purpose: Risk stratification after surgery for colorectal cancer liver metastases (CRLM) is achieved using clinicopathologic variables, however, is of limited accuracy. We sought to derive and externally validate a multigene expression assay prognostic of overall survival (OS) that is superior to clinicopathologic variables in patients with surgically resected CRLM.Experimental Design: We measured mRNA expression in prospectively collected frozen tumor from 96 patients with surgically resected CRLM at Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY). We retrospectively generated a 20-gene molecular risk score (MRS) and compared its prognostic utility for OS and recurrence-free survival (RFS) with three common clinical risk scores (CRS). We then tested the prognostic ability of the MRS in an external validation cohort (European) of 119 patients with surgically resected CRLM at the University Medical Center Utrecht (Utrecht, the Netherlands) and Paul Brousse Hospital (Villejuif, France).Results: For OS in the MSKCC cohort, MRS was the strongest independent prognosticator (HR, 3.7–4.9; P < 0.001) followed by adjuvant chemotherapy (HR, 0.3; P ≤ 0.001). For OS in the European cohort, MRS was the only independent prognosticator (HR, 3.5; P = 0.007). For RFS, MRS was also independently prognostic in the MSKCC cohort (HR, 2.4–2.6; P ≤ 0.001) and the European cohort (HR, 1.6–2.5; P ≤ 0.05).Conclusions: Compared with CRSs, the MRS is more accurate, broadly applicable, and an independent prognostic biomarker of OS in resected CRLM. This MRS is the first externally validated prognostic multigene expression assay after metastasectomy for CRLM and warrants prospective validation. Clin Cancer Res; 22(10); 2575–82. ©2016 AACR.

Univariate and multivariate analyses of recurrence free survival in derivation (Table 1) and validation (Table 2) cohorts.

Genes selected for molecular risk score (MRS).

Immediate portal reperfusion is mandatory following hepatectomy combined with portal vein (PV) resection. This retrospective study analyzes the feasibility and the outcomes of the Rex shunt (RS) for reconstruction of the left portal vein (LPV) and reperfusion of the remnant left liver or lobe following hepatectomy for cancer combined with resection of the PV in adult patients.From 2018 to 2021, an RS was used in the above setting to achieve R0 resection or when the standard LPV reconstruction failed or was deemed technically impossible.There were 6 male and 5 female patients (median age, 58 years) with perihilar cancer (5 cases) or miscellaneous cancers invading the PV (6 cases). A major hepatectomy was performed in 10/11 patients. The RS was indicated to achieve R0 resection or for technical reasons in 8 and 3 cases, respectively, and was feasible in all consecutive attempts with (10 cases) or without an interposed synthetic graft (1 case). Two fatal complications (PV thrombosis and pulmonary embolism) and three non-severe complications occurred in four patients within 90 days of surgery. Two patients died of tumor recurrence with a patent RS at 13 and 29 months, and 7 were recurrence free with a patent shunt with a follow-up of 1 to 37 months (median, 15 months).In case of remnant left liver or lobe following hepatectomy combined with resection of the PV, the RS may help to achieve R0 resection and is a valuable option to perform technically satisfying portal reperfusion of the remnant left liver or lobe.

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48–66) with the 3-CTx versus 48.4% (95% CI: 39–57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

The results of this study were presented during the 13th Congress of the E-AHPBA on June 3th 2019, in Amsterdam.; International audience; BACKGROUND: Major bile duct injuries (BDI) following cholecystectomy require complex reconstructive surgery. The aim was to collect the liver transplantations (LT) performed in France for major BDI following cholecystectomy, to analyze the risk factors and to report the results. METHODS: National multicenter observational retrospective study. All the patients who underwent a LT in France between 1994 and 2017, for BDI following cholecystectomy, were included. RESULTS: 30 patients were included. 25 BDI occurred in non hepato-biliary expert centers, 20 were initially treated in these centers. Median time between injury and LT was 3 years in case of an associated vascular injury (11 injuries), versus 11.7 years without vascular injury (p = 0.006). Post-transplant morbidity rate was 86.7%, mortality 23.5% at 5 years. CONCLUSION: Iatrogenic BDI remains a real concern with severe cases, associated with vascular damages or leading to cirrhosis, with no solution but LT. It is associated with high morbidity and not optimal results. This enlights the necessity of early referral of all major BDI in expert centers to prevent dramatic outcome. Decision to perform transplantation should be taken before dismal infectious situations or biliary cirrhosis and access to graft should be facilitated by Organ Sharing Organizations.

The ABO blood group system may influence tumorigenesis, but its prognostic value in liver transplantation (LT) for hepatocellular carcinoma (HCC) has never been assessed.All consecutive patients who underwent LT for HCC between 2013 and 2017 at 9 centers were analyzed. Predictors of tumor recurrence were identified using multivariable analysis, while comparison between group A and non-A recipients was performed after propensity score matching.Among 925 LT recipients, 406 were blood group A, 94 group B, 380 group O, and 45 group AB. On multivariable analysis, group A was associated with tumor recurrence (hazard ratio [HR] = 1.574 [95% confidence interval; 95% CI = 1.034-2.394] P = 0.034). After propensity score matching, 1- and 5-y recurrence rates were 7.4% and 20.1% in group A recipients versus 3.3% and 13.2% in non-A recipients (HR = 1.66 [95% CI = 1.12-2.45], P = 0.011). One and 5-y recurrence-free survivals were 85.2% and 66.8% in group A recipients versus 88.5% and 71.3% in non-A recipients (HR = 1.38 [95% CI = 1.01-1.90], P = 0.045). Among recipients within Milan criteria (n = 604), 1- and 5-y recurrence rates were 5.8% and 12.7% in group A recipients versus 3.1% and 12.2% in non-A recipients (HR = 1.197 [95% CI = 0.721-1.987], P = 0.485). Among recipients outside Milan criteria (n = 182), 1- and 5-y recurrence rates were 12.1% and 43.8% in group A recipients versus 3.9% and 15.6% in non-A recipients (HR = 3.175 [95% CI = 1.526-6.608], P = 0.002).ABO blood system influences the oncological outcome of recipients undergoing LT for HCC. Its incorporation in the prognostication model of LT for HCC may allow improving the management of LT candidates.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Background. The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex. Methods. Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome. Results. European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000). Conclusions. An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size.

BACKGROUND: Obesity is associated with increased oncological risk and outcomes but the evidence surrounding the effect of body mass index (BMI) on increased risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is still questionable. The purpose of this retrospective study of a large cohort of adult patients transplanted for HCC was to investigate the effect of BMI on the incidence of HCC recurrence and outcome. METHODS: Data from 427 adult recipients transplanted for HCC between 2000 and 2017 were collected. Patients were classified at time of LT according to the World Health Organization BMI classification into 3 groups; group 1: BMI

Background The aim of this ancillary study of the SARAH trial is to compare health-related quality of life (HRQoL) in patients with locally advanced or inoperable hepatocellular carcinoma (HCC) treated with transarterial radioembolisation (TARE) or sorafenib. Methods This study included randomised patients who received either TARE or at least one dose of sorafenib with no major deviation in the protocol and who had at least one QoL follow-up assessment in addition to the baseline evaluation. QoL was assessed from the date of randomisation using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, until disease progression or other reasons for stopping study participation. Data were analysed using linear mixed and time-dependent models. Results A total of 285 patients were included (122 and 163, in the TARE and sorafenib groups, respectively). Questionnaire completion rates were similar (77.5% versus 80.4%, in the TARE and sorafenib groups, respectively, p = 0.25). Longitudinal HRQoL analysis showed a significant treatment and time effects for fatigue and global health status, and significant treatment, time and treatment by time interaction effects for appetite loss, diarrhoea and social functioning. The median time to deterioration for the global health status was 3.9 months (95% confidence interval [CI] 3.7–4.3) versus 2.6 months (95% CI 2.0–3.0) in the TARE and sorafenib groups, respectively. Conclusions HRQoL was preserved longer with TARE than with sorafenib in locally advanced HCC. These data could be used to optimise management of patients with advanced or inoperable HCC.

The role of positron emission tomography / computed tomography (PET/CT) in hepatocellular carcinoma (HCC) management is not clearly defined. Our objective was to analyze the utility of dual-PET/CT (18F-FDG + 18F-Choline) imaging findings on the BCLC staging and treatment decision for HCC patients.Between January 2011 and April 2019, 168 consecutive HCC patients with available baseline dual-PET/CT imaging data were retrospectively analyzed. To identify potential refinement criteria for surgically-treated patients, survival Kaplan-Meier curves of various standard-of-care and dual-PET/CT baseline parameters were estimated. Finally, multivariate cox proportional hazard ratios of the most relevant clinico-biological and/or PET parameters were estimated.Dual-PET/CT findings increased the score of BCLC staging in 21 (12.5%) cases. In 24.4% (n=41) of patients, the treatment strategy was modified by the PET findings. Combining AFP levels at a threshold of 10 ng/ml with 18F-FDG or 18F-Choline N status significantly impacted DFS (p0.05). In particular, the combined criteria of the N+ status assessed by 18F-Choline with AFP threshold of 10 ng/ml provided a highly predictive composite parameter for estimation of DFS according to multivariate analysis (HR=10.6, p0.05).The 18F-Choline / AFP composite parameter appears promising, and further prospective studies are mandatory to validate its oncological impact.

To date, surgery of colorectal liver metastases is the only chance of long-term survival with the principle of resecting all the metastases to be potentially curative (R0-R1 resection). However, 10-20% of patients are initially resectable. Along with the increasing efficacy of chemotherapy, around 20% of initially unresectable patients could be switched to secondary resectability after tumor downsizing with real hope of long-term survival. However, still a majority of patients remain "curatively" unresectable while responding to chemotherapy, owing to the impossibility to resect all the initial tumoral disease. For such extensive cases, cytoreductive surgery might provide a survival benefit, provided an objective tumor response with chemotherapy and optimal cytoreduction with almost no macroscopic residual disease.

Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients who underwent iCCA resection between 2000 and 2019 in two tertiary French medical centers. We report overall survival (OS) and disease-free-survival (DFS). Univariate and multivariate analyses were performed to determine associated factors. Results: 195 patients were analyzed. The number of R0, R1par and R1vasc patients was 128 (65.7%), 57 (29.2%) and 10 (5.1%), respectively. The 1- and 2-year OS rates in the R0, R1par and R1vasc groups were 83%, 87%, 57% and 69%, 75%, 45%, respectively (p = 0.30). The 1- and 2-year DFS rates in the R0, R1par and R1vasc groups were 58%, 50%, 30% and 43%, 28%, 10%, respectively (p = 0.019). Resection classification (HR 1.56; p = 0.003) was one of the independent predictors of DFS in multivariate analysis. Conclusions: the survival outcomes after R1par resection are intermediate to those after R0 or R1vasc resection. R1vasc resection should be avoided in patients with iCCA as it does not provide satisfactory oncological outcomes.

International audience; BACKGROUND: Liver resection is a curative treatment for hepatocellular carcinoma (HCC) and an alternative to liver transplantation (LT). However, post-liver resection recurrence rates remain high. This study aimed to determine whether liver stiffness measurement (LSM) correlated with recurrence and to propose a method for predicting HCC recurrence exclusively using pre-liver resection criteria. METHODS: This retrospective monocentric study included patients who had undergone LR liver resection for HCC between 2015 and 2018 and who had (1) preoperative alpha-fetoprotein scores indicating initial transplant viability and (2) available preoperative LSM data. We developed a predictive score for recurrence over time using Cox univariate regression and multivariate analysis with a combination plot before selecting the optimal thresholds (receiver operating characteristic curves + Youden test). RESULTS: Sixty-six patients were included. After an average follow-up of 40 months, the recurrence rate was 45% (n = 30). Three-year overall survival was 88%. Four preoperative variables significantly impacted the time to recurrence: age ≥70 years, LSM ≥11 kPa, international normalized ratio (INR) ≥1.2, and maximum HCC diameter ≥3 cm. By assigning 1 point per positive item, patients with a score

The scarcity of livers for transplantation is rising, and new strategies to extend the donor pool are being explored. One solution is to use marginal grafts from extended criteria donors, presenting, for example, liver steatosis. As current preservation solutions (UW, HTK, and IGL-1) were mainly designed for static cold storage (SCS) only, IGL-2, a modified version of IGL-1, was developed to be suitable for SCS and dynamic preservation, such as hypothermic oxygenated perfusion (HOPE). In this study, we investigated the combined effect of IGL-2, SCS, and HOPE and compared it to the most used preservation solution (UW and Belzer MPS). Four experimental groups with six rats each were designed using Zucker rats. All groups underwent 24 h of SCS (in IGL-2 or UW) + 2 h of normothermic machine perfusion (NMP) at 37 °C to mimic transplantation. HOPE (IGL-2 or Belzer MPS) was performed before NMP on half of the rats. The IGL-2 group demonstrated lower transaminases and a significantly low level of glycocalyx proteins, CASP3, and HMGB1 in the perfusates. These data suggest the protective role of IGL-2 for fatty livers in preserving the endothelial glycocalyx, apoptosis, and inflammation.

To expand the pool of organs, hypothermic oxygenated perfusion (HOPE), one of the most promising perfusion protocols, is currently performed after cold storage (CS) at transplant centers (HOPE-END). We investigated a new timing for HOPE, hypothesizing that performing HOPE before CS (HOPE-PRE) could boost mitochondrial protection allowing the graft to better cope with the accumulation of oxidative stress during CS. We analyzed liver injuries at 3 different levels. Histologic analysis demonstrated that, compared to classical CS (CTRL), the HOPE-PRE group showed significantly less ischemic necrosis compared to CTRL vs HOPE-END. From a biochemical standpoint, transaminases were lower after 2 hours of reperfusion in the CTRL vs HOPE-PRE group, which marked decreased liver injury. qPCR analysis on 37 genes involved in ischemia-reperfusion injury revealed protection in HOPE-PRE and HOPE-END compared to CTRL mediated through similar pathways. However, the CTRL vs HOPE-PRE group demonstrated an increased transcriptional level for protective genes compared to the CTRL vs HOPE-END group. This study provides insights on novel biomarkers that could be used in the clinic to better characterize graft quality improving transplantation outcomes.

Summary High‐risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end‐stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0–10. Low‐risk (0–3), medium‐risk (4–5), and high‐risk (6–10) groups were identified with significantly different 5‐year survival rates ranging 56.9% (95% CI 52.8–60.7%), 46.3% (95% CI 41.1–51.4%), and 32.1% (95% CI 23.5–41.0%), respectively (P, The retransplantation risk score.

BACKGROUND Surgical resection and radiofrequency ablation (RFA) represent two possible strategy in treatment of hepatocellular carcinoma (HCC) in Milan criteria. AIM To evaluate short- A nd long-term outcome in elderly patients (70 years) with HCC in Milan criteria, which underwent liver resection (LR) or RFA. METHODS The study included 594 patients with HCC in Milan criteria (429 in LR group and 165 in RFA group) managed in 10 European centers. Statistical analysis was performed using the Kaplan-Meier method before and after propensity score matching (PSM) and Cox regression. RESULTS After PSM, we compared 136 patients in the LR group with 136 patients in the RFA group. Overall survival at 1, 3, and 5 years was 91%, 80%, and 76% in the LR group and 97%, 67%, and 41% in the RFA group respectively (P = 0.001). Diseasefree survival at 1, 3, and 5 years was 84%, 60% and 44% for the LR group, and 63%, 36%, and 25% for the RFA group (P = 0.001).Postoperative Clavien-Dindo IIIIV complications were lower in the RFA group (1% vs 11%, P = 0.001) in association with a shorter length of stay (2 d vs 7 d, P = 0.001).In multivariate analysis, Model for End-stage Liver Disease (MELD) score (10) [odds ratio (OR) = 1.89], increased value of international normalized ratio (1.3) (OR = 1.60), treatment with radiofrequency (OR = 1.46) ,and multiple nodules (OR = 1.19) were independent predictors of a poor overall survival while a high MELD score (10) (OR = 1.51) and radiofrequency (OR = 1.37) were independent factors associated with a higher recurrence rate. CONCLUSION Despite a longer length of stay and a higher rate of severe postoperative complications, surgery provided better results in long-term oncological outcomes as compared to ablation in elderly patients (70 years) with HCC in Milan criteria. © 2021 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved.

Two‐stage hepatectomy (TSH) is one of the specific surgical techniques that can expand the pool of resectable patients with initially unresectable colorectal liver metastases (CRLM). The indication of TSH for CRLM is only bilateral, multinodular disease, which cannot be resected by a single hepatectomy. TSH is nowadays considered an effective treatment for selected patients, with acceptable morbidity/mortality rates and promising long‐term outcomes. However, not all eligible patients can benefit from the TSH strategy. One of the most important issues is dropout from the strategy (failure to complete both of the two sequential procedures), because the survival of such patients is drastically worse compared with patients who can complete both stages. Another important issue is the early recurrence rate and subsequent poor survival even after completion of TSH. Thus, the selection of appropriate patients who can really benefit from the TSH strategy is crucial. This review discusses the optimal patient selection for TSH, which should be helpful for the development of treatment strategies for patients with extensive CRLM., Although two‐stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM) is nowadays considered an effective treatment for selected patients, with acceptable morbidity/mortality rates and promising long‐term outcomes, not all eligible patients can benefit from this strategy. In this review, we discuss the optimal patient selection for TSH, which should be helpful for the development of treatment strategies for patients with extensive CRLM.

Hepatocellular carcinoma recurrence after liver transplantation is a well-known complication but the development of de novo hepatocellular carcinoma in non-cirrhotic allograft with no previous history of hepatic malignancy either in the donor or the recipient is extremely rare. A 33-year-old man underwent deceased donor liver transplantation due to HBV-HDV cirrhosis in 1991. The donor was healthy, with negative viral serology. Pretransplant assessment and explant liver pathology revealed no tumor. He developed an 8 cm mediastinal thymus cancer in 2014, a chronic myeloid leukemia in 2015 and a 16 mm renal cell carcinoma in 2017. After 27 years, in 2018, his routine follow-up sonography showed incidentally a 37 mm hepatic nodule in segment VII which revealed after percutaneous liver guided biopsy a hepatocellular carcinoma. As no extra hepatic metastasis was noted, segmentectomy was done. The pathological report confirmed a moderately differentiated hepatocellular carcinoma nodule of 50 mm diameter with absence of microvascular invasion and the non-tumoral liver showed histological features of NASH (SAF score: S1A2F3, NAS score: A3F3 and LAFSc:5) with absence of HBsAg and HBcAg. This case emphasizes the importance of long-term close surveillance by imaging of the graft even in the absence of viral recurrence and graft cirrhosis.

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early. ispartof: LIVER TRANSPLANTATION vol:27 issue:4 pages:491-501 ispartof: location:United States status: published

Improved chemotherapy response rates have lead to "disappearing" colorectal liver metastases (dCRLM). We aim to assess management patterns of dCRLM from an international body of hepatobiliary surgeons.A survey was designed, tested for item relevance, readability and content validity, and distributed to the AHPBA, IHPBA and ANZHPBA.The majority of 226 respondents were15 years from training (69%), practiced in academia (82%) and devoted50% of their practice to hepatobiliary (75%). Surgeons utilize CT(45%) or MRI(47%) for preoperative planning with a preferred imaging interval of6 weeks. Nearly all have experienced dCRLM (99%) and 63% of surgeons have waited a few months to assess for durability of response prior to definitive surgical/ablative therapy. Only 24% place fiducial markers for lesions1-cm prior to neoadjuvant chemotherapy. Intra-operatively, 97% of surgeons perform ultrasound, and 71% ablation. When a tumor has "disappeared," 49% elect for observation and 31% resect if the dCRLM is superficial. Of those electing observation, 87% believe there is effective treatment with progression on surveillance imaging.Nearly all surgeons have experienced dCRLM with half choosing observation over intervention due to the belief that these lesions may be re-addressed in the future.

Background & Aims Despite improvements in medical and surgical techniques, post-hepatectomy liver failure (PHLF) remains the leading cause of postoperative death. High postoperative portal vein pressure (PPV) and portocaval gradient (PCG), which cannot be predicted by current tools, are the most important determinants of PHLF. Therefore, we aimed to evaluate a digital twin to predict the risk of postoperative portal hypertension (PHT). Methods We prospectively included 47 patients undergoing major hepatectomy. A mathematical (0D) model of the entire blood circulation was assessed and automatically calibrated from patient characteristics. Hepatic flows were obtained from preoperative flow MRI (n = 9), intraoperative flowmetry (n = 16), or estimated from cardiac output (n = 47). Resection was then simulated in these 3 groups and the computed PPV and PCG were compared to intraoperative data. Results Simulated post-hepatectomy pressures did not differ between the 3 groups, comparing well with collected data (no significant differences). In the entire cohort, the correlation between measured and simulated PPV values was good (r = 0.66, no adjustment to intraoperative events) or excellent (r = 0.75) after adjustment, as well as for PCG (respectively r = 0.59 and r = 0.80). The difference between simulated and measured post-hepatectomy PCG was ≤3 mmHg in 96% of cases. Four patients suffered from lethal PHLF for whom the model satisfactorily predicted their postoperative pressures. Conclusions We demonstrated that a 0D model could correctly anticipate postoperative PHT, even using estimated hepatic flow rates as input data. If this major conceptual step is confirmed, this algorithm could change our practice toward more tailor-made procedures, while ensuring satisfactory outcomes. Lay summary Post-hepatectomy portal hypertension is a major cause of liver failure and death, but no tool is available to accurately anticipate this potentially lethal complication for a given patient. Herein, we propose using a mathematical model to predict the portocaval gradient at the end of liver resection. We tested this model on a cohort of 47 patients undergoing major hepatectomy and demonstrated that it could modify current surgical decision-making algorithms.

Postoperative early recurrence after hepatic resection for hepatocellular carcinoma (HCC) poses a challenge to surgeons, and the effect of a surgical margin is still controversial. This study aimed to identify an ideal margin to prevent early recurrence. A total of 226 consecutive patients who underwent primary curative hepatic resection for solitary and primary HCC were enrolled. The definition of early recurrence was determined using the minimum P value approach. Logistic regression analysis was used to identify the risk factors of early recurrence. The receiver-operating characteristic (ROC) curve was used to identify the optimal cut-off of the surgical margin and early recurrence. Recurrence within 8 months induced the poorest overall survival (P = 2×10−15). ROC analysis showed that the optimal cut-off value of the surgical margin was 7 mm. The risk factors of early recurrence (≤ 8-month recurrence) were preoperative alpha-fetoprotein levels ≥ 100 ng/ml (Odds ratio [OR] 4.92 [2.28–10.77], P 7-mm margin is important to prevent early recurrence. Patients with HCC and alpha-fetoprotein levels > 100 ng/ml, non-capsule formation, or microvascular invasion may have a survival benefit from a ≥ 7-mm margin.

Background Hepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato-Biliary-Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors. Methods Eight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations. Results The eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two. A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy. Conclusions These guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher-quality evidence.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil-leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first- and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2-70.4] and resulted in median PFS and OS of 8.7 months [7.5-9.9] and 19.9 months [15.4-24.5]. Corresponding figures in second line were 37.5% [22.5-52.5], 6.7 months [4.8-8.9] and 16.3 months [11.8-20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia–reperfusion injury that occurs in the complex route of the graft from “harvest to revascularization”. Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics., This study was supported by the European Commission H2020-MSCA-ITN-ETN-2016 “FOIE GRAS—Metabolism and the Liver-Gut Axis in Non-Alcoholic Fatty Liver Disease” and the Marie Curie Fellow to Rui Teixeira da Silva.

IMPORTANCE: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR. OBJECTIVE: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality. DESIGN, SETTING, AND PARTICIPANTS: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible. INTERVENTIONS: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab. MAIN OUTCOMES AND MEASURES: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol. RESULTS: A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics. CONCLUSIONS AND RELEVANCE: Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01606098