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ABSTRACT: BACKGROUND: Only a small proportion of alcoholic patients develop advanced liver disease, suggesting that factors other than alcohol intake may influence alcoholic liver disease (ALD) progression. We have shown that body mass index (BMI) is an independent risk factor for fibrosis in alcohol-induced liver disease and that adipose tissue inflammation is correlated with liver lesions in alcoholic patients. The aim of this study was to determine whether visceral adipose tissue, as assessed by abdominal height measurement, affected individual susceptibility to fibrosis in alcoholic patients. METHODS: We included 127 consecutive alcoholic patients with abnormal liver test findings for whom liver histology data were available. Abdominal height was measured with a Holtain-Kahn abdominal caliper. We carried out univariate comparisons followed by multivariate regression analysis, to investigate the relationship between abdominal height and fibrosis score. RESULTS: Abdominal height (p < 0.005), waist circumference (p < 0.05), fasting blood glucose concentration (p < 0.05), serum triglyceride concentration (p < 0.05), serum bilirubin (p < 0.005), and BMI (p = 0.05) were higher, whereas high-density lipoprotein (HDL) cholesterol level (p < 0.01) was lower in the 72 patients with significant (F2-F4) fibrosis than in the 55 patients with F0-F1 fibrosis. In multivariate regression analysis, only abdominal height (β = 7.2, p < 0.002) was independently and positively correlated with fibrosis score, which was also negatively correlated with HDL cholesterol level (β = -1.04, p < 0.05). CONCLUSIONS: We provide the first demonstration that abdominal height may be a predictor of significant fibrosis in patients with ALD. Our findings support a role for visceral fat accumulation, independent of BMI and of metabolic syndrome criteria, in the onset of alcoholic liver damage.
Alcoholism Clinical and Experimental Research 09/2012; · 3.34 Impact Factor
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European journal of cancer (Oxford, England: 1990) 09/2009; 45 Suppl 1:332-42. · 4.12 Impact Factor
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Sylvie Naveau,
Guillaume Gaudé, Amani Asnacios,
Hélène Agostini,
Annie Abella,
Nadège Barri-Ova,
Barbara Dauvois,
Sophie Prévot,
Yen Ngo,
Mona Munteanu,
Axel Balian,
Micheline Njiké-Nakseu,
Gabriel Perlemuter,
Thierry Poynard
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ABSTRACT: FibroTest has been validated as a biomarker of fibrosis in patients with chronic viral hepatitis, with a similar prognostic value as biopsy. The aim of the study was to compare the diagnostic and prognostic values of FibroTest versus the recently patented biomarkers, FibrometerA, and Hepascore. A total of 218 consecutive patients with ALD and available liver biopsy examination were included. Biomarkers were compared using univariate area under the ROC curves (AUROC) and multivariate analysis (logistic regression and Cox). The median follow-up was 8.2 years. Eighty-five patients died, including 42 deaths related to liver complications. The diagnostic values of FibrometerA and Hepascore did not differ from that of FibroTest for advanced fibrosis (all AUROC = 0.83 +/- 0.03) and cirrhosis (FibroTest and FibrometerA = 0.94 +/- 0.02, Hepascore = 0.92 +/- 0.02), and were significantly greater than those of nonpatented biomarkers (APRI, Forns, FIB4; P < 0.01). In multivariate analysis the most significant was FibroTest (P = 0.001), without independent diagnostic value for FibrometerA (P = 0.19), and Hepascore (P = 0.40). The prognostic values of FibroTest (AUROC for survival or non liver disease-related death = 0.79 +/- 0.04), FibrometerA (0.80 +/- 0.04), Hepascore (0.78 +/- 0.04), did not differ from that of biopsy fibrosis staging (0.77 +/- 0.04). In multivariate analysis the most significant were FibroTest (P = 0.004) and biopsy (P = 0.03), without independent prognostic values for FibrometerA (P = 0.41) and Hepascore (P = 0.28). In patients with alcoholic liver disease, FibrometerA and Hepascore did not improve the diagnostic and prognostic values of FibroTest.
Hepatology 09/2008; 49(1):97-105. · 11.66 Impact Factor
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Amani Asnacios,
Laetitia Fartoux,
Olivier Romano,
Chloe Tesmoingt,
Samy Louafi S,
Touraj Mansoubakht,
Pascal Artru,
Thierry Poynard,
Olivier Rosmorduc,
Mohamed Hebbar,
Julien Taieb
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ABSTRACT: The authors conducted a phase 2 trial of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with the gemcitabine plus oxaliplatin (GEMOX) regimen in patients with documented progressive hepatocellular carcinoma (HCC).
Forty-five untreated patients with advanced-stage progressive HCC were prospectively enrolled. Treatment consisted of cetuximab at a dose of 400 mg/m2 initially then 250 mg/m2 weekly, plus gemcitabine at a dose of 1000 mg/m2 on Day 1 and oxaliplatin at a dose of 100 mg/m2 on Day 2, every 2 weeks. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal.
Overall, 306 cycles were administered. Grade 3 to 4 hematologic toxicity consisted of thrombocytopenia (24%), neutropenia (20%), and anemia (4%). Grade 3 oxaliplatin-induced neurotoxicity occurred in 5 patients (11%) and grade 3 cutaneous toxicity in 7 patients (16%). There were no treatment-related deaths. The confirmed response rate was 20% and disease stabilization was obtained in 40% of patients. The median progression-free and overall survival times were 4.7 months and 9.5 months, respectively. The 1-year survival rate was 40%.
In poor-prognosis patients with progressive advanced-stage HCC, the GEMOX-cetuximab combination appears to be active and to have manageable toxicity. A comparative randomized trial is now being planned.
Cancer 07/2008; 112(12):2733-9. · 4.77 Impact Factor
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ABSTRACT: Well-differentiated metastatic endocrine carcinomas are difficult to manage because of variable disease outcome. New prognostic factors are required. These tumors overexpress somatostatin receptors (sst), implying the use of somatostatin analogs for tumor localization by somatostatin receptor scintigraphy using indium-111-pentetreotide ((111)In-pentetreotide) and for medical treatment. The aim of the present study was to evaluate the correlation between (111)In-pentetreotide scintigraphy, sst receptor expression, and prognosis.
Between 1994 and 2002, 48 consecutive patients with well-differentiated endocrine carcinomas and a negative (111)In-pentetreotide scintigraphy were retrospectively paired according to sex, age, and tumor localization with 50 patients with well-differentiated endocrine carcinomas and a positive tracer uptake at (111)In-pentetreotide scintigraphy. Overall survival and expression of sst1 to sst5 receptors by immunohistochemistry were assessed.
The lack of tracer uptake at the (111)In-pentetreotide scintigraphy seemed to be a poor prognostic factor (P = .007) for overall survival by Kaplan-Meier test and in multivariate analysis; age and absence of clinical secretory syndrome also seemed to be poor prognostic factors. The tracer uptake (positive (111)In-pentetreotide scintigraphy) correlated with the tumor expression of somatostatin receptor sst2 (P < .001) but not with that of sst1, sst3, sst4, or sst5. In a bivariate analysis, lack of sst2 expression also significantly correlated with poor prognosis.
We demonstrate the prognostic value of (111)In-pentetreotide scintigraphy in well-differentiated malignant endocrine tumors. In these tumors, sst2 somatostatin receptor expression correlates with both tracer uptake and a better prognosis.
Journal of Clinical Oncology 03/2008; 26(6):963-70. · 18.37 Impact Factor
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ABSTRACT: New systemic therapies are needed to improve the prognosis of patients with advanced-stage hepatocellular carcinoma (HCC). In a Phase II trial involving previously untreated patients with advanced HCC, the more favorable schedule from a previous pilot study was evaluated.
Thirty-four patients with previously untreated advanced-stage HCC were prospectively enrolled. The GEMOX regimen consisted of gemcitabine 1000 mg/m(2) on Day 1 and oxaliplatin 100 mg/m(2) on Day 2. The treatment was repeated every 2 weeks until disease progression or limiting toxicity.
Thirty-two patients were assessable for efficacy and 33 for toxicity. In all, 323 treatment cycles were administered. No toxic deaths occurred. Hematological grade 3-4 toxicity consisted of thrombocytopenia (27% of patients) and neutropenia (24%), including 2 febrile neutropenia and anemia (9%). Grade 3 oxaliplatin-induced neurotoxicity was observed in 3 (9%) patients. The overall response rate was 18% (95% confidence interval [CI]: 8-34) and disease stabilization was observed in 58% of patients (including 5 minor responses), giving a disease control rate of 76%. Median progression-free and overall survival times were, respectively, 6.3 months (95% CI: 4.3-10.1 months) and 11.5 months (95% CI: 8.5-14.3 months). Treatment was significantly more effective in patients with nonalcoholic cirrhosis than in those with alcoholic cirrhosis.
The GEMOX regimen seems to be well tolerated and active in advanced HCC, especially in patients with underlying nonalcoholic liver disease. A Phase II study of the GEMOX regimen plus cetuximab is ongoing.
Cancer 05/2007; 109(7):1384-90. · 4.77 Impact Factor
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ABSTRACT: Pancreatic cancer is one of the most aggressive and devastating human malignancies. The present study was conducted to determine whether in vivo sst2 gene transfer into human pancreatic tumors would impair tumor progression, and to characterize sst2 antitumoral bystander mechanisms. sst2 administration, using the synthetic vector PEI, strongly inhibited tumor progression of human pancreatic adenocarcinoma, in vivo. sst2 gene transfer induced intratumoral production of its ligand somatostatin. Disruption of this autocrine loop by RNA interference completely reversed sst2 antitumoral activity. Mice depleted of natural killer (NK) cells did not hamper sst2 tumor growth inhibition. However, microvessel density and vascular endothelial growth factor (VEGF) expression were markedly reduced in sst2-transfected tumors, whereas sst3 somatostatin receptor was upregulated. Depleting somatostatin by RNA interference completely abolished the sst2 inhibitory effect on VEGF expression and tumor angiogenesis, and sst2-induced sst3 expression in peripheral tumor vessels. We conclude that in vivo sst2 gene transfer elicited intratumoral somatostatin production and strongly impaired human pancreatic tumor growth. NK cells were not involved in this antitumoral bystander effect. VEGF and tumor vascularization were identified as novel targets for sst2-mediated antitumoral bystander effect. sst3 somatostatin receptor was upregulated in sst2-transfected tumors. Therefore, in vivo gene delivery of sst2 receptor to target the angiogenic process in pancreatic ductal adenocarcinoma might be a new therapeutic approach for treatment of pancreatic cancer in patients with unresectable disease.
Human Gene Therapy 11/2005; 16(10):1175-93. · 4.22 Impact Factor
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ABSTRACT: The majority of patients cannot benefit from the conventional curative treatments that are currently used for hepatocellular carcinoma (HCC), which remains a world health problem. Interleukin (IL)-12 is one of the most potent anti-tumor cytokines. The aim of the present study was to examine the anti-tumor effect and toxicity of intrahepatic delivery of IL-12 using an ex vivo gene therapy approach in a murine model of HCC.
Syngenic fibroblasts or MM45T-Li HCC tumor cells were genetically modified in vitro to express IL-12 using a polycistronic TFG murine IL-12 retroviral vector (TFGmIL-12) coding for both p35 and p40 murine IL-12 subunits. Hepatocellular carcinoma was generated using direct intrahepatic inoculation of the tumor cell line into the left liver lobe of BALB/c mice.
Direct liver expression of IL-12 by the injected genetically modified tumor cells induced a marked inhibition of tumor growth. This effect was associated with an early infiltration of macrophages, and lymphocytes forming numerous intralobular foci. There was no significant liver toxicity, as shown by normal biochemical liver tests. At a later time, the intralobular foci were rare and consisted mainly of CD4+ T cells, while CD8+ T cells were present in the lobule. Intrahepatic expression of IL-12 did not modify circulating or splenic B lymphocytes or natural killer (NK) cells. The inhibition of tumor growth was maintained in nude mice even when depleted in NK cells. Importantly, in a second model, treatment of established day 7 liver tumors in BALB/c mice using direct intra-tumor injection of syngenic fibroblasts that were genetically modified to express IL-12 significantly reduced tumor size.
In conclusion, these data provide evidence that experimental HCC can be efficiently and safely treated using ex vivo IL-12 gene therapy, which seems promising for future clinical studies.
Journal of Gastroenterology and Hepatology 05/2004; 19(4):388-96. · 2.87 Impact Factor
