Comparing indications, complexity and outcomes of laparoscopic liver resection between centers with and without a liver transplant program: a French nationwide study.

BACKGROUND: There are no data to evaluate the difference in populations and impact of centers with liver transplant programs in performing laparoscopic liver resection (LLR). METHODS: This was a multicenter study including patients undergoing LLR for benign and malignant tumors at 27 French centers from 1996 to 2018. The main outcomes were postoperative severe morbidity and mortality. RESULTS: A total of 3154 patients were included, and 14 centers were classified as transplant centers (N = 2167 patients, 68.7 %). The transplant centers performed more difficult LLRs and more resections for hepatocellular carcinoma (HCC) in patients who more frequently had cirrhosis. A higher rate of performing the Pringle maneuver, a lower rate of blood loss and a higher rate of open conversion (all p < 0.05) were observed in the transplant centers. There was no association between the presence of a liver transplant program and either postoperative severe morbidity (<10 % in each group; p = 0.228) or mortality (1 % in each group; p = 0.915). CONCLUSIONS: Most HCCs, difficult LLRs, and cirrhotic patients are treated in transplant centers. We show that all centers can achieve comparable safety and quality of care in LLR independent of the presence of a liver transplant program.

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.

An Efficient 5-Aminolevulinic Acid Photodynamic Therapy Treatment for Human Hepatocellular Carcinoma.

Photodynamic therapy (PDT) is a two-stage treatment relying on cytotoxicity induced by photoexcitation of a nontoxic dye, called photosensitizer (PS). Using 5-aminolevulinic acid (5-ALA), the pro-drug of PS protoporphyrin IX, we investigated the impact of PDT on hepatocellular carcinoma (HCC). Optimal 5-ALA PDT dose was determined on three HCC cell lines by analyzing cell death after treatment with varying doses. HCC-patient-derived tumor hepatocytes and healthy donor liver myofibroblasts were treated with optimal 5-ALA PDT doses. The proliferation of cancer cells and healthy donor immune cells cultured with 5-ALA-PDT-treated conditioned media was analyzed. Finally, therapy efficacy on humanized SCID mice model of HCC was investigated. 5-ALA PDT induced a dose-dependent decrease in viability, with an up-to-four-fold reduction in viability of patient tumor hepatocytes. The 5-ALA PDT treated conditioned media induced immune cell clonal expansion. 5-ALA PDT has no impact on myofibroblasts in terms of viability, while their activation decreased cancer cell proliferation and reduced the tumor growth rate of the in vivo model. For the first time, 5-ALA PDT has been validated on primary patient tumor hepatocytes and donor healthy liver myofibroblasts. 5-ALA PDT may be an effective anti-HCC therapy, which might induce an anti-tumor immune response.

Paradigm shift: should preoperative 3D reconstruction models become mandatory before hepatectomy for hepatocellular carcinoma (HCC)? Results of a multicenter prospective trial.

BACKGROUND: A preoperative surgical strategy before hepatectomy for hepatocellular carcinoma is fundamental to minimize postoperative morbidity and mortality and to reach the best oncologic outcomes. Preoperative 3D reconstruction models may help to better choose the type of procedure to perform and possibly change the initially established plan based on conventional 2D imaging. METHODS: A non-randomized multicenter prospective trial with 136 patients presenting with a resectable hepatocellular carcinoma who underwent open or minimally invasive liver resection. Measurement was based on the modification rate analysis between conventional 2D imaging (named "Plan A") and 3D model analysis ("Plan B"), and from Plan B to the final procedure performed (named "Plan C"). RESULTS: The modification rate from Plan B to Plan C (18%) was less frequent than the modification from Plan A to Plan B (35%) (OR = 0.32 [0.15; 0.64]). Concerning secondary objectives, resection margins were underestimated in Plan B as compared to Plan C (-3.10 mm [-5.04; -1.15]). CONCLUSION: Preoperative 3D imaging is associated with a better prediction of the performed surgical procedure for liver resections in HCC, as compared to classical 2D imaging.

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling. RESULTS: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies. CONCLUSION: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. LAY SUMMARY: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Neo-Adjuvant Use of Sorafenib for Hepatocellular Carcinoma Awaiting Liver Transplantation.

Data on efficacy and safety of sorafenib in a neoadjuvant setting for HCC awaiting liver transplantation (LT) are heterogeneous and scarce. We aimed to investigate the trajectory of patients treated with sorafenib while awaiting LT. All patients listed for HCC and treated with sorafenib were included in a monocentric observational study. A clinical and biological evaluation was performed every month. Radiological tumor response evaluation was realized every 3 months on the waiting list and every 6 months after LT. Among 327 patients listed for HCC, 62 (19%) were treated with Sorafenib. Sorafenib was initiated for HCC progression after loco-regional therapy (LRT) in 50% of cases and for impossibility of LRT in 50% of cases. The mean duration of treatment was 6 months. Thirty six patients (58%) dropped-out for tumor progression and 26 (42%) patients were transplanted. The 5-year overall and recurrent-free survival after LT was 77% and 48% respectively. Patients treated for impossibility of LRT had acceptable 5-year intention-to-treat overall and post-LT survivals. Conversely, patients treated for HCC progression presented high dropout rate and low intention-to-treat survival. Our results suggest that it is very questionable in terms of utility that patients treated for HCC progression should even be kept listed once the tumor progression has been observed.

Right hepatectomy: mishaps of extra-hepatic portal vein division.

En-bloc clamping of the hepatic pedicle is commonly performed during liver resection in order to reduce bleeding during parenchymal transection. Selective vascular clamping of the ipsilateral portal vein branch and artery is considered preferable to avoid ischemia-reperfusion injury to the future liver remnant and there has as yet been no reports of serious morbidity related to this technique. Herein we report three adverse incidents associated with attempts at extrahepatic control and division of the right portal vein during hepatectomy. Although extrahepatic control of the right portal vein is simple in a majority of patients caution is advised in the presence of anatomical variations of the right portal vein, liver dysmorphia, preoperative portal vein embolization and during the learning curve of laparoscopic liver resection. A Pringle maneuver may be preferable to hemihepatic inflow occlusion for repeat hepatectomies.

Prognostic impact of surgical margins for hepatocellular carcinoma according to preoperative alpha-fetoprotein level.

BACKGROUND: HCC are known to have satellite nodules and microvascular invasions requiring sufficient margins. An alpha-fetoprotein (AFP) level >100 ng/mL is associated with worse pathological features in HCC. In practice, large resection margins, particularly >1 cm, are infrequently retrieved on the specimens. METHODS: 397 patients from 5 centres were included from 2012 to 2017. The primary endpoint was time-to-recurrence in relation to AFP level (> or <100 ng/ml) as well as surgical margins (> or <1 cm). The secondary endpoint was overall survival (OS). RESULTS: The median follow-up was 25 months. In Low AFP group, median time to recurrence (TTR) for patients with margins <1 cm was 36 months and for patients with margins ≥1 cm was 34 months (p = 0.756), and overall survival (OS) was not significantly different according to margins (p = 0.079). In High-AFP group, patients with margins <1 cm had a higher recurrence rate than patients with margins ≥1 cm (p = 0.016): median TTR for patients with margins <1 cm was 8 months whereas it was not reached for patients with margins ≥1 cm. Patients with margins <1 cm had a significantly worse OS compared to the patients with margins ≥1 cm (p = 0.043). CONCLUSION: Preoperative AFP level may help determine margins to effectively treat high AFP tumours. For low-AFP tumours, margins didn't have an impact on TTR or OS.

Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis.

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.

Predicting Intraoperative Difficulty of Open Liver Resections: The DIFF-scOR Study, An Analysis of 1393 Consecutive Hepatectomies From a French Multicenter Cohort.

OBJECTIVE: The aim of this study was to build a predictive model of operative difficulty in open liver resections (LRs). SUMMARY BACKGROUND DATA: Recent attempts at classifying open-LR have been focused on postoperative outcomes and were based on predefined anatomical schemes without taking into account other anatomical/technical factors. METHODS: Four intraoperative variables were perceived by the authors as to reflect operative difficulty: operation and transection times, blood loss, and number of Pringle maneuvers. A hierarchical ascendant classification (HAC) was used to identify homogeneous groups of operative difficulty, based on these variables. Predefined technical/anatomical factors were then selected to build a multivariable logistic regression model (DIFF-scOR), to predict the probability of pertaining to the highest difficulty group. Its discrimination/calibration was assessed. Missing data were handled using multiple imputation. RESULTS: HAC identified 2 clusters of operative difficulty. In the "Difficult LR" group (20.8% of the procedures), operation time (401 min vs 243 min), transection time (150 vs.63 minute), blood loss (900 vs 400 mL), and number of Pringle maneuvers (3 vs 1) were higher than in the "Standard LR" group. Determinants of operative difficulty were body weight, number and size of nodules, biliary drainage, anatomical or combined LR, transection planes between segments 2 and 4, 4, and 8 or 7 and 8, nonanatomical resections in segments 2, 7, or 8, caval resection, bilioentric anastomosis and number of specimens. The c-statistic of the DIFF-scOR was 0.822. By contrast, the discrimination of the DIFF-scOR to predict 90-day mortality and severe morbidity was poor (c-statistic: 0.616 and 0.634, respectively). CONCLUSION: The DIFF-scOR accurately predicts open-LR difficulty and may be used for various purposes in clinical practice and research.

Transcatheter aortic valve replacement (TAVR) as bridge therapy restoring eligibility for liver transplantation in cirrhotic patients.

Severe aortic stenosis is a widespread valve disease, constituting a contraindication to organ transplantation due to cardiovascular morbidity and projected mortality. Mortality after conventional surgical aortic valve replacement in cirrhotic patients depends upon the Child-Pugh class. In the past few years, transcatheter aortic valve replacement has progressively become the treatment of choice for high-risk patients with severe aortic stenosis. Here, we report the cases of 3 cirrhotic patients who became eligible for liver transplantation after successful transcatheter aortic valve replacement as bridge therapy.

Definition and Prospective Assessment of Functional Recovery After Liver Transplantation: A New Objective Consensus-Based Metric for Safe Discharge.

Standardized discharge criteria are critical to reduce premature discharge and avoid unnecessary hospital stays. No such criteria exist for patients undergoing liver transplantation (LT). To achieve a consensus-based checklist of criteria for safe patient discharge after LT, this mixed-method study included the following: a systematic literature review and expert discussion to draft a first checklist of post-LT discharge criteria, defining patient recovery and indications for hospital discharge (functional recovery); an exploratory online electronic Delphi (e-Delphi) study; a single-center pilot study to test checklist feasibility; and a final e-Delphi study with an extended interdisciplinary expert panel to validate the final checklist. The first round provided a 10-point discharge checklist with 5 patient-centered items derived from discharge criteria after liver surgery and 5 graft-centered items derived from expert discussion. The restricted panel (9 experts) e-Delphi provided 100% consensus after the second round, with slight modifications to the criteria. During the pilot study, 19 of 45 (42.2%) patients included fulfilled the complete checklist (100% of 10 items) after median (IQR) 16 (8-21) days (functional recovery) and a length of stay of 20 (9-24) days. The item with the lowest completion rate was minimum serum tacrolimus level in the target on 2 consecutive blood samples (n = 21; 47%), achieved at 13 (9-15) days. The extended panel (66 experts) e-Delphi provided 95%-98% consensus after the third round, with slight modifications of the criteria. This study provided substantial consensus on discharge criteria after LT. We anticipate that these criteria will be useful in clinical practice to guide patient discharge and increase the comparability of results between future studies.

Analysis of Liver Resection Versus Liver Transplantation on Outcome of Small Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma in the Setting of Cirrhosis.

This multicenter study compares the outcomes of patients with cirrhosis undergoing liver transplantation (LT) or liver resection (LR) between January 2002 and July 2015 who had intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) found incidentally in the native liver. A total of 49 (65%) LT and 26 (35%) LR patients with cirrhosis and histologically confirmed iCCA/cHCC-CCA ≤5 cm were retrospectively analyzed. LT patients had significantly lower tumor recurrence (18% versus 46%; P = 0.01), for which the median diameter of the largest nodule (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12]; P = 0.006) and tumor differentiation (HR, 3.74; 95% CI 1.71-8.17; P = 0.001) were independently predictive. The LT group had significantly higher 5-year recurrence-free survival (RFS; 75% versus 36%; P = 0.004). In patients with tumors >2 cm but ≤5 cm, LT patients had a lower recurrence rate (21% versus 48%; P = 0.06) and a higher 5-year RFS (74% versus 40%; P = 0.06). Independent risk factors for recurrence were LT (protective; HR, 0.23; 95% CI, 0.07-0.82; P = 0.02), the median diameter of the largest nodule (HR, 1.10; 95% CI, 1.02-1.73; P = 0.007), and tumor differentiation (HR, 4.16; 95% CI, 1.37-12.66; P = 0.01). In the LT group, 5-year survival reached 69% and 65% (P = 0.40) in patients with tumors ≤2 cm and >2-5 cm, respectively, and survival was also comparable between iCCA and cHCC-CCA patients (P = 0.29). LT may offer a benefit for highly selected patients with cirrhosis and unresectable iCCA/cHCC-CCA having tumors ≤5 cm. Efforts should be made to evaluate tumor differentiation, and these results need to be confirmed prospectively in a larger population.

Peritoneal Carcinomatosis Risk and Long-Term Survival Following Hepatectomy for Spontaneous Hepatocellular Carcinoma Rupture: Results of a Multicenter French Study (FRENCH-AFC).

BACKGROUND: Spontaneous rupture of hepatocellular carcinoma (HCC) remains a life-threatening complication, with a reported mortality rate of between 16 and 30% and an incidence rate of approximately 3% in Europe. Survival data and risk factors after ruptured HCC are lacking, especially for peritoneal metastasis (PM). OBJECTIVES: The aims of this study were to evaluate the pattern of recurrence and mortality after hepatectomy for ruptured HCC, and to focus on PM. METHODS: We retrospectively reviewed the files of patients admitted to 14 French surgical centers for spontaneous rupture of HCC between May 2000 and May 2012. RESULTS: Overall, 135 patients were included in this study. The median disease-free survival and overall survival (OS) rates were 16.1 (11.0-21.1) and 28.7 (26.0-31.5) months, respectively, and the median follow-up period was 29 months. At last follow-up, recurrences were observed in 65.1% of patients (n = 88). The overall rate of PM following ruptured HCC was 12% (n = 16). Surgical management of PM was performed for six patients, with a median OS of 36.6 months. An α-fetoprotein level > 30 ng/mL (p = 0.0009), tumor size at rupture > 70 mm (p = 0.0009), and vascular involvement (p < 0.0001) were found to be independently associated with an increased likelihood of recurrence. No risk factor for PM was observed. CONCLUSION: This large-cohort French study confirmed that 12% of patients had PM after ruptured HCC. A curative approach may be an option for highly selected patients with exclusive PD because of the survival benefit it could provide.

Asymmetric kinetics of volume and function of the remnant liver after major hepatectomy as a key for postoperative outcome - A case-matched study.

BACKGROUND: The kinetics of remnant liver (RL) function is unknown after major hepatectomy (MH), especially in case of post-hepatectomy liver failure (PHLF). This study investigated the change in RL function after MH using 99mTc-labelled-mebrofenin SPECT-scintigraphy and its correlation with RL volume and PHLF. METHODS: From 2011 to 2015, 125 patients undergoing MH had volumetric assessment by CT and functional SPECT-scintigraphy preoperatively and at day 7 (POD7) and 1 month (1M). RL volume and function changes were compared in (i) overall population and (ii) 17 patients with vs. 42 without PHLF (ISGLS) matched on preoperative RL function. RESULTS: Increase in RL function correlated poorly with volume increase at POD7 (r = 0.035, p = 0.43) and 1M (r = 0.394, p < 0.0001). Overall, function increase on POD7 (+38.8%) was lower than volume (+49.4%), but comparable at 1M (+78.8% vs. +73%). PHLF patients showed lower function increase on POD7 (+2.1% [-89%-77.8%] vs. +50% [-39%-218%]; p = 0.006). At 1M, 4 PHLF patients died with no function increase despite significant volumetric gain. CONCLUSIONS: We first showed via sequential SPECT-scintigraphy that RL function increase after MH is slower than volume increase. A poor kinetic of function was correlated with PHLF as early as POD7, contrasting with substantial volume gain in PHLF patients.

An ordinal model to predict the risk of symptomatic liver failure in patients with cirrhosis undergoing hepatectomy.

BACKGROUND & AIMS: Selection criteria for hepatectomy in patients with cirrhosis are controversial. In this study we aimed to build prognostic models of symptomatic post-hepatectomy liver failure (PHLF) in patients with cirrhosis. METHODS: This was a cohort study of patients with histologically proven cirrhosis undergoing hepatectomy in 6 French tertiary care hepato-biliary-pancreatic centres. The primary endpoint was symptomatic (grade B or C) PHLF, according to the International Study Group of Liver Surgery's definition. Twenty-six preoperative and 5 intraoperative variables were considered. An ordered ordinal logistic regression model with proportional odds ratio was used with 3 classes: O/A (No PHLF or grade A PHLF), B (grade B PHLF) and C (grade C PHLF). RESULTS: Of the 343 patients included, the main indication was hepatocellular carcinoma (88%). Laparoscopic liver resection was performed in 112 patients. Three-month mortality was 5.25%. The observed grades of PHLF were: 0/A: 61%, B: 28%, C: 11%. Based on the results of univariate analyses, 3 preoperative variables (platelet count, liver remnant volume ratio and intent-to-treat laparoscopy) were retained in a preoperative model and 2 intraoperative variables (per protocol laparoscopy and intraoperative blood loss) were added to the latter in a postoperative model. The preoperative model estimated the probabilities of PHLF grades with acceptable discrimination (area under the receiver-operating characteristic curve [AUC] 0.73, B/C vs. 0/A; AUC 0.75, C vs. 0/A/B) and the performance of the postoperative model was even better (AUC 0.77, B/C vs. 0/A; AUC 0.81, C vs. 0/A/B; p <0.001). CONCLUSIONS: By accurately predicting the risk of symptomatic PHLF in patients with cirrhosis, the preoperative model should be useful at the selection stage. Prediction can be adjusted at the end of surgery by also considering blood loss and conversion to laparotomy in a postoperative model, which might influence postoperative management. LAY SUMMARY: In patients with liver cirrhosis, the risk of a hepatectomy is difficult to appreciate. We propose a statistical tool to estimate this risk, preoperatively and immediately after surgery, using readily available parameters and on online calculator. This model could help to improve the selection of patients with the best risk-benefit profiles for hepatectomy.

Effect of pharmacological preconditioning with sevoflurane during hepatectomy with intermittent portal triad clamping.

BACKGROUND: During hepatectomy, intermittent portal triad clamping (IPC) reduces ischemia-reperfusion injuries. Pharmacological preconditioning with sevoflurane revealed similar properties. The aim of the study was to evaluate the combination of a sevoflurane preconditioning regimen with IPC on ischemia-reperfusion injuries. METHODS: Three regimens of anesthesia were applied: group SEV with continuous application of sevoflurane, group PRO with continuous propofol infusion and group PC where continuous propofol was substituted by sevoflurane (adjusted to reach MAC∗1.5) for 15 min before IPC. Endpoints were the values of AST and ALT, factor V, prothrombin time, bilirubinemia over the 5-postoperative days (POD), morbidity and mortality at POD30 and POD90. RESULTS: The ALT values at POD5 were lower in the PC group (n = 27) 74 (48 -98) IU/L compared to PRO (n = 26) and SEV (n = 67) respectively 110 (75 -152) and 100 (64 -168) IU/L (p = 0.038). The variation of factor V compared to preoperative values was less important in the PC and SEV groups respectively -14% and -16% vs -30% (PRO) (p = 0.047). CONCLUSION: Our study suggests that sevoflurane attenuates ischemia-reperfusion injuries on liver function, compared to propofol, without benefit for a specific regimen of pharmacological preconditioning when IPC is applied.

Half of Postoperative Deaths After Hepatectomy may be Preventable: A Root-cause Analysis of a Prospective Multicenter Cohort Study.

OBJECTIVE: To perform a retrospective root-cause analysis of the causes of postoperative mortality after hepatectomy. BACKGROUND: Mortality after liver resection has not decreased over the past decade. METHODS: The study population was a prospective cohort of hepatectomies performed at hepatic, pancreatic, and biliary (HPB) centers between October 2012 and December 2014. Of the 1906 included patients, 90 (5%) died within 90 days of surgery. Perioperative data were retrieved from the original medical records. The root-cause analysis was performed independently by a senior HBP-surgeon and a surgical HBP-fellow. The objectives were to record the cause of death and then assess whether (1) the attending surgeon had identified the cause of death and what was it?, (2) the intra- and postoperative management had been appropriate, (3) the patient had been managed according to international guidelines, and (4) death was preventable. A typical root cause of death was defined. RESULTS: The cause of death was identified by the index surgeon and by the root-cause analysis in 84% and 88% of cases, respectively. Intra- and postoperative management procedures were inadequate in 33% and 23% of the cases, respectively. Guidelines were not followed in 57% of cases. Overall, 47% of the deaths were preventable. The typical root cause of death was insufficient evaluation of the tumor stage or tumor progression in a patient with malignant disease resulting in a more invasive procedure than expected. CONCLUSION: Measures to ensure compliance with guidelines and (in the event of unexpected operative findings) better within-team communication should be implemented systematically.

Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-on-chronic liver failure grade 3.

BACKGROUND & AIMS: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute-on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade. METHODS: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non-transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups). RESULTS: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed. CONCLUSIONS: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality.

Sensitizing Surgeons to Their Outcome Has No Measurable Short-term Benefit.

OBJECTIVE: Investigate if involving surgeons in outcome prediction-research and having them use a dedicated Electronic-Health-Record that provides feedback, improves patients' outcome. BACKGROUND: Improvement of clinical outcome mainly relies on the declaration of adverse events, identification of their predictors, self-assessment, and feedback. METHODS: Thirteen French Hepato-Pancreato-Biliary-centers made commitment to include all patients undergoing elective hepatectomies in an observational study. Each center was given access to a dedicated website, where perioperative data were prospectively collected. The website provided real-time individual and comparative feedback of outcome and was also intended to perform prognostication studies. The hypothesis was that by using this strategy, the length-of-stay would be reduced by 10%. Power-calculation implied the inclusion of 1720 patients. Secondary endpoints were 90-day mortality, severe morbidity, and the comprehensive-complication index. RESULTS: Only 5 of the 13 participating centers were fully compliant in enrolling their patients and the inclusion period was extended by 1-year (October 2012-October 2015) to meet the objective. During this period, the collaborative group published 9 studies based on the study data (median impact factor = 8.327) that identified quantitative clinical variables, qualitative clinical variables, and nonclinical variables influencing outcome. For patients enrolled by the 5 active centers (n = 1752), there was no improvement in length of stay (13.3 vs 12.4 days, P = 0.287), severe complications (23.6 vs 20.5%, P = 0.134), the complication comprehensive index (24.0 vs 24.9, P = 0.448), mortality (4.1 vs 3.9%, P = 0.903), or unplanned readmissions (7.2 vs 8.4%, P = 0.665), even after adjusting for confounders. CONCLUSION: Simply sensitizing surgeons to their outcome has no measurable short-term clinical benefit.