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Biblio - Bibliographie IAL
Bibliographie IAL

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Recherche bibliographique scientifique

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Accueil > Références bibliographiques

biblio

2013



  • Copeland, BT, Bowman, MJ, Boucheix, C & Ashman, LK 2013, « Knockout of the tetraspanin Cd9 in the TRAMP model of de novo prostate cancer increases spontaneous metastases in an organ-specific manner », Int J Cancer, viewed sans date, .
    Résumé : Prostate cancer is an extremely heterogeneous disease; patients that do progress to late-stage metastatic prostate cancer have limited treatment options, mostly palliative. Molecules involved in the metastatic cascade may prove beneficial in stratifying patients to assign appropriate treatment modalities and may also prove to be therapeutic antimetastatic targets. The tetraspanin group of molecules are integral membrane proteins that associate with motility-related proteins such as integrins. Clinical studies have mostly shown that reduced expression levels of the tetraspanin CD9 are correlated with tumour progression in a range of cancers. Furthermore, functional studies have shown CD9 to be involved in cell motility and adhesion and that it may influence metastasis. The effects of endogenous CD9 on prostate cancer initiation and progression were analysed by crossing a Cd9(-) (/-) (KO) murine model with a model of de novo developing and spontaneously metastasising prostate cancer, namely the transgenic adenocarcinoma of mouse prostate model. Our study demonstrates for the first time that ablation of Cd9 had no detectable effect on de novo primary tumour onset, but did significantly increase metastasis to the liver but not the lungs.


  • Czaja, MJ, Ding, WX, Donohue, TM, Friedman, SL, Kim, JS, Komatsu, M, Lemasters, JJ, Lemoine, A, Lin, JD, Ou, JH, Perlmutter, DH, Randall, G, Ray, RB, Tsung, A & Yin, XM 2013, « Functions of autophagy in normal and diseased liver », Autophagy, vol. 9, no. 8, viewed sans date, .
    Résumé : Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases.

  • Dahan, J, Nouet, Y, Jouvion, G, Levillayer, F, Adib-Conquy, M, Cassard-Doulcier, AM, Tebbi, A, Blanc, F, Remy, L, Chen, J, Cairo, S, Werts, C, Si-Tahar, M, Tordjmann, T, Buendia, MA & Wei, Y 2013, « The LIM-only protein FHL2 activates NF-kappaB signaling in the control of liver regeneration and hepatocarcinogenesis », Mol Cell Biol.
    Résumé : The four and a half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in NF-kappaB signaling in the liver. We show that FHL2 enhanced TRAF6 activity in transcriptional activation of NF-kappaB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of Toll-like receptor-NF-kappaB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-kappaB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2-/- macrophages showed significantly reduced production of TNF and IL-6 following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2-/- mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-kappaB signaling orchestrates inflammatory crosstalk between hepatocytes and hepatic immune cells that promotes chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-kappaB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-kappaB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.
  • Darnaud, M, Faivre, J & Moniaux, N 2013, « Targeting gut flora to prevent progression of hepatocellular carcinoma », J Hepatol, vol. 58, no. 2, p. 385-7.
    Résumé : Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma(HCC), a long-term consequence of chronic liver injury, inflammation,and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in nonbone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
  • De Simone, P, Beckebaum, S, Koneru, B, Fung, J & Saliba, F 2013, « Everolimus with reduced tacrolimus in liver transplantation », Am J Transplant, vol. 13, no. 5, p. 1373-4.
    Résumé : De Simone, P; Beckebaum, S; Koneru, B; Fung, J; Saliba, F; Comment; Letter; Research Support, Non-U.S. Gov't; United States; Am J Transplant. 2013 May;13(5):1373-4. doi: 10.1111/ajt.12215. Epub 2013 Apr 19.
  • De Simone, P, Saliba, F & Fischer, L 2013, « End of the line for sirolimus in liver transplant recipients with hepatitis C virus? », Liver Transpl, vol. 19, no. 2, p. 236-7.
    Résumé : De Simone, Paolo; Saliba, Faouzi; Fischer, Lutz; Comment; Letter; United States; Liver Transpl. 2013 Feb;19(2):236-7. doi: 10.1002/lt.23590.

  • Delord, JP, Ravaud, A, Bennouna, J, Fumoleau, P, Favrel, S, Pinel, MC, Ferre, P & Saliba, F 2013, « Phase I and pharmacokinetic study of IV vinflunine in cancer patients with liver dysfunction », Invest New Drugs, vol. 31, no. 3, p. 724-33.
    Résumé : Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.
  • Deniziaut, G, Ballot, E & Johanet, C 2013, « Antineutrophil cytoplasmic auto-antibodies (ANCA) in autoimmune hepatitis and primary sclerosing cholangitis », Clin Res Hepatol Gastroenterol, vol. 37, no. 1, p. 105-7.
    Résumé : Deniziaut, Gabrielle; Ballot, Eric; Johanet, Catherine; France; Clin Res Hepatol Gastroenterol. 2013 Feb;37(1):105-7. doi: 10.1016/j.clinre.2012.07.008. Epub 2012 Sep 19.
    Mots-clés : Antibodies, Antineutrophil Cytoplasmic/ immunology Cholangitis, Autoimmune/ immunology Humans, Sclerosing/ immunology Hepatitis.

  • Denost, Q, Laurent, C, Adam, JP, Capdepont, M, Vendrely, V, Collet, D & Sa Cunha, A 2013, « Pancreaticoduodenectomy following chemoradiotherapy for locally advanced adenocarcinoma of the pancreatic head », HPB (Oxford).
    Résumé : OBJECTIVES: The aim of this study was to assess oncological outcomes in patients treated with pancreaticoduodenectomy for advanced pancreatic head adenocarcinoma after preoperative chemoradiotherapy and to compare these with outcomes in patients treated with surgery alone. METHODS: From 2004 to 2009, patients treated with pancreaticoduodenectomy for pancreatic head adenocarcinoma were included in a retrospective comparative study. Patients with locally advanced adenocarcinoma were treated with preoperative chemoradiotherapy (CRT group) and were compared with those treated with surgery alone (SURG group). RESULTS: A total of 111 patients were included; these comprised 72 patients in the SURG group and 39 patients in the CRT group. The median follow-up was 21 months. Patients in the CRT group presented with a more advanced tumoral status. Microscopic resection rates were similar in both groups, but nodal status and vascular or lymphatic emboli were lower in the CRT group. At 3 years, the SURG and CRT groups exhibited similar overall (36% and 51%, respectively) and disease-free (35% and 37%, respectively) survival (P = 0.10). CONCLUSIONS: In patients with advanced pancreatic head adenocarcinoma, a good response after preoperative chemoradiotherapy results in a survival rate similar to that in patients treated with surgery alone in whom the initial prognosis is better.

  • Dianat, N, Steichen, C, Vallier, L, Weber, A & Dubart-Kupperschmitt, A 2013, « Human pluripotent stem cells for modelling human liver diseases and cell therapy », Curr Gene Ther, vol. 13, no. 2, p. 120-32, viewed sans date, .
    Résumé : The liver is affected by many types of diseases, including metabolic disorders and acute liver failure. Orthotopic liver transplantation (OLT) is currently the only effective treatment for life-threatening liver diseases but transplantation of allogeneic hepatocytes has now become an alternative as it is less invasive than OLT and can be performed repeatedly. However, this approach is hampered by the shortage of organ donors, and the problems related to the isolation of high quality adult hepatocytes, their cryopreservation and their absence of proliferation in culture. Liver is also a key organ to assess the pharmacokinetics and toxicology of xenobiotics and for drug discovery, but appropriate cell culture systems are lacking. All these problems have highlighted the need to explore other sources of cells such as stem cells that could be isolated, expanded to yield sufficiently large populations and then induced to differentiate into functional hepatocytes. The presence of a niche of "facultative" progenitor and stem cells in the normal liver has recently been confirmed but they display no telomerase activity. The recent discovery that human induced pluripotent stem cells can be generated from somatic cells has renewed hopes for regenerative medicine and in vitro disease modelling, as these cells are easily accessible. We review here the present progresses, limits and challenges for the generation of functional hepatocytes from human pluripotent stem cells in view of their potential use in regenerative medicine and drug discovery.
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  • Dimitrio, L, Clairambault, J & Natalini, R 2013, « A spatial physiological model for p53 intracellular dynamics », J Theor Biol, vol. 316, p. 9-24, viewed sans date, .
    Résumé : In this paper we design and analyse a physiologically based model representing the accumulation of protein p53 in the nucleus after triggering of ATM by DNA damage. The p53 protein is known to have a central role in the response of the cell to cytotoxic or radiotoxic insults resulting in DNA damage. A reasonable requirement for a model describing intracellular signalling pathways is taking into account the basic feature of eukaryotic cells: the distinction between nucleus and cytoplasm. Our aim is to show, on a simple reaction network describing p53 dynamics, how this basic distinction provides a framework which is able to yield expected oscillatory dynamics without introducing either positive feedbacks or delays in the reactions. Furthermore we prove that oscillations appear only if some spatial constraints are respected, e.g. if the diffusion coefficients correspond to known biological values. Finally we analyse how the spatial features of a cell influence the dynamic response of the p53 network to DNA damage, pointing out that the protein oscillatory dynamics is indeed a response that is robust towards changes with respect to cellular environments. Even if we change the cell shape or its volume or better its ribosomal distribution, we observe that DNA damage yields sustained oscillations of p53.
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  • Dohan, A, Ferlicot, S, Bessede, T, Soyer, P & Rocher, L 2013, « Low-grade mucinous cystic tumor mimicking urinary bladder tumor: imaging-pathologic correlation », Urology, vol. 81, no. 5, p. e33-4, viewed sans date, .
    Résumé : Mucin-producing cystitis glandularis is a rare proliferative and metaplastic change of the bladder mucosa that produces large amounts of mucus, thus taking a pseudotumoral pattern and resulting in urinary tract obstruction. We report a case of florid mucin-producing cystitis glandularis mimicking bladder carcinoma in a 77-year-old man that was documented by computed tomography and magnetic resonance imaging. Computed tomography showed diffuse, circumferential, irregular, and lobulated thickening of the bladder wall suggestive of urinary bladder carcinoma. Magnetic resonance imaging showed findings consistent with mucinous content and suggested the correct diagnosis preoperatively.
    Mots-clés : Aged Cystectomy Cystitis/*diagnosis/metabolism/surgery Diagnosis, Differential Humans Magnetic Resonance Imaging/*methods Male Mucus/*secretion Tomography, X-Ray Computed/*methods Urinary Bladder Neoplasms/*diagnosis Urothelium/pathology/secretion.

  • Durrbach, A & Francois, H 2013, « Intracellular lactate flux: a new regulator of the allogenic immune response », Transpl Int, vol. 26, no. 1, p. 20-1, viewed sans date, .
    Résumé : Durrbach, Antoine Francois, Helene eng Comment England 2012/12/15 06:00 Transpl Int. 2013 Jan;26(1):20-1. doi: 10.1111/tri.12035.
  • Escaut, L, Bouam, S, Frank-Soltysiak, M, Rudant, E, Saliba, F, Kassis, N, Presiozi, P & Vittecoq, D 2013, « Eradication of an outbreak of vancomycin-resistant Enterococcus (VRE): the cost of a failure in the systematic screening », Antimicrob Resist Infect Control, vol. 2, no. 1, p. 18.
    Résumé : BACKGROUND: Vancomycin-resistant enterococci (VRE) are still a concern in hospital units tending to seriously ill patients. However, the cost-effectiveness of active surveillance program to identify asymptomatically VRE colonized patient remains debatable. This work aims at evaluating the cost of a failure in the active surveillance of VRE that had resulted in an outbreak in a French University Hospital. FINDINGS: A VRE outbreak was triggered by a failure in the systematic VRE screening in a medico-surgical ward specialised in liver transplantation as a patient was not tested for VRE. This failure was likely caused by the reduction of healthcare resource. The outbreak involved 13 patients. Colonized patients were grouped in a dedicated part of the infectious diseases unit and tended by a dedicated staff. Transmission was halted within two months after discovery of the index case.The direct cost of the outbreak was assessed as the cost of staffing, disposable materials, hygiene procedures, and surveillance cultures.The loss of income from spare isolation beds was computed by difference with the same period in the preceding year. Payments were drawn from the hospital database. The direct cost of the outbreak (2008 Euros) was [euro sign]60 524 and the loss of income reached [euro sign]110 915. CONCLUSIONS: Despite this failure, the rapid eradication of the VRE outbreak was a consequence of the rapid isolation of colonized patient. Yet, eradicating even a limited outbreak requires substantial efforts and resources. This underlines that special attention has to be paid to strictly adhere to active surveillance program.


  • Ettahar, A, Ferrigno, O, Zhang, MZ, Ohnishi, M, Ferrand, N, Prunier, C, Levy, L, Bourgeade, MF, Bieche, I, Romero, DG, Colland, F & Atfi, A 2013, « Identification of PHRF1 as a Tumor Suppressor that Promotes the TGF-beta Cytostatic Program through Selective Release of TGIF-Driven PML Inactivation », Cell Rep, viewed sans date, .
    Résumé : The homeodomain protein TGIF (TG-interacting factor) restricts TGF-beta/Smad cytostatic signaling by interfering with the nucleocytoplasmic transit of the tumor suppressor cPML. Here, we identify PHRF1 as a ubiquitin ligase that enforces TGIF decay by driving its ubiquitination at lysine 130. In so doing, PHRF1 ensures redistribution of cPML into the cytoplasm, where it associates with SARA and coordinates activation of Smad2 by the TGF-beta receptor. The PHRF1 gene resides within the tumor suppressor locus 11p15.5, which displays frequent loss in a wide variety of malignancies, including breast cancer. Remarkably, we found that the PHRF1 gene is deleted or silenced in a high proportion of human breast cancer samples and cancer cell lines. Reconstitution of PHRF1 into deficient cells impeded their propensity to form tumors in vivo, most likely because of the reemergence of TGF-beta responsiveness. These findings unveil a paradigm behind inactivation of the cPML tumor suppressor network in human malignancies.
  • Eveno, C, Karoui, M, Gayat, E, Luciani, A, Auriault, ML, Kluger, MD, Baumgaertner, I, Baranes, L, Laurent, A, Tayar, C, Azoulay, D & Cherqui, D 2013, « Liver resection for colorectal liver metastases with peri-operative chemotherapy: oncological results of R1 resections », HPB (Oxford), vol. 15, no. 5, p. 359-64.
    Résumé : BACKGROUND: Retrospective analysis of outcomes of R0 (negative margin) versus R1 (positive margin) liver resections for colorectal metastases (CLM) in the context of peri-operative chemotherapy. METHODS: All CLM resections between 2000 and 2006 were reviewed. Exclusion criteria included: macroscopically incomplete (R2) resections, the use of local treatment modalities, the presence of extra-hepatic disease and no peri-operative chemotherapy. R0/R1 status was based on pathological examination. RESULTS: Of 86 eligible patients, 63 (73%) had R0 and 23 (27%) had R1 resections. The two groups were comparable for the number, size of metastases and type of hepatectomy. The R1 group had more bilobar CLM (52% versus 24%, P = 0.018). The median follow-up was 3.1 years. Five-year overall and disease-free survival were 54% and 21% for the R0 group and 49% and 22% for the R1 group (P = 0.55 and P = 0.39, respectively). An intra-hepatic recurrence was more frequent in the R1 group (52% versus 27%, P = 0.02) and occurred more frequently at the surgical margin (22% versus 3%, P = 0.01). DISCUSSION: R1 resections were associated with a higher risk of intra-hepatic and surgical margin recurrence but did not negatively impact survival suggesting that in the era of efficient chemotherapy, the risk of an R1 resection should not be considered as a contraindication to surgery.
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  • Farges, O, Regimbeau, JM, Fuks, D, Le Treut, YP, Cherqui, D, Bachellier, P, Mabrut, JY, Adham, M, Pruvot, FR & Gigot, JF 2013, « Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma », Br J Surg, vol. 100, no. 2, p. 274-83.
    Résumé : BACKGROUND: Indications for preoperative biliary drainage (PBD) in the context of hepatectomy for hilar malignancies are still debated. The aim of this study was to investigate current European practice regarding biliary drainage before hepatectomy for Klatskin tumours. METHODS: This was a retrospective analysis of all patients who underwent formal or extended right or left hepatectomy for hilar cholangiocarcinoma between 1997 and 2008 at 11 European teaching hospitals, and for whom details of serum bilirubin levels at admission and at the time of surgery were available. PBD was performed at the physicians' discretion. The primary outcome was 90-day mortality. Secondary outcomes were morbidity and cause of death. The association of PBD and of preoperative serum bilirubin levels with postoperative mortality was assessed by logistic regression, in the entire population as well as separately in the right- and left-sided hepatectomy groups, and was adjusted for confounding factors. RESULTS: A total of 366 patients were enrolled; PBD was performed in 180 patients. The overall mortality rate was 10.7 per cent and was higher after right- than left-sided hepatectomy (14.7 versus 6.6 per cent; adjusted odds ratio (OR) 3.16, 95 per cent confidence interval 1.50 to 6.65; P = 0.001). PBD did not affect overall postoperative mortality, but was associated with a decreased mortality rate after right hepatectomy (adjusted OR 0.29, 0.11 to 0.77; P = 0.013) and an increased mortality rate after left hepatectomy (adjusted OR 4.06, 1.01 to 16.30; P = 0.035). A preoperative serum bilirubin level greater than 50 micromol/l was also associated with increased mortality, but only after right hepatectomy (adjusted OR 7.02, 1.73 to 28.52; P = 0.002). CONCLUSION: PBD does not affect overall mortality in jaundiced patients with hilar cholangiocarcinoma, but there may be a difference between patients undergoing right-sided versus left-sided hepatectomy.
    Mots-clés : Bile Duct Neoplasms/mortality/ surgery Bile Ducts.

  • Frescaline, G, Bouderlique, T, Mansoor, L, Carpentier, G, Baroukh, B, Sineriz, F, Trouillas, M, Saffar, J-L, Courty, J, Lataillade, J-J, Papy-Garcia, D & Albanese, P 2013, « Glycosaminoglycan mimetic associated to human mesenchymal stem cell-based scaffolds inhibit ectopic bone formation, but induce angiogenesis in vivo », Tissue Eng Part A, vol. 19, no. 13-14, p. 1641-53, viewed sans date, .
    Résumé : Tissue engineering approaches to stimulate bone formation currently combine bioactive scaffolds with osteocompetent human mesenchymal stem cells (hMSC). Moreover, osteogenic and angiogenic factors are required to promote differentiation and survival of hMSC through improved vascularization through the damaged extracellular matrix (ECM). Glycosaminoglycans (GAGs) are ECM compounds acting as modulators of heparin-binding protein activities during bone development and regenerative processes. GAG mimetics have been proposed as ECM stabilizers and were previously described for their positive effects on bone formation and angiogenesis after local treatment. Here, we developed a strategy associating the GAG mimetic [OTR4120] with bone substitutes to optimize stem cell-based therapeutic products. We showed that [OTR4120] was able to potentiate proliferation, migration, and osteogenic differentiation of hMSC in vitro. Its link to tricalcium phosphate/hydroxyapatite scaffolds improved their colonization by hMSC. Surprisingly, when these combinations were tested in an ectopic model of bone formation in immunodeficient mice, the GAG mimetics inhibit bone formation induced by hMSC and promoted an osteoclastic activity. Moreover, the inflammatory response was modulated, and the peri-implant vascularization stimulated. All together, these findings further support the ability of GAG mimetics to organize the local ECM to coordinate the host response toward the implanted biomaterial, and to inhibit the abnormal bone formation process on a subcutaneous ectopic site.
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  • Ghigna, MR, Reineke, T, Rince, P, Schuffler, P, El Mchichi, B, Fabre, M, Jacquemin, E, Durrbach, A, Samuel, D, Joab, I, Guettier, C, Lucioni, M, Paulli, M, Tinguely, M & Raphael, M 2013, « Epstein-Barr virus infection and altered control of apoptotic pathways in posttransplant lymphoproliferative disorders », Pathobiology, vol. 80, no. 2, p. 53-9, viewed sans date, .
    Résumé : Posttransplant lymphoproliferative disorders (PTLD) represent a spectrum of lymphoid diseases complicating the clinical course of transplant recipients. Most PTLD are Epstein-Barr virus (EBV) associated with viral latency type III. Several in vitro studies have revealed an interaction between EBV latency proteins and molecules of the apoptosis pathway. Data on human PTLD regarding an association between Bcl-2 family proteins and EBV are scarce. We analyzed 60 primary PTLD for expression of 8 anti- (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (Bak and Bax), the so-called BH3-only proteins (Bad, Bid, Bim, and Puma), as well as the apoptosis effector cleaved PARP by immunohistochemistry. Bim and cleaved PARP were both significantly (p = 0.001 and p = 5.251e-6) downregulated in EBV-positive compared to EBV-negative PTLD [Bim: 6/40 (15%), cleaved PARP: 10/43 (23%), vs. Bim: 13/16 (81%), cleaved PARP: 12/17 (71%)]. Additionally, we observed a tendency toward increased Bcl-2 protein expression (p = 0.24) in EBV-positive PTLD. Hence, we provide evidence of a distinct regulation of Bcl-2 family proteins in EBV-positive versus negative PTLD. The low-expression pattern of the proapoptotic proteins Bim and cleaved PARP together with the high-expression pattern of the antiapoptotic protein Bcl-2 by trend in EBV-positive tumor cells suggests disruption of the apoptotic pathway by EBV in PTLD, promoting survival signals in the host cells.

  • Giron-Michel, J, Azzi, S, Ferrini, S, Chouaib, S, Camussi, G, Eid, P & Azzarone, B 2013, « Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal homeostasis », Cytokine Growth Factor Rev, vol. 24, no. 1, p. 13-22, viewed sans date, .
    Résumé : Experiments in IL-15(-/-) and IL-15Ralpha(-/-) mice show that intra-renal IL-15, through IL-15Ralpha behaves as an epithelial survival factor. Recent data highlight new functions of IL-15 in renal homeostasis mediated by IL-15Rgamma (CD132). Indeed, in CD132+ renal epithelial tubular cells IL-15 preserves E-cadherin expression inhibiting epithelial-mesenchymal transition (EMT). By contrast, during allograft rejection, the increased intra-graft IL-15 expression favors tubular destruction facilitating the intraepithelial recruitment of CD8 T cells expressing the E-cadherin ligand CD103. In renal cancer, loss of CD132 by epithelial cells defines a tumoral microenvironment where IL-15 triggers E-cadherin down-regulation and EMT. Finally, in CD132+ renal cancer stem cells IL-15 induces the generation of non-tumorigenic epithelial cells sensitive to cytotoxic drugs. These findings are discussed in the light of IL-15-based immunotherapy for renal cancer.

  • Gnemmi, V, Leteurtre, E, Sudour-Bonnange, H, Devisme, L, Guettier, C, Buob, D & Leroy, X 2013, « SALL4 is a marker of the embryonal subtype of hepatoblastoma », Histopathology.
    Résumé : AIMS: SALL4 is a marker of germ cell tumours. The aim of this study was to investigate SALL4 expression in blastemal tumours, particularly in hepatoblastoma. METHODS AND RESULTS: The study included 12 hepatoblastomas. Eight hepatoblastomas were pure epithelial tumours, and four were mixed epithelial and mesenchymal tumours. The patients were nine males and three females with a mean age of 14.6 months. Immunohistochemistry was performed with an antibody against SALL4, using an automated immunostainer. Seven of 12 hepatoblastomas showed nuclear staining only in the embryonal component. Fetal and mesenchymal components were negative. CONCLUSIONS: SALL4 is expressed in blastemal tumours, particularly in the embryonal subtype of hepatoblastoma. Pathologists need to be aware of such expression so that misdiagnosis can be avoided.

  • Golse, N, Bucur, PO, Adam, R, Castaing, D, Sa Cunha, A & Vibert, E 2013, « New paradigms in post-hepatectomy liver failure », J Gastrointest Surg, vol. 17, no. 3, p. 593-605, viewed sans date, .
    Résumé : INTRODUCTION: Liver failure after hepatectomy remains the most feared postoperative complication. Many risk factors are already known, related to patient's comorbidities, underlying liver disease, received treatments and type of resection. Preoperative assessment of functional liver reserve must be a priority for the surgeon. METHODS: Physiopathology of post-hepatectomy liver failure is not comparable to fulminant liver failure. Liver regeneration is an early phenomenon whose cellular mechanisms are beginning to be elucidated and allowing most of the time to quickly recover a functional organ. In some cases, microscopic and macroscopic disorganization appears. The hepatocyte hyperproliferation and the asynchronism between hepatocytes and non-hepatocyte cells mitosis probably play a major role in this pathogenesis. RESULTS: Many peri- or intra-operative techniques try to prevent the occurrence of this potentially lethal complication, but a better understanding of involved mechanisms might help to completely avoid it, or even to extend the possibilities of resection. CONCLUSION: Future prevention and management may include pharmacological slowing of proliferation, drug or physical modulation of portal flow to reduce shear-stress, stem cells or immortalized hepatocytes injection, and liver bioreactors. Everything must be done to avoid the need for transplantation, which remains today the most efficient treatment of liver failure.
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  • Goyer, P, Karoui, M, Vigano, L, Kluger, M, Luciani, A, Laurent, A, Azoulay, D & Cherqui, D 2013, « Single-center multidisciplinary management of patients with colorectal cancer and resectable synchronous liver metastases improves outcomes », Clin Res Hepatol Gastroenterol, vol. 37, no. 1, p. 47-55.
    Résumé : BACKGROUND: Management of patients with synchronous liver metastasis (SLM) is complex and the surgical decision process should be based on a comprehensive oncological strategy. The aim of the study was to compare outcome of single-center management of patients with colorectal cancer (CRC) and resectable SLM to those of referred patients for liver resection only after removal of their primary tumor (PT). METHODS: Between 2000 and 2007, 47 patients with CRC and SLM underwent resection of both the PT and metastases under our care (unicentric) and 32 were referred after resection of their PT. RESULTS: The two groups were comparable for demographics, PT and metastatic disease data. In unicentric group, 23% received upfront chemotherapy with the PT in place, 53% had a combined CRC and SLM resection, 11% had a two-stage hepatectomy with resection of the primary during the first stage and 36% underwent delayed hepatectomy. The number of surgical interventions, the delay between diagnosis and liver resection (9 vs. 5 months, P < 0.001), the median number of cycles of chemotherapy before hepatectomy (12 vs. 6 months, P < 0.001) were significantly higher in the referred group. Postoperative morbidity was significantly higher in the referred group (75 vs. 47%, P = 0.023). The median follow-up was 43 months. OS and DFS were not significantly different between the two groups. CONCLUSION: Although the survival benefit is not proven, single-center management of patients with CRC and resectable SLM reduces the number of interventions, the number of cycles of chemotherapy and postoperative morbidity.
    Mots-clés : 80 and over Colorectal Neoplasms/ pathology/ surgery Female Hepatectomy Humans Liver Neoplasms/ secondary/ surgery Male Middle Aged Patient Care Team Referral and Consultation Retrospective Studies Treatment Outcome, Adult Aged Aged.

  • Grelier, A, Cras, A, Balitrand, N, Delmau, C, Lecourt, S, Lepelletier, Y, Riesterer, H, Freida, D, Lataillade, J-J, Lebousse-Kerdiles, M-C, Cuccini, W, de Latour, RP, Marolleau, J-P, Uzan, G, Larghero, J & Vanneaux, V 2013, « Toll-like receptor 3 regulates cord blood-derived endothelial cell function in vitro and in vivo », Angiogenesis.
    Résumé : Circulating endothelial progenitor cells (cEPC) are capable of homing to neovascularisation sites, in which they proliferate and differentiate into endothelial cells. Transplantation of cEPC-derived cells, in particular those isolated from umbilical cord blood (UCB), has emerged as a promising approach in the treatment of cardio-vascular diseases. After in vivo transplantation, these cells may be exposed to local or systemic inflammation or pathogens, of which they are a common target. Because Toll-like receptors (TLR) are critical in detecting pathogens and in initiating inflammatory responses, we hypothesized that TLR may govern UCB cEPC-derived cells function. While these cells expressed almost all TLR, we found that only TLR3 dramatically impaired cell properties. TLR3 activation inhibited cell proliferation, modified cell cycle entry, impaired the in vitro angiogenic properties and induced pro-inflammatory cytokines production. The anti-angiogenic effect of TLR3 activation was confirmed in vivo in a hind-limb ischemic mice model. Moreover, TLR3 activation consistently leads to an upregulation of miR-29b, -146a and -155 and to a deregulation of cytoskeleton and cell cycle regulator. Hence, TLR3 activation is likely to be a key regulator of cEPC-derived cells properties.

  • Groheux, D, Espié, M, Giacchetti, S & Hindié, E 2013, « Performance of FDG PET/CT in the clinical management of breast cancer », Radiology, vol. 266, no. 2, p. 388-405, viewed sans date, .
    Résumé : In this analysis, the role of metabolic imaging with fluorine 18 fluorodeoxyglucose (FDG) in breast cancer is reviewed. The analysis was limited to recent works by using state-of-the-art positron emission tomography (PET)/computed tomography (CT) technology. The strengths and limitations of FDG PET/CT are examined in various clinical settings, and the following questions are answered: Is FDG PET/CT useful to differentiate malignant from benign breast lesions? Can FDG PET/CT replace sentinel node biopsy for axillary staging? What is the role of FDG PET/CT in initial staging of inflammatory or locally advanced breast cancer? What is the role of FDG PET/CT in initial staging of clinical stage IIA and IIB and primary operable stage IIIA breast cancer? How does FDG PET/CT compare with conventional techniques in the restaging of cancer in patients who are suspected of having disease recurrence? What is the role of FDG PET/CT in the assessment of early response to neoadjuvant therapy and of response to therapy for metastatic disease? Some recommendations for clinical practice are given.
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  • Groheux, D, Giacchetti, S, Delord, M, Hindié, E, Vercellino, L, Cuvier, C, Toubert, M-E, Merlet, P, Hennequin, C & Espié, M 2013, « 18F-FDG PET/CT in staging patients with locally advanced or inflammatory breast cancer: comparison to conventional staging », J Nucl Med, vol. 54, no. 1, p. 5-11, viewed sans date, .
    Résumé : UNLABELLED: The prognosis of patients with locally advanced breast cancer (LABC) remains poor. We prospectively investigated the impact of (18)F-FDG PET/CT at initial staging in this clinical setting and compared PET/CT performance with that of conventional distant work-up. METHODS: During 60 mo, consecutive patients with LABC (clinical T4 or N2-N3 disease) underwent (18)F-FDG PET/CT. The yield was assessed in the whole group and separately for noninflammatory and inflammatory cancer. The performance of PET/CT was compared with that of a conventional staging approach including bone scanning, chest radiography, or dedicated CT and abdominopelvic sonography or contrast-enhanced CT. RESULTS: 117 patients with inflammatory (n = 35) or noninflammatory (n = 82) LABC were included. (18)F-FDG PET/CT confirmed N3 nodal involvement in stage IIIC patients and revealed unsuspected N3 nodes (infraclavicular, supraclavicular, or internal mammary) in 32 additional patients. Distant metastases were visualized on PET/CT in 43 patients (46% of patients with inflammatory carcinoma and 33% of those with noninflammatory LABC). Overall, (18)F-FDG PET/CT changed the clinical stage in 61 patients (52%). Unguided conventional imaging detected metastases in only 28 of the 43 patients classified M1 with PET/CT (65%). (18)F-FDG PET/CT outperformed conventional imaging for bone metastases, distant lymph nodes, and liver metastases, whereas CT was more sensitive for lung metastases. The accuracy in diagnosing bone lesions was 89.7% for planar bone scanning versus 98.3% for (18)F-FDG PET/CT. The accuracy in diagnosing lung metastases was 98.3% for dedicated CT versus 97.4% for (18)F-FDG PET/CT. CONCLUSION: (18)F-FDG PET/CT had the advantage of allowing chest, abdomen and bone to be examined in a single session. Almost all distant lesions detected by conventional imaging were depicted with PET/CT, which also showed additional lesions.
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  • Groheux, D, Hatt, M, Hindié, E, Giacchetti, S, de Cremoux, P, Lehmann-Che, J, Martineau, A, Marty, M, Cuvier, C, Cheze-Le Rest, C, de Roquancourt, A, Visvikis, D & Espié, M 2013, « Estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast tumors: early prediction of chemosensitivity with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography during neoadjuvant chemotherapy », Cancer, vol. 119, no. 11, p. 1960-8, viewed sans date, .
    Résumé : BACKGROUND: The objective of this prospective study was to evaluate the ability of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Sixty-four consecutive patients underwent (18)F-FDG PET/CT scanning at baseline and after the second course of neoadjuvant chemotherapy (NAC). The evolution (Δ) between the 2 scans of image parameters (maximum standardized uptake value [SUV(max)], SUV(mean), metabolic tumor volume, and total lesion glycolysis [TLG]) was measured. Correlations between early changes in PET-derived parameters and pathologic response observed in surgical specimens after the completion of 8 courses of NAC were estimated with Mann-Whitney U tests. Response prediction on the basis of clinical data, histologic type, or molecular markers also was assessed (Fisher exact test). Receiver operating characteristic (ROC) analysis was used to compare the area under the curve (AUC) of each parameter. RESULTS: The best prediction of chemosensitivity was obtained with ΔTLG (-49% ± 31% in nonresponders vs -73% ± 25% in responders; P < .0001). Among the biologic parameters, only negative progesterone receptor status (57% responders vs 31% nonresponders; P = .04) and luminal B subtype (63% responders vs 22% nonresponders; P = .02) were predictive of a pathologic response. ROC analysis resulted in an AUC of 0.81, 0.73, 0.71, and 0.63 for ΔTLG, ΔSUV(max), luminal subtype, and progesterone receptor status, respectively. CONCLUSIONS: When patients responded to NAC, the majority of ER-positive/HER2 negative tumors exhibited partial tumor shrinkage; and the PET parameters that combined volume and activity measurements, such as TLG, offered better accuracy for early prediction than the SUV(max). Negative progesterone receptor status and luminal B subtype had weaker predictive power than PET-derived parameters.
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  • Guerrieri, F, Piconese, S, Lacoste, C, Schinzari, V, Testoni, B, Valogne, Y, Gerbal-Chalouin, S, Samuel, D, Bréchot, C & Faivre, J 2013, « The sodium/iodide symporter NIS is a transcriptional target of the p53 family members in liver cancer cells », Cell Death Dis, vol. In Press.
  • Gugenheim, J, Bredt, LC, Iannelli, A, Decaens, T, Roudot-Thoraval, F, Meyer, C, Durand, F, Bernard, PH, Boillot, O, Sulpice, L, Calmus, Y, Hardwigsen, J, Ducerf, C, Pageaux, GP, Dharancy, S, Chazouilleres, O, Cherqui, D, Duvoux, C & Hadni-Bresson, S 2013, « Recurrence after Liver Transplantation for Hepatocellular Carcinoma According to Up-to-Seven Criteria », Hepatogastroenterology, vol. 60, no. 126, p. 799-806.
    Résumé : Background/Aims: The Up7 criteria for HCC have recently emerged to identify potential candidates for OLT. The aim of this study was to assess the validity of the Up7 criteria according to the pathological analysis of the explanted livers. Methodology: For recurrence risk calculation 669 HCC transplanted patients were classified according to both the pathological Milan and Up7 criteria. In order to identify potential predictors of recurrence, selected biological tumor markers and morphological features were then tested by Cox regression. Results: The 5-year HCC recurrence rate for the Milan out/Up7 in subgroup (n=87), was significantly higher than patients meeting Milan criteria (n=299), 15.8% vs. 9.4% (p=0.0290). For patients within the Up7 criteria (n=383), only pre-OLT AFP level >1000ng/mL and microvascular invasion were significant predictors for recurrence, and for those beyond the Up7 criteria (n=286), pre-OLT AFP level >1000ng/mL, poor differentiation grade and microvascular invasion remained significant. Conclusions: Compared to the current Milan staging system, HCC patients within the pathological Up7 criteria were associated with a higher, but acceptable risk of recurrence after OLT, and along with tumor burden, other parameters can potentially be used for further refinement of HCC staging, such as AFP levels and microvascular invasion.

  • Haim-Boukobza, S, Balabanian, K, Teicher, E, Bourgeade, M, Perlemuter, G, Roque-Afonso, AM & Duclos-Vallee, JC 2013, « Blockade of CCR5 to protect the liver graft in HIV/HCV co-infected patients », J Hepatol.
    Résumé : Haim-Boukobza, Stephanie; Balabanian, Karl; Teicher, Elina; Bourgeade, Marion; Perlemuter, Gabriel; Roque-Afonso, Anne-Marie; Duclos-Vallee, Jean-Charles; J Hepatol. 2013 Apr 9. pii: S0168-8278(13)00216-X. doi: .

  • Hatt, M, Groheux, D, Martineau, A, Espié, M, Hindié, E, Giacchetti, S, de Roquancourt, A, Visvikis, D & Cheze-Le Rest, C 2013, « Comparison between 18F-FDG PET image-derived indices for early prediction of response to neoadjuvant chemotherapy in breast cancer », J Nucl Med, vol. 54, no. 3, p. 341-9, viewed sans date, .
    Résumé : UNLABELLED: The goal of this study was to determine the best predictive factor among image-derived parameters extracted from sequential (18)F-FDG PET scans for early tumor response prediction after 2 cycles of neoadjuvant chemotherapy in breast cancer. METHODS: 51 breast cancer patients were included. Responder and nonresponder status was determined by histopathologic examination according to the tumor and node Sataloff scale. PET indices (maximum and mean standardized uptake value [SUV], metabolically active tumor volume, and total lesion glycolysis [TLG]), at baseline and their variation (Δ) after 2 cycles of neoadjuvant chemotherapy were extracted from the PET images. Their predictive value was investigated using Mann-Whitney U tests and receiver-operating-characteristic analysis. Subgroup analysis was also performed by considering estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, triple-negative, and HER2-positive tumors separately. The impact of partial-volume correction was also investigated using an iterative deconvolution algorithm. RESULTS: There were 24 pathologic nonresponders and 27 responders. None of the baseline PET parameters was correlated with response. After 2 neoadjuvant chemotherapy cycles, the reduction of each parameter was significantly associated with response, the best prediction of response being obtained with ΔTLG (96% sensitivity, 92% specificity, and 94% accuracy), which had a significantly higher area under the curve (0.91 vs. 0.82, P = 0.01) than did ΔSUVmax (63% sensitivity, 92% specificity, and 77% accuracy). Subgroup analysis confirmed a significantly higher accuracy for ΔTLG than ΔSUV for ER-positive/HER-negative but not for triple-negative and HER2-positive tumors. Partial-volume correction had no impact on the predictive value of any of the PET image-derived parameters despite significant changes in their absolute values. CONCLUSION: Our results suggest that the reduction after 2 neoadjuvant chemotherapy cycles of the metabolically active volume of primary tumor measurements such as ΔTLG predicts histopathologic tumor response with higher accuracy than does ΔSUV measurements, especially for ER-positive/HER2-negative breast cancer. These results should be confirmed in a larger group of patients as they may potentially increase the clinical value and efficiency of (18)F-FDG PET for early prediction of response to neoadjuvant chemotherapy.
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  • Hezode, C, Fontaine, H, Dorival, C, Larrey, D, Zoulim, F, Canva, V, de Ledinghen, V, Poynard, T, Samuel, D, Bourliere, M, Zarski, JP, Raabe, JJ, Alric, L, Marcellin, P, Riachi, G, Bernard, PH, Loustaud-Ratti, V, Metivier, S, Tran, A, Serfaty, L, Abergel, A, Causse, X, Di Martino, V, Guyader, D, Lucidarme, D, Grando-Lemaire, V, Hillon, P, Feray, C, Dao, T, Cacoub, P, Rosa, I, Attali, P, Petrov-Sanchez, V, Barthe, Y, Pawlotsky, JM, Pol, S, Carrat, F & Bronowicki, JP 2013, « Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20\mbox-CUPIC) - NCT01514890 », J Hepatol.
    Résumé : BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia <8g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age 65years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (12g/dl for females, 13g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count 100,000/mm3 (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count 100,000/mm3 and serum albumin <35g/L should not be treated with the triple therapy.

  • Innominato, PF, Giacchetti, S, Moreau, T, Bjarnason, GA, Smaaland, R, Focan, C, Garufi, C, Iacobelli, S, Tampellini, M, Tumolo, S, Carvalho, C, Karaboué, A, Poncet, A, Spiegel, D, Lévi, F, Biology, IA for R on T in & Group, CC 2013, « Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer », Cancer, vol. 119, no. 14, p. 2564-73, viewed sans date, .
    Résumé : BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy. Cancer 2013;119:2564-2573. © 2013 American Cancer Society.
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  • Jamme, F, Kascakova, S, Villette, S, Allouche, F, Pallu, S, Rouam, V & Refregiers, M 2013, « Deep UV autofluorescence microscopy for cell biology and tissue histology », Biol Cell, vol. 105, no. 7, p. 277-88.
    Résumé : BACKGROUND INFORMATION: Autofluorescence spectroscopy is a powerful tool for molecular histology and for following metabolic processes in biological samples as it does not require labelling. However, at the microscopic scale, it is mostly limited to visible and near infrared excitation of the samples. Several interesting and naturally occurring fluorophores can be excited in the UV and deep UV (DUV), but cannot be monitored in cellulo nor in vivo due to a lack of available microscopic instruments working in this wavelength range. To fulfil this need, we have developed a synchrotron-coupled DUV microspectrofluorimeter which is operational since 2010. An extended selection of endogenous autofluorescent probes that can be excited in DUV, including their spectral characteristics, is presented. The distribution of the probes in various biological samples, including cultured cells, soft tissues, bone sections and maize stems, is shown to illustrate the possibilities offered by this system. In this work we demonstrate that DUV autofluorescence is a powerful tool for tissue histology and cell biology. RESULTS: To fulfil this need, we have developed a synchrotron-coupled DUV microspectrofluorimeter which is operational since 2010. An extended selection of endogenous autofluorescent probes that can be excited in DUV, including their spectral characteristics, is presented. The distribution of the probes in various biological samples, including cultured cells, soft tissues, bone sections and maize stems, is shown to illustrate the possibilities offered by this system. In this work we demonstrate that DUV autofluorescence is a powerful tool for tissue histology and cell biology. CONCLUSIONS: In this work we demonstrate that DUV autofluorescence is a powerful tool for tissue histology and cell biology.
  • Jean-Philippe, A, Alexandre, J, Christophe, L, Denis, C, Masson, B, Fernandez-Cruz, L & Sa-Cunha, A 2013, « Laparoscopic spleen-preserving distal pancreatectomy: splenic vessel preservation compared with the Warshaw technique », JAMA Surg, vol. 148, no. 3, p. 246-52.
    Résumé : OBJECTIVE: To compare preservation with the division of the splenic vessels in the surgical management of laparoscopic spleen-preserving distal pancreatectomy. DESIGN: Bicentric retrospective study. SETTING: Prospectively maintained databases. PATIENTS: Between January 1997 and January 2011, 140 patients who underwent laparoscopic spleen-preserving distal pancreatectomy for benign or lowgrade malignant tumors in the body/tail of the pancreas were included. Patients treated with the attempted splenic vessel preservation were compared with patients treated with the attempted division of the splenic vessels (Warshaw technique). MAIN OUTCOME MEASURES: Operative outcomes and postoperative morbidity were evaluated. RESULTS: The outcomes of 55 patients in the splenic vessel preservation group were compared with those of 85 patients in the Warshaw technique group. The clinical characteristics were similar in both groups, except for tumor size, which was significantly greater in the Warshaw technique group (33.6 vs. 42.5 mm; P=.001). The mean operative time, mean blood loss, and rate of conversion to the open procedure did not differ between the 2 groups. The rate of successful spleen preservation was significantly improved following the splenic vessel preservation technique (96.4% vs. 84.7%; P=.03). Complications related to the spleen only occurred in the Warshaw technique group (0% vs. 10.5%; P=.03), requiring a splenectomy in 4 patients (4.7%). The mean length of stay was shorter in the splenic vessel preservation group (8.2 vs. 10.5 days; P=.01). CONCLUSIONS: The short-term benefits associated with the preservation of the splenic vessels should lead to an increased preference for this technique in selected patients undergoing laparoscopic spleen-preserving distal pancreatectomy for benign or low-grade malignant tumors in the body/tail of the pancreas.
    Mots-clés : Aged, Blood, Female, Humans, Laparoscopy, Male, methods, Middle, Pancreatectomy/, Retrospective, Spleen/, Studies, supply.

  • Jeblaoui, A, Haim-Boukobza, S, Marchadier, E, Mokhtari, C & Roque-Afonso, AM 2013, « Genotype 4 Hepatitis E Virus in France: An Autochthonous Infection With a More Severe Presentation », Clin Infect Dis.
    Résumé : Among hepatitis E virus (HEV) infections diagnosed in 2011 by the French Reference Centre for HEV, 9 were due to genotype 4, which until recently was limited to Asia. Sequences from autochthonous cases formed a single cluster very similar to Belgian swine sequences. Clinical presentation differed from genotype 3 infections.
  • Johanet, C & Ballot, E 2013, « Autoantibodies in autoimmune hepatitis: anti-liver kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies », Clin Res Hepatol Gastroenterol, vol. 37, no. 2, p. 216-8.
    Résumé : Johanet, Catherine; Ballot, Eric; France; Clin Res Hepatol Gastroenterol. 2013 Apr;37(2):216-8. doi: 10.1016/j.clinre.2013.02.004. Epub 2013 Mar 21.


  • Karkouche, R, Rocher, L, Guettier, C, Corcos, G, Benoit, G, Fernandez, H & Ferlicot, S 2013, « Bilateral renal lymphangiomatosis: imaging and histopathologic findings », Abdom Imaging, viewed sans date, .
    Résumé : Renal lymphangiomatosis is an extremely rare disease characterized by developmental malformation of the lymphatic system surrounding the kidneys. We present the case of a 22-year-old pregnant female discovered because of worsening. Ultrasound, computed tomography, and magnetic resonance imaging studies were performed. An 18 x 11 x 10 cm voluminous cystic subcapsular lesion compressing the left kidney and subcapsular cysts of the right kidney were found. After the delivery, marsupialization was performed and the pathological analysis confirmed the diagnosis of lymphangiomatosis. A review of the literature is proposed.
  • Kluger, MD & Cherqui, D 2013, « Laparoscopic resection of hepatocellular carcinoma », Recent Results Cancer Res, vol. 190, p. 111-26.
    Résumé : The current treatment of HCC is truly multidisciplinary. Notwithstanding, surgical management remains the gold standard which other therapies are compared to. Operative management is divided into transplantation and resection; the latter is further subdivided among open and laparoscopic approaches. Resection has become safer, remains superior to locoregional treatments, and can be a life-prolonging bridge to transplantation. The decision to pursue laparoscopic resection for HCC is driven by safety and a view toward the long-term management of both the malignancy and the underlying liver disease. For patients with a solitary HCC <5 cm in segments 2, 3, 4b, 5, and 6, no evidence of extrahepatic tumor burden, compensated liver disease, and the absence of significant portal hypertension, laparoscopy has an important role. Under these circumstances, resection can be performed with reduced mortality and morbidity and equivalent oncologic outcomes, disease-free survival, and overall survival when compared with similarly selected cirrhotic patients undergoing open resection. Blood loss and transfusion requirements are low, and laparoscopy itself does not expose the patient to complications and does not increase the risk of cancer recurrence or dissemination. Finally, because HCC recurrence remains high in the cirrhotic liver, treatment following surgical resection mandates routine surveillance and treatment by locoregional therapy, reresection, or transplantation as required-the latter two of which are facilitated by an initial laparoscopic resection.
    Mots-clés : Carcinoma, Hepatocellular/mortality/ surgery Disease-Free Survival Hepatectomy Humans Laparoscopy Liver/pathology/surgery Liver Cirrhosis/complications/mortality/surgery Liver Neoplasms/mortality/ surgery Neoplasm Recurrence, Local/mortality/surgery Treatment Outcome.
  • Kluger, MD, Tayar, C, Belli, A, Salceda, JA, Van Nhieu, JT, Luciani, A & Cherqui, D 2013, « A foregut cystic neoplasm with diagnostic and therapeutic similarities to mucinous cystic neoplasms of the pancreas », JOP, vol. 14, no. 4, p. 446-9.
    Résumé : CONTEXT: Greater utilization of cross-sectional abdominal imaging has increased the diagnostic frequency of cystic neoplasms of the pancreas. The "International Consensus Guidelines 2012 for the Management of IPMN and MCN of the Pancreas" illustrates a diagnostic and therapeutic algorithm for these lesions based on current knowledge. CASE REPORT: We present a case of a 49-year-old woman with two years of intermittent epigastric pain found to have an 8.5 cm head of the pancreas mass on CT. Evaluation was consistent with a mucinous cystic neoplasm for which she underwent an uneventful pancreaticoduodenectomy. Histology revealed a bronchogenic cyst of the head of the pancreas. DISCUSSION: Bronchogenic cysts are congenital anomalies of the ventral foregut that can migrate into the abdomen prior to fusion of the diaphragm. They can easily be misdiagnosed for other benign and malignant retroperitoneal lesions. Similarly to mucinous cystic neoplasms, bronchogenic cysts have been reported to undergo malignant transformation. They can also become infected and hemorrhage. Therefore, resection should be performed in appropriate risk candidates. It is possible, with increased use of high resolution cross-sectional imaging, that these lesions may be identified with greater frequency in the abdomen and confused with other pancreatic neoplasms. The presence of ciliated respiratory epithelium and cartilage on pathology provides for definitive diagnosis.
  • Kluger, MD, Vigano, L, Barroso, R & Cherqui, D 2013, « The learning curve in laparoscopic major liver resection », J Hepatobiliary Pancreat Sci, vol. 20, no. 2, p. 131-6.
    Résumé : Laparoscopic major hepatectomy remains a relatively rare operation because it is a difficult and technically demanding procedure, and a standard, safe, reproducible technique has not been widely adopted. This is compounded by "major hepatectomy" encompassing multiple different operations each with their own anatomic and procedural considerations. In 2010, we investigated our learning curve for laparoscopic liver resection. We found a significant increase in the number of major hepatectomies performed over a 12-year period, with concurrent reductions in the use of hand-assistance, pedicle clamping, median clamping time, median operative time, blood loss and morbidity. This learning curve was confirmed by a subsequent multinational study. Both hospital and surgeon volume have been shown to affect outcomes, and defining a sufficient number of repetitions before the learning curve plateaus is not easy for laparoscopic major hepatectomy. We recommend that laparoscopic competencies be developed upon a foundation of open liver surgery and that laparoscopic major hepatectomy should only be attempted after competency with less technically complex laparoscopic resections. A center advanced along its institutional learning curve provides the collective expertise necessary for safe patient selection and management. An environment with colleagues willing to share their acquired proficiency allows the surgeon to observe and critique his or her performance against colleagues. Also, the guidance of like-minded surgeons supports technical development and improved outcomes. In conclusion, steady progress can be made along the learning curve through committed practice of increasingly complex tasks and with proper coaching in a high-volume environment.
  • Le Treut, YP, Gregoire, E, Klempnauer, J, Belghiti, J, Jouve, E, Lerut, J, Castaing, D, Soubrane, O, Boillot, O, Mantion, G, Homayounfar, K, Bustamante, M, Azoulay, D, Wolf, P, Krawczyk, M, Pascher, A, Suc, B, Chiche, L, de Urbina, JO, Mejzlik, V, Pascual, M, Lodge, JP, Gruttadauria, S, Paye, F, Pruvot, FR, Thorban, S, Foss, A & Adam, R 2013, « Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study », Ann Surg, vol. 257, no. 5, p. 807-15.
    Résumé : OBJECTIVE: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. BACKGROUND: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. METHODS: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. RESULTS: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. CONCLUSIONS: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.
    Mots-clés : Adolescent, Adult, Aged, Analysis, Europe, Female, Follow-Up, Humans, Liver, Male, Middle, Multivariate, Neoplasms/mortality/, Neuroendocrine, Outcome, Patient, Prognosis, Registries, Retrospective, secondary/, Selection, Studies, surgery, Survival, Transplantation, Treatment, Tumors/mortality/, Young.
  • Lebbe, C, Porcher, R, Marcelin, AG, Agbalika, F, Dussaix, E, Samuel, D, Varnous, S, Euvrard, S, Bigorie, A, Creusvaux, H, Legendre, C & Frances, C 2013, « Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients », Am J Transplant, vol. 13, no. 1, p. 207-13.
    Résumé : The aims of the study were to assess the risk of HHV8 transmission resulting from organ transplantation, and related morbidity in liver, heart and kidney transplant recipients. Donor and recipient serologies were screened between January 1, 2004 and January 1, 2005 using HHV8 indirect immunofluorescence latent assay (latent IFA) and indirect immunofluorescent lytic assay (lytic IFA). Recipients negative for latent IFA with a donor positive for at least one test were sequentially monitored for HHV8 viremia and underwent serological tests over a period of 2 years. The results showed that among 2354 donors, HHV8 seroprevalence was 9.9% (lytic IFA) and 4.4% (latent IFA). A total of 454 organ recipients (281 renal, 116 liver and 57 heart) were monitored over a 2-year period. Seroconversion was observed in 12 patients (cumulative incidence 28%) whose donor had positive latent IFA and in 36 patients (cumulative incidence 29%) whose donors were positive only for lytic IFA, without differences across types of transplants. Positive HHV8 viremia was detected in only 4 out of 89 liver transplant recipients during follow-up and not in recipients of other types of transplant. Two liver transplant recipients and one kidney transplant recipient developed KS. In conclusion, although HHV8 transmission is a frequent event after organ transplantation, HHV8-related morbidity is rather rare but can be life threatening. Donor screening is advisable for monitoring HHV8 seronegative liver transplant recipients.
    Mots-clés : Adult Female Fluorescent Antibody Technique Herpesviridae Infections/physiopathology/ transmission/virology Herpesvirus 8, Human/ isolation & purification Humans Male Middle Aged Organ Transplantation Tissue Donors Viremia.
  • Lee, SY, Cherqui, D & Kluger, MD 2013, « Extended Right Hepatectomy in a Liver with a Non-bifurcating Portal Vein: the Hanging Maneuver Protects the Portal System in the Presence of Anomalies », J Gastrointest Surg, vol. 17, no. 8, p. 1494-9.
    Résumé : INTRODUCTION: Variations in portal vein anatomy occur in 20-35 % of individuals. A non-bifurcating portal vein (PV) was suspected on preoperative imaging in a patient with a large right lobe hepatocellular carcinoma. The single PV curved within the liver parenchyma from right to left supplying second-order branches along its course. CASE REPORT: Utilizing the hanging maneuver, an extended right hemihepatectomy was safely performed. This approach allowed for preservation of the main PV and its left-sided branches while easily identifying the second-order right branches for ligation. CONCLUSION: Knowledge of portal vein variations and identification preoperatively by cross-sectional imaging are critical. The hanging maneuver aids in the preservation of the main portal vein and its left-sided branches during right hemihepatectomy in the presence of portal vein anomalies, and this technique can be used to improve safety in hepatobiliary surgery.


  • Lee, SY, Mooney, MA, Inra, ML, Juluru, K, Fox, AN, Olsen, SK, Brown, R. S., J, Emond, JC, Cherqui, D & Kluger, MD 2013, « Exposure to ionizing radiation during liver transplantation evaluation, waitlist time, and post-operative period: A cause for concern », Hepatology, viewed sans date, .
    Résumé : Substantial evidence has linked ionizing radiation exposure(RE) to oncogenesis. Patients evaluated for transplantation undergo extensive diagnostic imaging and have increased baseline cancer risk factors. The objective was to examine exposure in a cohort of patients undergoing evaluation and liver transplantation. Radiation exposure from all diagnostic examinations and procedures were retrospectively recorded. Radiation exposure is reported in millisieverts(mSv), a standardized measure of the detrimental biologic effect of radiation which allows for population-level comparisons. Seventy-four patients (69% male, mean 57 years) were evaluated, of which 13 of 35 subsequently listed patients were transplanted; an additional 18 previously evaluated patients were also transplanted during 2010. The most common indications were hepatitis C (55%) and hepatocellular carcinoma(HCC)(30%). The median observation period was 14 months. 1,826 imaging examinations were performed, of which 408(22%) involved considerable ionizing radiation, and were the focus of investigation. Median annualized effective RE was 51mSv[Interquartile range(IQR):19,126], with 10% exposed to almost twice the amount of radiation recommended for a 5-year period. Patients with HCC received significantly (p<0.00001) higher median annualized effective RE than patients without HCC, 137mSv (IQR:87,259) versus 32mSv(IQR:13,57), respectively. Computed tomography(CT) abdomen(23%) and chest(16%) accounted for the most common exposures, with CT abdomen accounting for 46% of overall cohort RE. Conclusion: Patients undergoing evaluation and liver transplantation at our center are exposed to very high levels of ionizing radiation. Although long-term effects in these patients are yet to be defined, the theoretical increased risk of malignancy must be given its due consideration. Routine use of non-radiating imaging and reconsideration of indications may be preferred and justified in this population. (Hepatology 2013;).

  • Lehmann-Che, J, Hamy, A-S, Porcher, R, Barritault, M, Bouhidel, F, Habuellelah, H, Leman-Detours, S, de Roquancourt, A, Cahen-Doidy, L, Bourstyn, E, de Cremoux, P, de Bazelaire, C, Albiter, M, Giacchetti, S, Cuvier, C, Janin, A, Espié, M, de Thé, H & Bertheau, P 2013, « Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15 », Breast Cancer Res, vol. 15, no. 3, p. R37, viewed sans date, .
    Résumé : INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.
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  • Levesque, E, Hoti, E, de La Serna, S, Habouchi, H, Ichai, P, Saliba, F, Samuel, D & Azoulay, D 2013, « The positive financial impact of using an Intensive Care Information System in a tertiary Intensive Care Unit », Int J Med Inform, vol. 82, no. 3, p. 177-84.
    Résumé : INTRODUCTION: In the French healthcare system, the intensive care budget allocated is directly dependent on the activity level of the center. To evaluate this activity level, it is necessary to code the medical diagnoses and procedures performed on Intensive Care Unit (ICU) patients. The aim of this study was to evaluate the effects of using an Intensive Care Information System (ICIS) on the incidence of coding errors and its impact on the ICU budget allocated. PATIENTS AND METHODS: Since 2005, the documentation on and monitoring of every patient admitted to our ICU has been carried out using an ICIS. However, the coding process was performed manually until 2008. This study focused on two periods: the period of manual coding (year 2007) and the period of computerized coding (year 2008) which covered a total of 1403 ICU patients. The time spent on the coding process, the rate of coding errors (defined as patients missed/not coded or wrongly identified as undergoing major procedure/s) and the financial impact were evaluated for these two periods. RESULTS: With computerized coding, the time per admission decreased significantly (from 6.8 +/- 2.8 min in 2007 to 3.6 +/- 1.9 min in 2008, p<0.001). Similarly, a reduction in coding errors was observed (7.9% vs. 2.2%, p<0.001). This decrease in coding errors resulted in a reduced difference between the potential and real ICU financial supplements obtained in the respective years (euro194,139 loss in 2007 vs. a euro1628 loss in 2008). CONCLUSION: Using specific computer programs improves the intensive process of manual coding by shortening the time required as well as reducing errors, which in turn positively impacts the ICU budget allocation.
  • Levesque, E & Samuel, D 2013, « Postliver transplantation pulmonary complications: is modified clinical pulmonary infection score applicable? », Transplantation, vol. 95, no. 7, p. e43-4.
    Résumé : Levesque, Eric; Samuel, Didier; Comment; Letter; United States; Transplantation. 2013 Apr 15;95(7):e43-4. doi: 10.1097/TP.0b013e3182848e45.
    Mots-clés : Bacterial/ epidemiology, Female Humans Liver Transplantation/ adverse effects Male Pneumonia.

  • Levesque, E, Duclos, J, Ciacio, O, Adam, R, Castaing, D & Vibert, E 2013, « Influence of larger graft weight to recipient weight on the post-liver transplantation course », Clin Transplant, vol. 27, no. 2, p. 239-47, viewed sans date, .
    Résumé : Size matching between recipient and donor livers is an important factor in organ allocation in the context of liver transplantation (LT). The aim of this study was to determine whether a large graft for recipient size influenced the post-transplant course. One hundred and sixty-two successive LT recipients were included and retrospectively divided into two groups: 25 (15%) had a graft-to-recipient weight ratio (GWRW) ≥ 2.5% and 137 (85%) had a GWRW <2.5%. Postoperative complications and outcomes were recorded. In the GWRW >2.5% group, more end-to-end caval replacement (72% vs. 38%, p = 0.003) and veno-venous bypass (48% vs. 23%, p = 0.01) were used. Peak AST/ALT values were higher in the GWRW >2.5% group (AST: 596 [70-5876] vs. 453 [29-5132] IU/l, p = 0.03; ALT: 773 [101-5025] vs. 383 [36-4921] IU/l, p = 0.02). Among postoperative complications, the rate of respiratory failure was higher in the GWRW >2.5% group (32% vs. 14%, p = 0.04). The rates of other complications did not differ between the two groups. Both groups had similar graft and patient survival rates at one yr. Using large grafts for recipient size did not impair liver function and did not modify graft and patient outcomes at one yr. However, a GWRW >2.5% appeared to be a determining factor for respiratory morbidity following LT.
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  • Linard, C, Busson, E, Holler, V, Strup-Perrot, C, Lacave-Lapalun, J-V, Lhomme, B, Prat, M, Devauchelle, P, Sabourin, J-C, Simon, J-M, Bonneau, M, Lataillade, J-J & Benderitter, M 2013, « Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs », Stem cells translational medicine, vol. 2, no. 11, p. 916-927.
    Résumé : The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.
    Mots-clés : Animals, Bone Marrow Cells, Collagen, Collagen Type I, Connective Tissue Growth Factor, Extracellular Matrix, Fibrosis, Humans, Inflammation, Interleukin-10, Male, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Mucous Membrane, Neovascularization, Pathologic, Proctitis, Radiation Injuries, Experimental, Rectum, Swine, Transforming Growth Factor beta.

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