[Show abstract][Hide abstract] ABSTRACT: Background:
The challenging diagnosis and poor prognosis of cholangiocarcinoma require the determination of biomarkers. Autoantibodies could be used in the clinic as diagnostic markers for the early detection of tumours. By proteomic approaches, several autoantibodies were proposed as potential markers. We tried in this study, to perform a serological proteome analysis, using various antigenic substrates, including tumours and human liver.
Sera from patients (n = 13) and healthy donors (n = 10) were probed on immunoblots performed using 2-dimensionally separated proteins from cholangiocarcinoma cell lines (CCLP1 and CCSW1), from the liver of healthy subject and interestingly, from tumour and adjacent non-tumour liver tissues from five patients with cholangiocarcinoma and tested with their corresponding serum. Spots of interest were identified using mass spectrometry and classified according gene ontology analysis.
A comparison of the whole immunoblotting patterns given by cholangiocarcinoma sera against those obtained with normal control sera enabled the definition of 862 spots. Forty-five different proteins were further analysed, corresponding to (1) spots stained with more than four of 13 (30 %) sera tested with the CCLP1 or the CCSW1 cell line and with the normal liver, and (2) to spots immunoreactive with at least two of the five sera probed with their tumour and non-tumour counter-part of cholangiocarcinoma. Immunoreactive proteins with catalytic activity as molecular function were detected at rates of 93 and 64 % in liver from healthy subjects or cholangiocarcinoma non-tumour tissues respectively, compared to 43, 33, 33 % in tumour tissues, or CCSW1 and CCLP1 cell lines. A second pattern was represented by structural proteins with rates of 7 and 7 % in normal liver or non-tumour tissues compared to 14, 33 and 67 % in tumour tissue, CCSW1 or CCLP1 cell lines. Proteins with a binding function were detected at rates of 7 % in non-tumour tissue and 14 % in tumour tissue. Using the extracted tumour tissue, serotransferrin was targeted by all cholangiocarcinoma-related sera.
Immunological patterns depended on the type of antigen substrate used; i.e. tumour versus non tumour specimens. Nevertheless, a combination of multiple autoantibodies tested with the most appropriate substrate might be more sensitive and specific for the diagnosis of cholangiocarcinoma.
Preview · Article · Dec 2016 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5.
No preview · Article · Jan 2016 · The Lancet Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Background:
Liver retransplantation remains the only option for recurrent graft failure. The aim of our study is identify predictive factors involved in patients and graft survival for patients undergoing repeat retransplantation (RRT).
From January 1985 to December 2012, 2940 liver transplantations were performed in 2477 patients at Paul Brousse Hospital, Villejuif, France. All patients who underwent 3rd, 4th and 5th transplantation were included in the study and retrospectively analyzed.
In the univariate analysis, the factors that were associated with 90-days patient postoperative survival were preoperative vasopressors support, preoperative extra hepatic sepsis, PNF as indication of RRT, recipient's MELD, urgent RRT, creatinine value at RRT and prothrombin ratio. The multivariate logistic regression confirmed the role of systemic septic status (OR=12.8, p=0.01) and vasopressor drug support (OR=4.7, p=0.05) as predictors of postoperative mortality. In the univariate analysis, the factors that were associated with patient 10 years long term survival (were vasopressor support, systemic septic patient, PNF as indication of RRT, RRT occurred between 1985 and 1999, recipient's MELD, creatinine value at RRT and prothrombin ratio. The multivariate logistic regression confirmed the role of systemic septic patient (OR=6.4, p=0.03) and the RRT between 1985 and 1999 (OR=3.6, p=0.05) as predictors of long term mortality.
RRT represent a valid alternative in selected patients. Selection should be oriented on patient needing 3rd transplant without extra hepatic sepsis and vasoactive drug support at moment of RRT. If necessary, 4th and 5th RRT could be performed with a decision made on case-by-case basis, despite a high postoperative mortality This article is protected by copyright. All rights reserved.
No preview · Article · Jan 2016 · Clinical Transplantation
[Show abstract][Hide abstract] ABSTRACT: Hepatocarcinogenesis is a multistep process characterized in patients with chronic liver diseases by a spectrum of hepatic nodules that mark the progression from regenerative nodules to dysplastic lesions followed by hepatocellular carcinoma (HCC). The differential diagnosis between precancerous dysplastic nodules and early HCC still represents a challenge for both radiologists and pathologists. We addressed the potential of Fourier transform-infrared (FTIR) microspectroscopy for grading cirrhotic nodules on frozen tissue sections.
The study was focused on 39 surgical specimens including normal livers (n = 11), dysplastic nodules (n = 6), early HCC (n = 1), progressed HCC on alcoholic cirrhosis (n = 10) or hepatitis C virus cirrhosis (n = 11). The use of the bright infrared source emitted by the synchrotron radiation allowed investigating the biochemical composition at the cellular level. Chemical mapping on whole tissue sections was further performed using a FTIR microscope equipped with a laboratory-based infrared source. The variance was addressed by principal component analysis.
Profound alterations of the biochemical composition of the pathological liver were demonstrated by FTIR microspectroscopy. Indeed, dramatic changes were observed in lipids, proteins and sugars highlighting the metabolic reprogramming in carcinogenesis. Quantifiable spectral markers were characterized by calculating ratios of areas under specific bands along the infrared spectrum. These markers allowed the discrimination of cirrhotic nodules, dysplastic lesions and HCC. Finally, the spectral markers can be measured using a laboratory FTIR microscope that may be easily implemented at the hospital.
Metabolic reprogramming in liver carcinogenesis can constitute a signature easily detectable using FTIR microspectroscopy for the diagnosis of precancerous and cancerous lesions.
Full-text · Article · Jan 2016 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is one of the main causes of end-stage liver disease and indications for liver transplantation (LT) worldwide. HCV infection always recurs on the graft in patients who undergo LT with detectable serum HCV RNA, leading to cirrhosis in 20-30% within 5 years after transplantation. Achieving a sustained virological response (SVR) greatly improves patient and graft survival. Recently, the efficacy of therapy has radically changed and improved based on new direct acting antiviral agents (DAAs) without pegylated-interferon (PEG-IFN) and/or ribavirin (RBV), leading to SVR rates of more than 90% in transplanted patients. The safety profile in this population is also good, with limited drug-drug interactions. However, there are very few data on patients on the waiting list. Even when the results of combined DAAs are good (>80%), SVR rates are lower than in patients without cirrhosis. This review reports recent available data on the treatment of HCV infection in the transplant setting and discusses new dilemmas and challenges.
Preview · Article · Jan 2016 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for
the treatment of metastatic melanoma and advanced/refractory non-small cell lung cancers. Therefore, their use will not be
limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer
centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse
events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although
severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed
appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription immune checkpoint
blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network
of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the
clinical care of patients under ICB immunotherapy.
No preview · Article · Dec 2015 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Background data:
In compensated cirrhotics with early hepatocellular carcinoma (HCC-cirr), upfront liver resection (LR) and salvage liver transplantation (SLT) in case of recurrence may have outcomes comparable to primary LT (PLT).
An intention-to-treat (ITT) analysis comparing PLT and SLT strategies.
Of 130 HCC-cirr patients who underwent upfront LR (group LR), 90 (69%) recurred, 31 could undergo SLT (group SLT). During the same period, 366 patients were listed for LT (group LLT); 26 dropped-out (7.1%), 340 finally underwent PLT (group PLT). We compared survival between groups LR and LLT, LR and PLT, and PLT and SLT.
Feasibility of SLT strategy was 34% (31/90). In an ITT analysis, group LLT had better 5-yr/10-yr overall survival (OS) compared with group LR (68%/58% vs. 58%/35%; P = 0.008). Similarly, 5-yr/10-yr OS and disease-free survival (DFS) were better in group PLT versus group LR (OS 73%/63% vs. 58%/35%, P = 0.0007; DFS 69%/61% vs. 27%/21%, P < 0.0001). Upfront resection and microvascular tumor invasion were poor prognostic factors for both OS and DFS, presence of satellite tumor nodules additionally predicted worse DFS. Group SLT had similar postoperative and long-term outcomes compared with group PLT (starting from time of LT) (OS 54%/54% vs. 73%/63%, P = 0.35; DFS 48%/48% vs. 69%/61%, P = 0.18, respectively).
In initially transplantable HCC-cirr patients, ITT survival was better in group PLT compared with group LR. SLT was feasible in only a third of patients who recurred after LR. Post SLT, short and long-term outcomes were comparable with PLT. Better patient selection for the "resection first" approach and early detection of recurrence may improve outcomes of the SLT strategy.
Full-text · Article · Dec 2015 · Annals of surgery
[Show description][Hide description] DESCRIPTION: Objective and subjective parameters are helpful in the accurate assessment of long-term outcome in liver transplantation (LT) recipients. Seventy-two recipients with a functional first graft at 10 years post-LT underwent liver biopsy and completed a quality of life (QOL) questionnaire. Logistic regression analysis was used to explore associations between histological, clinical and QOL criteria. Ten years after LT, fibrosis was detected in 53% of patients, and affected the general health perception, while ductopenia, present in 36%, affected the well-being (p=0.05). Hepatic steatosis (HS) was present in 33% of patients and was associated with the worst QOL score on multiple domains. When compared to patients without HS, patients with HS had significantly higher incidence of fibrosis (p=0.03), HCV virus infection (p=0.007), and more patients had retired from their job (p=0.03). Recurrent or de novo HCV-associated fibrosis and patient retirement as objective variables, and abdominal pain or discomfort and joint aches or pains as subjective variables, emerged as independent determinants of HS. In conclusion, long-term liver graft lesions, mainly HS presumably as a surrogate marker of HCV infection, may have a substantial impact on QOL 10 years after LT.
[Show abstract][Hide abstract] ABSTRACT: An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP-seq data show that MYC and MAX are associated with ncRNA de-regulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.
[Show abstract][Hide abstract] ABSTRACT: Liver transplantations for patients who are co-infected with HIV and HCV have always posed a challenge and still do, according to the results of a new study. This article discusses the factors that contribute to an increased risk of poor transplantation outcomes and how new treatment options might affect patient survival.
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft.
This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety.
The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011).
The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.
[Show abstract][Hide abstract] ABSTRACT: Should organs from hepatitis C antibody positive donors (HCVD+) be used for transplantation? Organ shortage forces transplant teams to use donor with extended criteria. The decision to transplant a HCVD+ graft is a balance between the risk of transmission of a virus that could lead to end stage liver diseases and the benefit of access to transplantation, specifically in patient with life-threatening disease. The other issue is the impact of HCV-related liver fibrosis in the donor graft on the long term outcome in the recipient. Thus, the use of HCVD+ demonstrated a shorter meantime on waiting list in kidney transplantation. When a HCVD+ graft is transplanted, the risk of HCV transmission depends on 1) the quality of screening of the donor, 2) the presence of viral replication in the donor at the time of transplantation and the ability to detect it, 3) the HCV status of the recipient but also the type of transplanted organ. In liver transplantation, use of HCVD+ graft is usually restricted to recipients with a chronic HCV infection. Several reports showed some competition between HCV donor and recipient strain without deleterious impact on graft and patient survival. Controversies are still on pending regarding quality of the graft and progression of fibrosis. The recent approval of direct antiviral acting agents (DAA) dramatically changes the landscape of HCV infection treatment. After transplantation, combinations of DAA show high efficacy and good safety profile. In the next future, extensive use of DAA should reduce the number of HCVD+ with a positive HCV RNA, limiting the risk of transmission but also the number of patients on waiting list for a disease related to HCV.
No preview · Article · Sep 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Background. Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. Methods. Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. Results. From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR) Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89%of the expectedmortality (P < 0.001). Cardiovascular death wasmarkedlymore common than that observed in patients undergoing Ltx for end-stage liver disease. Conclusions. Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in earlyonset
TTR Val30Met patients, requires consideration.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To compare the natural history of Familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.
We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies and muscle biopsies are reported. We also conducted a comprehensive literature review in order to further determine the range of phenotypic expression.
By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr and LateVal30Met FAP showed more rapid and severe disease progression: onset of gait disorders was three times more rapid (p<0.0001), the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p<0.0001). Median survival was much shorter in Ile107Val and LateVal30Met FAP (p=0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p=0.0005), difficult identification of amyloid deposits in nerve and muscle biopsies.
Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by the frequent large-fibers involvement, associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). This article is protected by copyright. All rights reserved.
Full-text · Article · Sep 2015 · Annals of Neurology