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La Revue de Médecine Interne 02/2011; 32(2):120-3. · 0.61 Impact Factor
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M J Pillaire, J Selves,
K Gordien,
P-A Gourraud,
C Gentil,
M Danjoux,
C Do,
V Negre,
A Bieth,
R Guimbaud,
D Trouche,
P Pasero,
M Méchali,
J S Hoffmann,
C Cazaux
Oncogene 04/2010; 29(14):2160. · 6.37 Impact Factor
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ABSTRACT: To assess the etiologies and outcome of liver granulomatosis.
We analyzed all consecutive liver granulomatosis diagnosed in our internal medicine department from 2000 to 2008.
Among 471 liver biopsies, 21 disclosed evidence of liver granulomatosis (4.5%), in sixteen women (76%) and five men, with a median age of 41years. Thirteen were caucasians (62%). At the time of diagnosis, six (28.5%) had isolated abnormal liver function tests, and fifteen (71.4%) presented with clinical manifestations. The underlying cause was identified in 18 cases (85.7%). Eleven (52.3%) were systemic diseases: five (23.8%) primary biliary cirrhosis, two (9.5%) primary sclerosing cholangitis, two (9.5%) common variable immunodeficiency, one (4.7%) Sjögren's syndrome, and one (4.7%) Behçet's disease. Two (9.5%) patients had sarcoidosis. Three (14.3%) liver granulomatosis were of infectious origin (tuberculosis, schistosomiasis, and hepatitis C virus), two (9.5%) were neoplastic (Hodgkin's lymphoma and liver cell adenoma), and three (14.3%) were idiopathic. With a median of 38 months of follow-up, four patients (19%, two common variable immunodeficiency and two sarcoidosis) developed portal hypertension, independently of cirrhosis. One patient died of cryptococcosis.
In accordance with other European studies, systemic diseases are the main causes of hepatic granulomas. Liver granulomatosis related to common variable immunodeficiency and sarcoidosis are at risk of portal hypertension.
La Revue de Médecine Interne 12/2009; 31(2):97-106. · 0.61 Impact Factor
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M-J Pillaire, J Selves,
K Gordien,
P-A Gourraud,
P-A Gouraud,
C Gentil,
M Danjoux,
C Do,
V Negre,
A Bieth,
R Guimbaud,
D Trouche,
P Pasero,
M Méchali,
J-S Hoffmann,
C Cazaux
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ABSTRACT: Colorectal cancer is one of the most frequent cancers worldwide. As the tumor-node-metastasis (TNM) staging classification does not allow to predict the survival of patients in many cases, additional prognostic factors are needed to better forecast their outcome. Genes involved in DNA replication may represent an underexplored source of such prognostic markers. Indeed, accidents during DNA replication can trigger 'replicative stress', one of the main features of cancer from earlier stages onward. In this study, we assessed the expression of 47 'DNA replication' genes in primary tumors and adjacent normal tissues from a homogeneous series of 74 patients. We found that genes coding for translesional (TLS) DNA polymerases, initiation of DNA replication, S-phase signaling and protection of replication forks were significantly deregulated in tumors. We also observed that the overexpression of either the MCM7 helicase or the TLS DNA polymerase POLQ (if also associated with a concomitant overexpression of firing genes) was significantly related to poor patient survival. Our data suggest the existence of a 'DNA replication signature' that might represent a source of new prognostic markers. Such a signature could help in understanding the molecular mechanisms underlying tumor progression in colorectal cancer patients.
Oncogene 11/2009; 29(6):876-87. · 6.37 Impact Factor
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ABSTRACT: To help increase the number of transplants available for hepatocellular carcinoma in cirrhotic livers, this single-centre retrospective study compared the safety and feasibility of new, more liberal, selection criteria--no more than five tumours, with the largest tumour no greater than 5 cm (5/5 criteria)--with classical criteria.
Data from operations performed in 1990-2005 were extracted from preoperative radiological findings and postoperative specimen analyses, and four groups were constructed: Paul Brousse, Milan, University of California, San Francisco (UCSF) and 5/5 criteria. A fifth group comprised patients whose tumour load exceeded the 5/5 criteria. Survival and recurrence rates were compared.
For the 110 patients in the study, survival rates (overall and disease-free) were 72.8 and 66.8 per cent at 5 and 10 years respectively, with a 5.5 per cent recurrence rate. The 5-year survival rate was 65, 77, 68 and 77 per cent for Paul Brousse, Milan, UCSF and 5/5 preoperative radiological criteria, with recurrence rates of 4, 4, 3 and 3 per cent, respectively. On multivariable analysis, the only factor that influenced survival was tumour load in excess of the 5/5 criteria.
Use of the more liberal 5/5 criteria for selecting patients for liver transplantation results in similar disease-free and overall survival rates to classical criteria.
British Journal of Surgery 08/2009; 96(7):785-91. · 4.61 Impact Factor
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ABSTRACT: The Tip60 histone acetyltransferase belongs to a multimolecular complex that contains many chromatin remodeling enzymes including the ATPase p400, a protein involved in nucleosomal incorporation of specific histone variants and that can directly or indirectly repress some Tip60-dependent pathways. Tip60 activity is critical for the cellular response to DNA damage and is affected during cancer progression. Here, we found that the ratio between Tip60 and p400 mRNAs is affected in most colorectal carcinoma. Strikingly, reversing the p400/Tip60 imbalance by Tip60 overexpression or the use of siRNAs resulted in increased apoptosis and decreased proliferation of colon-cancer-derived cells, suggesting that this ratio defect is important for cancer progression. Furthermore, we demonstrate that the p400/Tip60 ratio controls the oncogene-induced DNA damage response, a known anticancer barrier. Finally, we found that it is also critical for the response to 5-fluorouracil, a first-line treatment against colon cancer. Together, our data indicate that the p400/Tip60 ratio is critical for colon cancer cells proliferation and response to therapeutic drugs through the control of stress-response pathways.
Oncogene 02/2009; 28(12):1506-17. · 6.37 Impact Factor
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ABSTRACT: Cell cycle checkpoints and DNA repair act in concert to ensure DNA integrity during perturbation of normal replication or in response to genotoxic agents. Deficiencies in these protective mechanisms can lead to cellular transformation and ultimately tumorigenesis. Here we focused on Rev3, the catalytic subunit of the low-fidelity DNA repair polymerase zeta. Rev3 is believed to play a role in double-strand break (DSB)-induced DNA repair by homologous recombination. In line with this hypothesis, we show the accumulation of chromatin-bound Rev3 protein in late S-G2 of untreated cells and in response to clastogenic DNA damage as well as an gamma-H2AX accumulation in Rev3-depleted cells. Moreover, serine 995 of Rev3 is in vitro phosphorylated by the DSB-inducible checkpoint kinase, Chk2. Our data also disclose a significant reduction of rev3 gene expression in 74 colon carcinomas when compared to the normal adjacent tissues. This reduced expression is independent of the carcinoma stages, suggesting that the downregulation of rev3 might have occurred early during tumorigenesis.
Oncogene 08/2008; 27(47):6093-101. · 6.37 Impact Factor
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N Kamar,
J-M Mansuy,
O Cointault, J Selves,
F Abravanel,
M Danjoux,
P Otal,
L Esposito,
D Durand,
J Izopet,
L Rostaing
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ABSTRACT: Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney-pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.
American Journal of Transplantation 07/2008; 8(8):1744-8. · 6.39 Impact Factor
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ABSTRACT: Hepatic venous pressure gradient (HVPG) is a prognostic marker in patients with cirrhosis. Transient elastography measures liver stiffness (LS).
To assess the correlation between LS and HVPG and to investigate the performance of transient elastography for the diagnosis of significant portal hypertension (PHT).
Liver stiffness was measured by Fibroscan in 150 consecutive patients who underwent a liver biopsy with haemodynamic measurements. Usual clinical and biological data were collected. Significant PHT was defined as a HVPG > or = 10 mmHg.
Hepatic venous pressure gradient was found to be > or = 10 mmHg in 76 patients. Cirrhosis was diagnosed in 89 patients. HVPG was found to be correlated with: LS (rho = 0.858; P < 0.001) and inversely correlated with prothrombin index (rho = -0.718; P < 0.001). Regarding significant PHT, AUROC for LS and prothrombin index were 0.945 [0.904-0.987] and 0.892 [0.837-0.947] respectively. The cut-off value of 21 kPa accurately predicted significant PHT in 92% of the 144 patients for whom LS was successful.
Liver stiffness measurement is correlated with HVPG and transient elastography identifies patients with significant PHT.
Alimentary Pharmacology & Therapeutics 06/2008; 27(12):1261-8. · 3.77 Impact Factor
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ABSTRACT: We report on three cases of severe disseminated Herpes simplex type-2 (HSV-2) infection that occurred in two orthotopic liver-transplant (OLT) and one renal-transplant patients. In two cases, i.e., in the OLT patients, this was associated with HSV-2-related acute hepatitis. The rapid onset of IV acyclovir (ACV) therapy led to recovery within 8-12 days. Although rare, HSV-2-disseminated infection, in the context of organ transplantation may be life-threatening, but can be cured if ACV therapy is initiated early in the course of this disease.
Infection 03/2008; 36(1):62-4. · 2.66 Impact Factor
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ABSTRACT: The low-fidelity DNA polymerases thought to be specialized in DNA damage processing are frequently misregulated in cancers. We show here that DNA polymerase kappa (polkappa), prone to replicate across oxidative and aromatic adducts and known to function in nucleotide excision repair (NER), is downregulated in colorectal tumour biopsies. Contrary to the replicative poldelta and polalpha, for which only activating domains were described, we identified an upstream 465-bp-long repressor region in the promoter of POLK. We also found an activating 237-bp region that includes stimulating protein-1 (SP1) and cyclic AMP-responsive element (CRE)-binding sites. Mutations at one CRE-binding site led to a dramatic 80% decrease in promoter activity. Alterations of the SP1-binding site also affected, to a lesser extent, the transcription. Gel shift assays confirmed the role played by CRE/SP1 recognition sequences. Moreover, ectopic expression of SP1 or CRE-binding protein (CREB) protein favoured polkappa transcription. Finally, we found that polkappa downexpression in colorectal biopsies correlated with a decreased level of CREB and SP1 transcripts. This work shows that the promoter of POLK is cis-controlled and suggests that silencing of CREB and SP1 proteins could contribute to downregulation of this repair polymerase in colorectal tumours.
Oncogene 06/2007; 26(23):3387-94. · 6.37 Impact Factor
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ABSTRACT: Fulminant hepatitis E has not been well characterized in industrialized countries. The aim of this study was to prospectively describe patients with acute hepatitis E presenting as fulminant hepatic failure, i.e. with encephalopathy and prothrombin index <50%. Between February 1997 and April 2005, seven patients with encephalopathy were diagnosed with acute hepatitis E using viral RNA detection. These patients were compared with 33 patients diagnosed with a mild form (absence of encephalopathy) of acute hepatitis E during the same time period. Patients were 65 +/- 11 years old. Five were active drinkers and six had chronic liver disease. All hepatitis E virus sequences evaluated (5/7) were of genotype 3. All patients but two died (71%). Four patients had no travel history. When compared with patients with a mild form of acute hepatitis E, active alcohol abuse and chronic liver disease were more frequent in patients with the severe form. Duration of hospitalization was longer. Aspartate transferase and bilirubin levels were significantly higher. Prothrombin index and accelerin levels were lower and death was more frequent. Acute nontravel-associated hepatitis E can appear as fulminant hepatitis with encephalopathy and coagulation disorders. Prognosis is severe and this may be due to the age at which it occurs and frequent underlying chronic liver disease.
Journal of Viral Hepatitis 06/2007; 14(5):298-303. · 4.09 Impact Factor
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J M Péron,
C Bureau,
P Gourdy,
H Lulka,
A Souque,
B Calippe, J Selves,
T Al Saati,
J Bernad,
P Cordelier,
B Couderc,
L Pradayrol,
B Pipy,
L Buscail,
J P Vinel
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ABSTRACT: Peritoneal carcinomatosis from pancreatic cancer has a poor prognosis with a median survival of 3.1 months. This is mainly due to lack of effective treatment. Interleukin 12 (IL12) is a proinflammatory cytokine that has a potent antitumoral effect by stimulating innate and adoptive immunity.
To examine the antitumoral effect and toxicity of intraperitoneal delivery of IL12 using an ex vivo gene therapy approach in a murine model of pancreatic peritoneal carcinomatosis.
Peritoneal carcinomatosis was generated by direct intraperitoneal inoculation of the pancreatic cancer cell line Capan-1 in athymic mice. Syngenic fibroblasts were genetically modified in vitro to secrete IL12 using a polycistronic TFG murine IL12 retroviral vector coding for both p35 and p40 murine IL12 subunits. Ex vivo gene therapy involved injection of the genetically modified fibroblasts intraperitoneally twice a week for 4 weeks.
Treatment of pre-established peritoneal carcinomatosis with fibroblasts genetically modified to express IL12 induced a marked inhibition of tumour growth as measured by comparison of the weights of the intraperitoneal tumour nodules in the treated and control animals (3.52 (SD 0.47) v 0.93 (SD 0.21) g, p<0.05) and improved survival. This effect was associated with infiltration of the peritoneal tumour nodules with macrophages. Peritoneal lavage confirmed enhancement of the innate peritoneal inflammatory activity, with an increased number of activated macrophages and natural killer cells. Moreover, macrophages harvested from animals with peritoneal carcinomatosis and treated with IL12-expressing fibroblasts expressed an activated proinflammatory antitumoral M1 phenotype that included strongly enhanced reactive oxygen species and nitric oxide production. There was no treatment-related toxicity.
Multiple injections of genetically modified fibroblasts to express IL12 is an effective and well-tolerated treatment for experimental murine pancreatic peritoneal carcinomatosis via activated innate immunity and in particular activated M1 macrophages.
Gut 02/2007; 56(1):107-14. · 10.11 Impact Factor
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ABSTRACT: The aim of our study was to assess the long-term liver histology in renal transplant patients infected with hepatitis C virus (HCV) who were treated with a cyclosporine-based regimen. Among 55 anti-HCV+/RNA+ patients, liver biopsies (LB) were requested every 3 to 4 years after transplantation: two LBs (n=55); three LBs (n=44); four LBs (n=10). Overall, the rate of liver fibrosis progression was 0.07+/-0.03 Metavir U/y. Only three patients out of 55 (5.4%) developed cirrhosis. Liver fibrosis remained stable throughout follow-up in 21 patients; increased in 21 patients; and improved in the remaining 13 patients. The incidence of posttransplant diabetes mellitus was low (9%). We concluded that HCV infection is not harmful to liver histology in more than 50% of renal transplant patients with grafts functioning more than 6 years. Cyclosporine might have beneficial effects on the natural course of HCV infection after renal transplantation.
Transplantation Proceedings 07/2006; 38(5):1329-32. · 1.00 Impact Factor
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Journal of Hepatology 10/2004; 41(3):499-500. · 9.26 Impact Factor
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ABSTRACT: Hereditary Non-Polyposis Colon Cancer (HNPCC) or Lynch's Syndrome remains an underappreciated clinical entity-perhaps due to the restrictiveness of the diagnostic criteria. Even though HNPCC makes up only a small fraction (2-3%) of Colorectal Cancer (CRC) compared with sporadic CRC, it is important to make the diagnosis to allow for targeted management of the patients and their kindreds and thus to reduce morbidity and mortality. Better knowledge of tumor characteristics including RER phenotype may allow for the application of less restrictive diagnostic criteria; but these characteristics are not specific to HNPCC and also occur in 15% of sporadic CRC. Nevertheless, a screening strategy combining a broader clinical selection (less strict than the Amsterdam criteria) with a study of tumoral phenotype may allow the identification of more cases of HNPCC. The physician caring for cases of CRC must be aware of these screening strategies and relevant clinical and biological clues which might indicate a more complete genetic investigation.
Journal de Chirurgie 01/2004; 140(6):317-23. · 0.50 Impact Factor
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ABSTRACT: Intra-vascular large cell lymphoma is a rare disease characterised by the proliferation of malignant cells within small blood vessels.
We report a case of intra-vascular lymphoma presenting with unexplained dyspnoea, hypoxaemia and associated neurological symptom. The diagnosis was made by liver biopsy but the patient ultimately died.
Earlier diagnosis with transbronchial biopsy might have improved the prognosis by allowing more prompt treatment.
Revue des Maladies Respiratoires 12/2003; 20(5 Pt 1):782-5. · 0.59 Impact Factor
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ABSTRACT: Treatment of chronic hepatitis C in renal-transplant (RT) recipients with alpha-interferon is associated with a high rate of acute rejection. We therefore evaluated the biochemical, virological, histological efficacies, as well as the safety of one year ribavirin monotherapy in 16 HCV-(+) RNA (+) RT patients (group A) matched to 32 HCV-(+) RNA (+) RT patients (group B) who did not receive ribavirin. Ribavirin was initially started at a daily dose of 1000 mg and then adapted to hemoglobin level. Ribavirin monotherapy was associated with a significant decrease in AST, ALT and gamma glutamyl transpeptidase levels. Serum creatinine decreased as well. When proteinuria was present (n = 5), this decreased or disappeared. There was no significant changes in HCV viremia. The histological analysis of liver biopsies revealed a significant progression in liver fibrosis with no improvement in inflammation scores. There was a significant decrease in hemoglobin levels, despite an important support by recombinant erythropoeitin. However, in three cases, ribavirin therapy had to be stopped. In group B, after 1 year of follow up, there was a significant increase in serum ALT and creatinine values. Proteinuria decreased in only 2 of 12 patients. In conclusion, one year ribavirin therapy in HCV-(+) RNA (+)ve RT has no impact upon liver histology, although it improves liver enzyme levels. It impact upon renal function remains unknown. Nevertheless when proteinuria is present it disappears.
Néphrologie 02/2003; 24(2):89-94.
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M P Castex,
A I Bertozzi,
H Rubie,
B Domenech,
E Duchayne, J Selves,
N Dastugue,
M Danjoux,
E Kulhein,
P Galinier,
A Robert
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ABSTRACT: The authors report the case of a ten-year-old girl, who had been treated for a malignant germinal tumour five years before, presenting with a leukaemia-like syndrome associating bone pain, liver and spleen nodules and bone marrow involvement. The cyto-pathological analysis showed undifferentiated cells and CD56 and protein S100 were found as the only positive markers. The child received several subsequent lines of chemotherapy and ultimately died of the disease.
Particular cytogenetic abnormalities were observed (iso1q10, iso6p10) and were in favor of an unusual NK cell lymphoma.
This analysis revealed a XY genotype (testicular feminization syndrome).
Archives de Pédiatrie 01/2002; 8(12):1337-40. · 0.30 Impact Factor
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L Alric,
M Duffaut, J Selves,
K Sandre,
M Mularczyck,
J Izopet,
H Desmorat,
C Bureau,
N Chaouche,
B Dalbergue,
J P Vinel
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ABSTRACT: Our aim was to assess whether histological response was improved by continuing interferon-alpha (IFN) treatment in patients with chronic hepatitis C (HCV) with a biochemical response and no viral clearance after a usual IFN treatment.
Fifty-seven patients with normal alanine aminotransferase (ALAT) levels and positive HCV RNA at the end of a 1 year IFN treatment were randomly assigned to either group 1 (n = 28) where IFN was stopped, or group 2 (n = 29) where IFN was continued for 1 more year with gradual reduction of the dose to keep serum ALAT activity below the upper limit of normal. Liver biopsies were obtained before, and then 6 months after the end of treatment.
Knodell's index improved between paired biopsies in group 2 (8.2+/-2.4 vs. 5.5+/-2.1), but not in group 1 (8+/-2.3 vs. 6.5+/-2). In post-treatment biopsies, the METAVIR activity score was significantly lower in group 2 than in group 1 (0.7+/-0.2 vs. 1.1+/-0.3, P < 0.05). In group 2, an improvement of the METAVIR fibrosis score was observed (1.3+/-0.4 vs. 1.1+/-0.2), whereas fibrosis progressed in group 1 (1.3+/-0.4 vs. 1.6+/-0.4).
Maintenance therapy by the minimal dose of IFN able to maintain biochemical response prevents histological progression in the sub-group of patients without virological response.
Journal of Hepatology 08/2001; 35(2):272-8. · 9.26 Impact Factor
