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Intraoperative Indocyanine Green Dye (ICG) routinely used in hepatobiliary surgery identifies different fluorescent patterns of hepatocellular carcinoma (HCC), a highly heterogeneous cancer. We aimed to correlate these patterns with gene mutations and extensive pathological features beyond the well-known tumor differentiation.Between February 2017 and December 2019, 21 HCC in 16 consecutive patients who underwent intraoperative ICG fluorescence imaging were included. Pathological review was performed by one pathologist blinded to fluorescence features. Random forest machine learning algorithm correlated pathological features of the tumor, peritumoral and non-tumoral liver, and gene mutations from a 28 gene-panel with rim and intra-lesion fluorescence.Three HCC had negative intra-lesion and rim-like emission, 7 HCC had homogeneous pattern and 11 heterogeneous patterns in whom 3 with rim-like emission. Rim emission was associated with peritumoral vascular changes, lower differentiation and lower serum AFP level. Homogeneous intra-lesion fluorescence was associated with lower necrosis rate, thinner capsule, absence of peritumoral liver changes, and higher serum AFP level. Heterogeneous HCC without rim harbored lesser TP53 and ARID1A mutations.Tumoral and peri-tumoral fluorescence classification of HCC yielded a possible intraoperative pathological and molecular characterization. These preliminary observations could lead to intraoperative refinement in surgical strategy.

The objectives of this study were to evaluate incidence and to identify the risk factors of occurrence and the predictive factors of symptomatic forms of nodular regenerative hyperplasia (NRH) after liver transplantation (LT).To identify risk factors of NRH following LT, we included 1648 patients transplanted from 2004 to 2018 and compared the patients developing NRH after LT to those who did not. To identify predictive factors of symptomatic NRH, we selected 115 biopsies displaying NRH and compared symptomatic to asymptomatic forms. Symptomatic NRH was defined as the presence of ascites, esophageal varices, hepatic encephalopathy, portal thrombosis, retransplantation, or death related to NRH.The incidence of NRH following LT was 5.1%. In multivariate analysis, the independent factor of developing NRH after LT was the donor's age (odds ratio [OR] = 1.02; confidence interval, 1.01-1.03; P = 0.02). Symptomatic forms occurred in 29 (25.2%) patients: 19 (16.5%) patients presented with ascites, 13 (11.3%) with esophageal varices, 4 (3.5%) with hepatic encephalopathy, and 8 (7%) with portal thrombosis. The median period before the onset of symptoms was 8.4 (1.5-11.3) y after LT. The spleen size at diagnosis/before LT ratio (OR = 12.5; 114.17-1.37; P = 0.0252) and thrombectomy during transplantation (OR = 11.17; 1.48-84.11; P = 0.0192) were associated with symptomatic NRH in multivariate analysis.NRH following LT is frequent (5.1%) and leads to symptomatic portal hypertension in 25.2% of patients. Using older grafts increases the risk of developing NRH after LT. Clinicians should screen for signs of portal hypertension, particularly in measuring spleen size.

Background The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. Objective To assess the potential effect of donor or recipient HED on liver transplant rejection. Design Retrospective cohort study. Setting Liver transplant units. Patients 1154 adults and 113 children who had a liver transplant between 2004 and 2018. Measurements Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. Results In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. Limitation The DSAs were measured only in children. Conclusion Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. Primary funding source Institut National de la Sante et de la Recherche Medicale.

International audience; INTRODUCTION: Hepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histological features of FCH after virological eradication. METHODS: From the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis. RESULTS: Diagnosis of FCH was made after a median [IQR] 6.0 [3.1-11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7-6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1-20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6-7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients. CONCLUSION: Our results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure.

Background & Aims In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. Methods This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3–D0)/D0. Results A total of 128 patients were included, with a median age of 52 (39–62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23–21.06; p Conclusion In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. Lay summary The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

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.

Assessing the risk of significant macrosteatosis in donors is crucial before considering hepatic graft procurement. We aimed to build a model to predict significant macrosteatosis based on noninvasive methods. From January 2012 to December 2018, liver attenuation indices and liver-to-spleen (L/S) ratio were measured in 639 brain-dead donors by local radiologists. Quantity and quality of steatosis were evaluated by an expert pathologist, blinded for attenuation indices measurement. Macrosteatosis ≥ 30% was found in 33 donors (5.2%). Body weight, body mass index (BMI), abdominal perimeters, history of alcohol abuse, L/S ratio, and liver parenchyma attenuation were associated with macrosteatosis ≥ 30%. The L/S ratio, BMI, and a history of alcohol abuse remained independent predictors in multivariate analysis and were used to build a predictive model (C-index: 0.77). The optimal cutoff to predict macrosteatosis ≥ 60% was 0.85. Our model, including L/S ratio, BMI, and history of alcohol, might be helpful to refine indication for liver biopsy before donation after brain death. External validation is required.

There are few reports on microvascular invasion (MVI) located intra- or extratumorally and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to evaluate patient outcome according to the location of MVI, and to build a nomogram predicting extratumoral MVI. We included 681 consecutive patients who underwent hepatic resection (HR) or liver transplantation (LT) for HCC from January 1994 to June 2012, and evaluated patient outcome according to the degree of vascular invasion (VI). A nomogram for predicting extratumoral MVI was created using 637 patients, excluding 44 patients with macrovascular invasion, and was validated using an internal (n = 273) and external patient cohort (n = 256). The 681 patients were classified into four groups based on pathological examination (148 no VI, 33 intratumoral MVI, 84 extratumoral MVI, and 29 macrovascular invasion in patients who underwent HR; 238 no VI, 50 intratumoral MVI, 84 extratumoral MVI, and 15 macrovascular invasion in patients who underwent LT). Multivariate analysis revealed that extratumoral MVI was an independent risk factor for overall survival in patients who underwent HR (hazard ratio 2.62, p

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 = 2×10A7-mm margin is important to prevent early recurrence. Patients with HCC and alpha-fetoprotein levels100 ng/ml, non-capsule formation, or microvascular invasion may have a survival benefit from a ≥ 7-mm margin.

Resume Introduction Le traitement chirurgical est le traitement de reference des volumineux carcinomes hepatocellulaires (VCHC) ≥ 5 cm. La fibrose peut constituer une contre-indication a la resection en raison du surrisque d’insuffisance hepatique postoperatoire mais son impact sur les suites postoperatoires et la recidive demeure mal defini. Notre objectif etait donc de comparer les facteurs pronostiques de survie chez les patients cirrhotiques ou non, apres hepatectomie pour VCHC. Methodes Les donnees des patients reseques pour VCHC entre 2012 et 2016 dans deux centres de reference ont ete analysees. Les resultats obtenus chez les patients cirrhotiques (fibrose F4) et non cirrhotiques (F0–F3) ont ete compares. Les patients ayant recu un traitement medical (sorafenib) ou radiologique (chimioembolisation intra-arterielle, radiofrequence) ont ete exclus. Resultats Soixante patients ont ete inclus. Les donnees preoperatoires et peroperatoires etaient identiques entre les deux groupes. Les patients cirrhotiques (n = 15) etaient plus souvent porteurs de nodules satellites a l’anatomopathologie definitive (73 % vs 44 % ; p = 0,073) mais leurs tumeurs etaient mieux differenciees que celles des patients non-cirrhotiques (p = 0,041). La survie mediane des patients cirrhotiques etait de 34 mois vs 29 mois chez les non-cirrhotiques (p = 0,8) et la survie sans recidive etait respectivement de 14 mois vs 18 mois (p = 0,9). Le degre de fibrose n’avait pas d’impact sur la survie globale (p = 0,2) ou la survie sans recidive (p = 0,6). Conclusion Le traitement chirurgical des VCHC chez les patients cirrhotiques permet d’obtenir des resultats oncologiques satisfaisants et comparables a ceux obtenus chez les patients non-cirrhotiques. Le traitement curatif des VCHC doit donc etre envisage, sous reserve d’une fonction hepatique conservee, quel que soit le degre de fibrose.

Effective individualized treatment of patients with colorectal liver metastases (CLM) requires tumor genotyping, usually based on the analysis of one single sample per patient. Therapy failure may partially be explained by sampling errors and/or intratumoral genetic heterogeneity. We aimed to demonstrate intratumoral genetic heterogeneity in CLM and enable pathologists to select tumor tissue for genotyping. All the tumors of 86 patients who underwent liver resection for a single CLM were reviewed. Of the 86 patients, 66 patients received chemotherapy and 20 patients did not receive chemotherapy before liver resection. All the tumor areas sampled were analyzed for KRAS, BRAF, PIK3CA, and NRAS mutations. The mutational status was tested in 74 cases, 7 cases had no tumoral cells due to complete responses and 5 blocks were unavailable. Of the 59/74 CLM with > 1 sample, 56 showed the same mutational status between the samples. The remaining 3 cases (5% of all cases) showed genetic heterogeneity for KRAS in 2 and BRAF in 1 patient. Genetic heterogeneity correlated with lower rate of viable tumor cells (p=0.009) and higher rate of mucin pools (p=0.013). We demonstrate for the first time the existence of genetic intratumoral heterogeneity in 5% of CLM. In routine practice, this low incidence does not require the genotyping of additional tumor samples. The correlation between the genetic heterogeneity and some histological components of the CLM should be verified by further in situ mutation assay.

Discussion of liver antibody-mediated rejection during the 2011, 2013, and 2015 Banff liver sessions raised concerns over reliability of complement fragment 4d (C4d) staining, precipitating a global survey followed by a tissue microarray staining quality assessment study among centers on formalin-fixed, paraffin-embedded tissue. Tissue microarray sections containing tissue plugs of resected native and allograft (with acute antibody-mediated rejection) liver, heart, and kidney (n = 33 total cores) were sent to 31 centers for C4d staining using local method(s) and pathologist scoring. Digital whole-slide images (n = 40) were then semiquantitatively scored by 7 experts for background, distribution, and intensity of portal vein and capillary, hepatic artery, sinusoidal, and central vein endothelia and portal and central stromal staining. Results showed that strong and diffuse portal vein and capillary C4d staining, as determined by both local and central pathologists, clearly distinguished allografts showing acute antibody-mediated rejection from native livers and from those with evidence of weaker donor-specific antibody. Downstream vascular endothelial cell C4d staining and assessment were more variable and difficult to identify. C4d staining in the majority of laboratories reliably detects acute liver allograft antibody-mediated rejection in formalin-fixed, paraffin-embedded tissues. Assessment should focus on portal veins and capillaries, sinusoids, and central veins present in peripheral core needle biopsies. C4d staining in one organ does not always translate to staining in another.

Gallbladder (GB) adenomyomatosis (ADM) is a benign, acquired anomaly, characterized by hypertrophy of the mucosal epithelium that invaginates into the interstices of a thickened muscularis forming so-called Rokitansky-Aschoff sinuses. There are three forms of ADM: segmental, fundal and more rarely, diffuse. Etiology and pathogenesis are not well understood but chronic inflammation of the GB is a necessary precursor. Prevalence of ADM in cholecystectomy specimens is estimated between 1% and 9% with a balanced sex ratio; the incidence increases after the age of 50. ADM, although usually asymptomatic, can manifest as abdominal pain or hepatic colic, even in the absence of associated gallstones (50% to 90% of cases). ADM can also be revealed by an attack of acalculous cholecystitis. Pre-operative diagnosis is based mainly on ultrasound (US), which identifies intra-parietal pseudo-cystic images and "comet tail" artifacts. MRI with MRI cholangiography sequences is the reference examination with characteristic "pearl necklace" images. Symptomatic ADM is an indication for cholecystectomy, which results in complete disappearance of symptoms. Asymptomatic ADM is not an indication for surgery, but the radiological diagnosis must be beyond any doubt. If there is any diagnostic doubt about the possibility of GB cancer, a cholecystectomy is justified. The discovery of ADM in a cholecystectomy specimen does not require special surveillance.

Resume L’adenomyomatose (ADM) vesiculaire est une anomalie benigne, acquise, caracterisee par une hypertrophie de la muqueuse s’invaginant au sein d’une musculeuse epaissie (sinus de Rokitansky-Aschoff). Il existe trois formes d’ADM : segmentaire, fundique et plus rarement diffuse. L’etiopathogenie est mal connue mais une inflammation vesiculaire chronique est necessaire. Sa prevalence sur piece de cholecystectomie est estimee entre 1 et 9 % avec un sex-ratio equilibre et une incidence qui augmente apres 50 ans. L’ADM, le plus souvent asymptomatique, peut se manifester par des douleurs abdominales aspecifiques ou de type colique hepatique, meme en l’absence de lithiase vesiculaire associee (50 a 90 % des cas). L’ADM peut aussi se reveler par une crise de cholecystite alithiasique. Le diagnostic repose principalement sur l’echographie qui identifie des images pseudokystiques intraparietales et des artefacts en « queue de comete ». L’IRM avec sequences de bili-IRM constitue l’examen de reference avec des images caracteristiques en « collier de perles ». Une ADM symptomatique constitue une indication de cholecystectomie qui permet une disparition complete des symptomes. Une ADM asymptomatique ne constitue pas une indication operatoire mais le diagnostic radiologique doit alors etre formel. En cas de doute diagnostique, notamment avec un cancer vesiculaire, une cholecystectomie est justifiee. La decouverte d’une ADM sur piece de cholecystectomie ne justifie pas de surveillance particuliere.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

International audience; BACKGROUND:Liver metastases of breast cancer are frequent and can recur even after "complete/R0" resection in combination with systemic and hormonal treatments. The aim of this study was to analyze throughout repeat hepatectomies for liver metastases the evolution of PI3KCA gene mutational status.METHODS:All liver metastases nodules (n = 70) from 19 women who underwent at least 2 liver resections were reexamined. DNA extraction from archived tumoral tissue was performed and the major 'hot spot' mutations in the helical and catalytic domains of PI3KCA have been analyzed using Massarray platform (Agena Bioscience) based on allelic discrimination PCR amplification followed by sensitive mass spectrometry detection.RESULTS:The two major somatic hot spot PI3KCA mutations were found in 27 (38.6%) nodules corresponding to 8 of the 19 patients (42%). The frequency of women whose breast cancer liver metastases (BCLM) carries PI3KCA mutations increased from the first to the third hepatectomy. Tumors carrying PI3KCA mutations are significantly larger and more frequently observed when resections were R0 compared to patients with no PI3KCA mutation.CONCLUSION:PI3KCA mutations are frequently observed in BCLM and persist along with the recurrence. Their identification in circulating tumor cells should become a useful biomarker in the routine practice of breast cancer management to prevent tumor recurrence and overcome the problems of intra- and inter-tumoral heterogeneity of the current biomarkers.

International audience; BACKGROUND & AIMS: Liver macrosteatosis (MS) is a major predictor of graft dysfunction after transplantation. However, frozen section techniques to quantify steatosis are often unavailable in the context of procurements, and the findings of preoperative imaging techniques correlate poorly with those of permanent sections, so that the surgeon is ultimately responsible for the decision. Our aim was to assess the accuracy of a non-invasive pocket-sized micro-spectrometer (PSM) for the real-time estimation of MS. METHODS: We prospectively evaluated a commercial PSM by scanning the liver capsule. A double pathological quantification of MS was performed on permanent sections. Initial calibration (training cohort) was performed on 35 livers (MS\textless/=60%) and an algorithm was created to correlate the estimated (PSM) and known (pathological) MS values. A second assessment (validation cohort) was then performed on 154 grafts. RESULTS: Our algorithm achieved a coefficient of determination R2=0.81. Its validation on the second cohort demonstrated a Lin's concordance coefficient of 0.78. Accuracy reached 0.91%, with reproducibility of 86.3%. The sensitivity, specificity, positive and negative predictive values for MS \textgreater/=30% were 66.7%, 100%, 100% and 98%, respectively. The PSM could predict the absence (\textless30%)/presence (\textgreater/=30%) of MS with a kappa coefficient of 0.79. Neither graft weight nor height, donor body mass index nor the CT-scan liver-to-spleen attenuation ratio could accurately predict MS. CONCLUSION: We demonstrated that a PSM can reliably and reproducibly assess mild-to-moderate MS. Its low cost and the immediacy of results may offer considerable added-value decision support for surgeons. This tool could avoid the detrimental and prolonged ischaemia caused by the pathological examination of (potentially) marginal grafts. This device now needs to be assessed in the context of a large-scale multicentre study. LAY SUMMARY: Macro-vacuolar liver steatosis is a major prognostic factor for outcomes after liver transplantation. However, it is often difficult for logistical reasons to get this estimation during procurement. Therefore, we developed an algorithm for a commercial, portable and affordable spectrometer to accurately estimate this content in a real-time fashion. This device could be of great interest for clinical decision-making to accept or discard a potential human liver graft.

// Mylene Sebagh 1, 2, * Marc-Antoine Allard 3, 4, * , Nelly Bosselut 2, 5 , Myriam Dao 1 , Eric Vibert 2, 3 , Maite Lewin 6 , Antoinette Lemoine 2, 5 , Daniel Cherqui 2, 3 , Rene Adam 3, 4 , Antonio Sa Cunha 3, 4 1 AP-HP Hopital Paul Brousse, Department of Pathology, Villejuif, France 2 Inserm U1193, Paris-Sud University, Villejuif, France 3 AP-HP Hopital Paul Brousse, Hepatobiliary Centre, Villejuif, France 4 Inserm U935, Paris-Sud University, Villejuif, France 5 AP-HP Hopital Paul Brousse, Department of Oncogenetics, Villejuif, France 6 AP-HP Hopital Paul Brousse, Radiology, Villejuif, France * Co-first authors Correspondence to: Mylene Sebagh, e-mail: mylene.sebagh@pbr.aphp.fr Keywords: colorectal liver metastases, pathological response, intermetastatic tumor heterogeneity, somatic gene profile Received: September 09, 2015 Accepted: January 29, 2016 Published: March 01, 2016 ABSTRACT Background: In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM. Methods: Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM. Results: Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2–32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity. Conclusions: Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling.

Microvascular invasion is the strongest prognostic factor of survival in patients with hepatocellular carcinoma. We therefore developed a predictive model for microvascular invasion of hepatocellular carcinoma to help guide treatment strategies in patients scheduled for either hepatic resection or liver transplantation.Patients with hepatocellular carcinoma who underwent hepatic resection or liver transplantation from 1994 to 2016 were divided into training and validation cohorts. A predictive model for microvascular invasion was developed based on microvascular invasion risk factors in the training cohort and validated in the validation cohort.A total of 910 patients (425 having received hepatic resection, 485 having received liver transplantation) were included in the training (n = 637) and validation (n = 273) cohorts. Multivariate analysis identified α-fetoprotein ≥100 ng/mL (relative risk 3.05, P.0001), tumor size ≥40 mm (relative risk 1.98, P = .0002), nonboundary hepatocellular carcinoma type (relative risk 1.91, P = .001), neutrophil-to-lymphocyte ratio (relative risk 1.86, P = .002), and aspartate aminotransferase (relative risk 1.53, P = .02) as associated with microvascular invasion. The estimated probability of microvascular invasion ranged from 17.0% in patients with none of these factors to 86.9% in the presence of all factors. This model achieved a C-index of 0.732 in the validation cohort. The 5-year overall survival of patients with ≥50% probability of microvascular invasion was poorer than that of patients with50% probability (hepatic resection; 39.1% vs 61.2%, P.0001, liver transplantation; 5-year overall survival, 54.8% vs 79.0%, P = .05).This model developed from preoperative data allows reliable prediction of microvascular invasion in candidates for either hepatic resection or liver transplantation.

Summary Background Hepatectomy remains the standard treatment for large hepatocellular carcinoma (LHCC) ≥ 5 cm. Fibrosis may constitute a contraindication for resection because of high risk of post-hepatectomy liver failure, but its impact on patient outcome and cancer recurrence remains ill defined. Our aim was to compare predictors of survival in patients with and without cirrhosis following hepatectomy for LHCC. Methods The data on consecutive patients undergoing hepatectomy for LHCC in two tertiary centres between 2012 and 2016 were reviewed. The outcomes of cirrhotic (F4) and non-cirrhotic (F0–F3) patients were compared. Patients with perioperative medical (sorafenib) or radiological (transarterial chemoembolization, radiofrequency) treatments were excluded. Results Sixty patients were included. Preoperative and intraoperative features were identical between both groups. Cirrhotics (n = 15) presented more satellite nodules on specimens (73% vs. 44%; P = 0.073) but better differentiated lesions than non-cirrhotics (P = 0.041). The median overall survival of cirrhotics was 34 vs. 29 months for non-cirrhotics (P = 0.8), and their disease-free survival was 14 versus 18 months (P = 0.9). Fibrosis stage did not impact overall (P = 0.2) nor disease-free survivals (P = 0.6). Conclusion Hepatectomy for LHCC in cirrhotics can achieve acceptable oncological results when compared to non-cirrhotic patients. Curative resection of LHCC should be attempted if liver function is acceptable, whatever the fibrosis stage.

Introduction: Long-term survival is still rarely achieved with current systemic treatment in patients with breast cancer liver metastases (BCLM). Extended survival after hepatectomy was examined in a select group of BCLM patients. Patients and methods: Hepatectomy for BCLM was performed in 139 consecutive patients between 1985 and 2012. Patients who survived

Resection of breast cancer liver metastases (BCLM) combined with systemic treatment is increasingly accepted but not offered as therapeutic option. New evidence of the additional value of surgery in these patients is scarce while prognoses without surgery remains poor.For this case matched analysis, all nationally registered patients with BCLM confined to the liver in the Netherlands (systemic group; N = 523) were selected and compared with patients who received systemic treatment and underwent hepatectomy (resection group; N = 139) at a hepatobiliary centre in France. Matching was based on age, decade when diagnosed, interval to metastases, maximum metastases size, single or multiple tumours, chemotherapy, hormonal or targeted therapy after diagnosis. Based on published guidelines, palliative systemic treatment strategies are similar in both European countries.Between 1983 and 2013, 3894 patients were screened for inclusion. Overall median follow-up was 80 months (95% CI 70-90 months). The median, 3- and 5-year overall survival of the whole population was 19 months, 29% and 19%, respectively. The resection and systemic group had median survival of 73 vs. 13 months (P 0.001), respectively. Three and 5-year survival was 18% and 10% for the systemic group and 75% and 54% for the resection group, respectively. After matching, the resection group had a median overall survival of 82 months with a 3- and 5-year overall survival of 81% and 69%, respectively, compared with a median overall survival of 31 months in the systemic group with a 3- and 5-year overall survival of 32% and 24%, respectively (HR 0.28, 95% CI 0.15-0.52; P 0.001).For patients with BCLM, liver resection combined with systemic treatment results in improved overall survival compared to systemic treatment alone. Liver resection should be considered in selected cases.

Objectives Appropriate patient selection is important to achieving good outcomes and obviating futile surgery in patients with huge (≥10 cm) hepatocellular carcinoma (HCC). The aim of this study was to identify independent predictors of futile outcomes, defined as death within 3 months of surgery or within 1 year from early recurrence following hepatectomy for huge HCC. Methods The outcomes of 149 patients with huge HCCs who underwent resection during 1995–2012 were analysed. Multivariate logistic regression analysis was performed to identify preoperative independent predictors of futility. Results Independent predictors of 3‐month mortality (18.1%) were: total bilirubin level >34 μmol/l [ P = 0.0443; odds ratio (OR) 16.470]; platelet count of P = 0.0098; OR 5.039), and the presence of portal vein tumour thrombosis ( P = 0.0041; OR 5.138). The last of these was the sole independent predictor of 1‐year recurrence‐related mortality (17.2%). Rates of recurrence‐related mortality at 3 months and 1 year were, respectively, 6.3% and 7.1% in patients with Barcelona Clinic Liver Cancer (BCLC) stage A disease, 12.5% and 14% in patients with BCLC stage B disease, and 37.8% ( P = 0.0002) and 75% ( P = 0.0002) in patients with BCLC stage C disease. Conclusions According to the present data, among patients submitted to hepatectomy for huge HCC, those with a high bilirubin level, low platelet count and portal vein thrombosis are at higher risk for futile surgery. The presence of portal vein tumour thrombosis should be regarded as a relative contraindication to surgery.

To investigate the prognostic significance of pathologic response (PR) after transarterial chemoembolization (TACE) in cirrhotic patients resected or transplanted for hepatocellular carcinoma (HCC), and to identify predictors of complete pathologic response (CPR).Between 1990 and 2010, 373 consecutive cirrhotic patients with HCC were treated by TACE followed by either liver resection (LR:184 patients) or liver transplantation (LT:189 patients). The PR was evaluated as the mean percentage of non-viable tumor area within each tumor. CPR was defined as the absence of any viable tumor area in all the present nodules.A total of 59 (32%) and 37 (20%) patients had CPR after LR and LT, respectively. Five-year overall survival (OS) was higher in patients with CPR compared to those without, after LR (58% vs. 34%; p=0.0006) and tends to be higher after LT (84% vs. 65%; p=0.09). The 5-year recurrence-free survival (RFS) rates were significantly higher in both groups (24% vs. 13% after LR; p=0.008 and 94% vs. 73% after LT, p=0.007). A cut-off value of90% necrosis emerged as an impacting factor on patient survival after LR or LT. On multivariate analysis stratified on the type of procedure (LR or LT), PR90% remained an independent factor of better OS and RFS. Independent factors associated with CPR were: a maximal tumor size30 mm (RR 2.17 [1.27-3.74]), a single tumor (RR 6.08 [3.29-12.07]), and an preoperative AFP100 ng/ml (see results section) (RR 3.99 [1.63-11.98]). The probability to achieve a CPR ranged from 2% in the absence of any factors to 48% in the presence of all factors.In cirrhotic patients with HCC, a complete or nearly complete PR improves long-term survival after LR and LT independently of other pathological factors. This underlines the importance of neoadjuvant treatment to obtain a significant decrease of active tumor load.

OBJECTIVE Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. METHODS All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug-drug interactions. RESULTS At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50-84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. CONCLUSION Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug-drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.

Whether hepatic arterial infusion (HAI) of oxaliplatin influences the rates of complete pathologic response (CPR) and severe oxaliplatin-related lesions (SOxL) in patients with colorectal liver metastases (CRLM) is unknown. This study aimed to compare the incidence of CPR and SOxL between systemic (intravenous, IV) and HAI administration.All patients with initially unresectable CRLM who had undergone hepatic resection in two expert centers between 2004 and 2010 after at least 6 cycles of oxaliplatin-based chemotherapy administered either via HAI (n = 18) or IV (n = 50) were included. The presence of CPR and SOxL were evaluated by two pathologists. A 1:2 case match using a propensity score was used.A CPR was observed significantly more often after HAI (33 vs. 10 %, P = 0.03). However, SOxL had occurred more frequently in patients in the HAI group versus the IV group, 66 and 20 %, respectively (P0.001). On a well-balanced cohort, HAI was associated with higher chance of CPR (odds ratio 9.33, 95 % confidence interval 1.59-54.7) but also higher risk of SOxL (odds ratio 13.7, 95 % confidence interval 3.08-61.3). A CPR markedly enhanced overall survival (OS) and disease-free survival (median OS of 114 vs. 42 months, P = 0.02; median disease-free survival of 51 vs. 12 months, P = 0.002). Patients with SOxL did not experience different outcome (median OS of 42 vs. 50 months, respectively; P = 0.92) CONCLUSIONS: HAI of oxaliplatin increases the likelihood of a CPR at the cost of a higher incidence of SOxL in patients with initially unresectable CRLM.

Recent data showed that metastatic colorectal (mCRC) tumors exhibiting extended RAS-BRAF mutations were resistant to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, making these drugs suitable for the so-called “super” wild-type (WT) patients only. This study aimed to compare the extended RAS-BRAF mutation frequency and characteristics according to location of tumor sampling. All consecutive mCRC specimens (N = 1659) referred to our institution from January 2008 till June 2014 were included in the analysis. Tumor genotyping (first for KRAS exon 2, then for BRAF exon 15, and later for KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) was performed with high-resolution melting analysis or allelic discrimination. The factors predicting for the presence of mutation were explored using multivariate binary logistic regression. Overall, the prevalence of KRAS exon 2 was 36.8 %, and it was lower in liver metastases (N = 138/490; 28.2 %) in comparison with primary tumors (N = 442/1086; 40.7 %), lung metastases (16/32; 50 %), or other metastatic sites (15/51; 29.4 %; P < 0.0001). Similarly, in the 1428 samples analyzed, BRAF mutations were less often found in liver metastases (N = 9/396; 2.3 %) as compared to primary tumors (N = 79/959; 8.2 %), lung metastases (N = 2/29; 6.9 %), or other metastatic locations (N = 2/44; 4.5 %; P < 0.0002). Overall occurrence of extended RAS mutation was 51.7 %. Of the 503 samples tested, the prevalence of extended RAS-BRAF mutations was twice as low in liver metastases (N = 53/151; 34.2 %) as compared to primary tumors (N = 191/322; 59.3 %, P < 0.0001). Univariate analysis identified age ≤65 years, male gender, and liver localization as predictors of super WT status. At multivariate analysis, only liver metastases were retained (RR 2.85 [95 % CI 1.91–4.30]). Colorectal liver metastases are twice as likely to exhibit a super WT genotype as compared to other tumor locations independently from other factors. This molecular feature has the potential to influence therapeutic strategy in mCRC patients.

International audience; Objective: To investigate safety and efficacy of temporary portal hemodynamics modulation with a novel percutaneously adjustable vascular ring (MID-AVR) onto a porcine model of 75% hepatectomy.Background: Postoperative liver failure is a leading cause of mortality after major hepatectomy. Portal flow modulation is an increasingly accepted concept to prevent postoperative liver failure. Nonetheless, the current strategies have shortcomings.Methods: Resection was performed under hemodynamic monitoring in 17 large, white pigs allocated into 2 groups. Eight pigs had ring around the portal vein for 3 days with the aim of reducing changes in hemodynamics due to hepatectomy. Analysis of hemodynamics, laboratory, and histopathological parameters was performed.Results: Percutaneous inflation, deflation, and removal of the MID-AVR were safe. Two (25%) pigs in the MID-AVR group and 4 (45%) controls died before day 3 (P = NS). A moderate increase of portal flow rate per liver mass after resection was associated with better survival (P = 0.017). The portocaval pressure gradient was lower after hepatectomy in the MID-AVR group (P = 0.001). Postoperative serum bilirubin levels were lower in the MID-AVR group (P = 0.007 at day 5). In the MID-AVR group, the Ki67 index was significantly higher on day 3 (P = 0.043) and the architectural derangement was lower (P < 0.05). Morphometric quantification of the bile canaliculi revealed a significantly lower number of intersection branches (P < 0.05) and intersection nodes (P < 0.001) on day 7 compared with the preoperative specimen, in the control group. These differences were not found in the ring group.Conclusions: MID-AVR is safe for portal hemodynamics modulation. It might improve liver regeneration by protecting liver microarchitecture.

Background: Pathological response (PR) to preoperative chemotherapy for colorectal liver metastases (CLM) is recognised as a prognostic factor of outcome. However, the optimal system to assess this parameter is still debated. This study focuses on current methods and proposes a possibly better method for assessing PR. Methods: Among 223 patients resected for CLM between 2004 and 2011, after more than three cycles of chemotherapy, the percentage of tumour cells, necrosis and fibrosis, and the tumour regression grade were assessed for each of 802 nodules. Pathological response was evaluated according to validated methods and their combinations. A new method combined the percentage of tumour cells and the size of all nodules as follows: , where n is each separate nodule, % is the percentage of remaining tumour cells within nodule n (%) and s is the size of nodule n (cm).The prognostic value of each method was calculated. Results: After a median follow-up of 47 months (3–106), the cumulative 5-year overall survival rate after liver resection was 59%. The proposed method categorised as follows: 0 residual tumour; 0.1–6-cm residual tumour; >6-cm residual tumour, and necrosis rate >50% stratified prognosis (P=0.0027; P=0.02), while the other methods did not. At multivariate analysis, our method remained an independent predictor of outcome (P=0.001). Conclusions: Combining the percentage of tumour cells multiplied by the size of each separate tumour seems to be a better method for assessing PR. External validation is required.

Background & Aims Hepatitis E virus (HEV) infection is a known cause of acute-on-chronic liver failure in developing countries, but its implication in Western countries remains unknown. HEV burden in the setting of severe acute alcoholic hepatitis (AAH) was assessed. Methods Patients admitted for severe AAH from 2007 to 2013, with available sera and histologically proven AAH, were included and managed according to current European guidelines. At admission, clinical and biological characteristics were collected; HEV serology and RNA detection were retrospectively performed. Results Eighty-four patients were included. Mean age was 50.8 ± 9.6 years, 65.5% were male, 91.7% were cirrhotic and 33.3% presented with encephalopathy. Mean MELD and Maddrey scores were respectively 32.4 ± 11.4 and 73.3 ± 37. Liver biopsy showed mild, moderate and severe hepatitis in 25 (29.8%), 23 (27.4%) and 32 (38.1%) patients respectively. Steroids were given to 61 patients (72.6%) of whom 35 (57.4%) presented corticoresistance (mean Lille score: 0.78 ± 0.21). During hospitalization, 24 patients (28.6%) died and 11 (13.1%) were transplanted. Three patients (3.6%) presented markers of acute HEV infection and 21 (25%) markers of past HEV infection. Patient with acute infection were men, cirrhotic, and 2/3 presented with encephalopathy. Steroids were given to two patients without any response. The third patient died. None were transplanted. Conclusions A substantial proportion of patients with severe AAH had markers of acute HEV infection, with similar clinical presentation and outcomes. Larger studies are needed to evaluate HEV impact on AAH management, resistance to steroids, and outcome.

Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease.

The postresection alpha-fetoprotein (AFP) in cirrhotic patients with hepatocellular carcinoma (HCC) may predict overall survival (OS) and recurrence beyond Milan criteria (MC) among the subgroup of initially transplantable patients.All patients with cirrhosis resected for HCC between January 1990 and December 2010 in a single institution and presenting a serum AFP value 15 ng/ml at diagnosis were included. The postresection AFP was analyzed as a dichotomized variable: normalization (norm + group) or not (norm - group) within the 90-day postresection period.Among 271 resected patients, 141 patients (52%) had a level of serum AFP ≥ 15 ng/ml at diagnosis. Five-year OS and median survival were 42% and 52 months in group norm + versus 20% and 23 months in the group norm - (P = 0.009). On multivariate analysis, the absence of AFP normalization was an independent factor of poor OS as well as microvascular invasion, and satellites nodules. Among theoretically transplantable patients, independent predictors of recurrence beyond MC were the absence of AFP normalization (risk ratio (RR) 5.02 [1.53-16.34]) and microvascular invasion (RR 4.76 [1.42-15.34]).The postresection AFP has an independent prognostic value. Transplantable patients resected for HCC without 90-day AFP normalization should be discussed for early liver transplantation.

Aims The discovery of unexpected peritoneal carcinomatosis (PC) at the time of hepatectomy for colorectal liver metastases (CLM) is usually considered a contraindication for continuing resection. The first aim of this study was to assess the long-term outcome of patients operated for CLM, and who presented unexpected PC during laparotomy. The second aim was to identify preoperative predictors of PC. Methods All patients at a single center between 1985 and 2010 who had unexpected PC, discovered during planed resection of CLM, and negative preoperative imaging for PC were selected. Clinicopathological data were retrospectively analyzed to assess survival outcomes and to identify predictors of unexpected PC. Results Out of the 1340 operated patients for CLM, 42 (3%) had unexpected PC. Only patients (n = 30; 71%) who had PC limited to two abdominal regions (Median peritoneal cancer index (PCI): 2 (1–6)) were resected. Twelve patients were not resected due to the extent of peritoneal disease. The overall survival of the 30 patients resected for CLM who had limited PC was 18% at 5 years (median: 42 months). On multivariate analysis, a previous history of PC, a pT4 stage and bilobar CLM were independent predictors of unexpected PC. Conclusion Unexpected PC should not be a contraindication for resection provided that the PCI is low and complete resection of all peritoneal and hepatic lesions can be achieved. Previous history of PC, a pT4 primary tumor and bilobar CLM are associated with increased risk of unexpected PC.

We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually.Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant.One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P0.001) in arm A.Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence.

Breast cancer liver metastases (BCLM) are considered the most lethal compared with other sites of metastases in patients with breast cancer. This study aimed to evaluate the outcome after hepatectomy for BCLM within current multidisciplinary treatment and to develop a clinically useful nomogram to predict survival.Between January 1985 and December 2012, 139 consecutive female patients underwent liver resection for BCLM at the authors' institution. Clinicopathologic data were collected and analyzed for survival outcome with determination of prognostic factors. A nomogram to predict survival was developed based on a multivariate Cox model. The predictive performance of the model was assessed according to the C-statistic and calibration plots.After a median follow-up period of 55 months, the overall 3- and 5-year survival rates after hepatectomy were respectively 58 and 47 %. The median overall survival period was 56 months, and the median disease-free survival period after surgical resection was 33 months. A single hepatic metastasis, no triple negative tumors, no microscopic vascular invasion, and perioperative hormonal or targeted therapy were related to improved overall survival. The model achieved good discrimination and calibration, with a C-statistic of 0.80.Liver resection for selected patients with breast cancer metastases can provide significant survival benefit. It should be part of a multidisciplinary treatment program in experienced liver surgery centers. The authors' nomogram facilitates personalized assessment of prognosis for these patients.