Stéphanie Truant

Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child‐Pugh score

Aliment Pharmacol Ther 2011; 34: 1193–1201

Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis.

Purpose: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results: We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell–like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. Clin Cancer Res; 20(4); 837–46. ©2013 AACR.

Laparoscopic resection of hepatocellular carcinoma: a French survey in 351 patients.

OBJECTIVES Current clinical studies report the results of laparoscopic resection of hepatocellular carcinoma (HCC) obtained in small cohorts of patients. Because France was involved in the very early development of laparoscopic surgery, the present study was conducted in order to report the results of a large, multicentre experience. METHODS A total of 351 patients underwent laparoscopic liver resection for HCC during the period from 1998 to 2010 in nine French tertiary centres. Patient characteristics, postoperative mortality and morbidity, and longterm survival were retrospectively reviewed. RESULTS Overall, 85% of the study patients had underlying liver disease. Types of resection included wedge resection (41%), left lateral sectionectomy (27%), segmentectomy (24%), and major hepatectomy (11%). Median operative time was 180 min. Conversion to laparotomy occurred in 13% of surgeries and intraoperative blood transfusion was necessary in 5% of patients. The overall morbidity rate was 22%. The 30-day postoperative mortality rate was 2%. Negative resection (R0) margins were achieved in 92% of patients. Rates of overall and progression-free survival at 1, 3 and 5 years were 90.3%, 70.1% and 65.9%, and 85.2%, 55.9% and 40.4%, respectively. CONCLUSIONS This multicentre, large-cohort study confirms that laparoscopic liver resection for HCC is a safe and efficient approach to treatment and can be proposed as a first-line treatment in patients with resectable HCC.

Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells

Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil- and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2alpha and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells.

Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis

Objective In alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in-depth molecular translational studies. Design We studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy. Results Livers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor α and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes. Conclusions AH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH.

Pre-operative management is associated with low rate of post-operative morbidity in penetrating Crohn?s disease

Aliment Pharmacol Ther 2010; 32: 459–465

Drop of Total Liver Function in the Interstages of the New Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Technique: Analysis of the "Auxiliary Liver" by HIDA Scintigraphy.

To induce rapid hepatic hypertrophy and to reduce posthepatectomy liver failure (PHLF), associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been recently developed for patients with a limited future remnant liver (FRL). Nevertheless, high morbidity rates and mortality up to 12 % were reported. As a potential explanation of the poor outcome of ALPPS, little is known about the improvement in FRL function in the interstages period that was shown to be determinant for ALPPS outcome. Here, we report a new technique of evaluation of the liver function in the setting of ALPPS using sequential hepatobiliary scintigraphy (HBS) using Technetium-99m labeled Hepatobiliary IminoDiacetic Acid (HIDA) compounds ((99m)Tc-mebrofenin) with single photon emission computed tomography. Five patients (53–80 years of age) scheduled for extended hepatectomy underwent ALPPS for colorectal liver metastases (N 1⁄4 4) in 4 cases and gallbladder carcinoma (N 1⁄4 1) after giving informed consent. The colorectal liver metastases’ patients had received extensive chemotherapy (6–25 cures). The first stage of ALPPS was preceded by portal vein embolization in 3 patients with an anticipated FRL to body weight ratio 0.5%, including 2 salvage ALPPS due to almost-nil hypertrophy after portal vein embolization. All patients had sequential determinations of FRL and total liver volumes by computed tomography volumetric measurement combined with functional assessment by HBS as previously described, in the immediate preoperative period of stage 1 and between the 2 stages after a delay of 5 to 7 days following the first stage in 4 patients and 11 days in the elderly patient who badly tolerated the liver partition. HBS results were reported as the mebrofenin uptake of the total liver and FRL (TLU and RLU; %/min m). The increase in FRL function was compared with the volume increase, with increase rates expressed as relative increases (ie, postoperative FRL— preoperative FRL/preoperative FRL). Preoperatively, the median FRL to body weight ratio was 0.43% (0.3%–0.5%). Hepatic biological parameters remained near

Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies.

Objective:To assess the relevance of the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure compared with 2 well-established criteria, 50–50 and PeakBili >7, as early predictors of posthepatectomy outcome. Background:There is limited data on the postoperative use of ISGLS definition of posthepatectomy liver failure as early predictor of outcome. Methods:Between 2007 and 2012, a total of 680 hepatectomies were analyzed from a prospective database. The value of each definition for prediction of 3-month major complications (Clavien III–V) and mortality was assessed either within 10 days of surgery or on postoperative day 5. Results:Three-month major morbidity and mortality rates were 16.5% and 4.4%, respectively. Within 10 days, 79 patients fulfilled ISGLS definition compared with 24 for 50–50 and 44 for PeakBili >7 criteria. Sensitivities of ISGLS definition and 50–50 and PeakBili >7 criteria for prediction of major morbidity and mortality were 35.8, 17.4, 24.8% and 56.7, 36.7, 56.7%, respectively. Patients with no positive score had a risk of death or major complication below 5% and 15%, respectively. In patients with a positive score, the ISGLS definition was the least relevant to predict major complications and mortality (positive predictive values of 49.4% and 21.8% vs 79.2% and 47.8% for 50–50 and 61.4% and 40.5% for PeakBili >7 criteria). The relative risk of death was 6.9 (95% confidence interval, 3.1–15.4) if the ISGLS definition was evaluated on postoperative day 5 versus 21.1 (95% confidence interval, 7.7–57.7) for 50–50 and 21.7 (95% confidence interval, 7.4–63.3) for PeakBili >7 criteria. Conclusions:ISGLS definition was less discriminatory than 50–50 and PeakBili >7 criteria in identifying patients at risk of posthepatectomy major complications or death.

Management of blunt hepatic trauma.

Management of blunt liver trauma has progressed over the last 20 years with the adoption of conservative non-operative management (CM) as the gold standard in 80-90% of patients. Clinical and hemodynamic changes, and CT imaging guide the conservative attitude or pose an indication for urgent surgical intervention in unstable patients. The adoption of CM for blunt liver trauma has resulted in an increased incidence of late complications. These consist principally of persistent hemorrhage, fistulas and bile leaks, the abdominal compartment syndrome, and hepatic necrosis or abscess. These late complications can be managed secondarily by planned interventions via laparotomy or laparoscopy, interventional radiology and/or endoscopic techniques in a non-emergency setting as indicated by circumstances and with the benefit of multidisciplinary consultation. These secondary interventions should not be considered a failure of conservative treatment, but rather as an anticipated eventuality in the management of these patients.

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV

BACKGROUND Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS EUDRACT 2007-004632-24, NCT00852228.