Hervé Gouérou

The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors

OBJECTIVE:Somatostatin analogs are the first-line drugs for controlling hormone-mediated symptoms of carcinoid tumors. Prospective and retrospective studies have suggested that somatostatin analogs also have antiproliferative activity. The octapeptide lanreotide is available in sustained-release form, obviating the need for daily injections.METHODS:A total of 46 patients were enrolled in this open, prospective, phase II trial. They received lanreotide 30 mg i.m. every 14 days for 6 months when they had symptomatic carcinoid tumors, and lanreotide 30 mg i.m. every 10 days if they had nonsymptomatic tumors. Nonsymptomatic tumors were progressive before the start of the study. Tumor size was assessed every 3 months by means of computed tomography. The assessment was centralized and was made by an external panel.RESULTS:In all, 30 patients had symptomatic neuroendocrine tumors and 16 had asymptomatic neuroendocrine tumors. Five patients in the group with symptomatic tumors and two in the group with nonsymptomatic tumors were considered not to be evaluable. The mean duration of treatment was 12 months in the group with symptomatic tumors and 13 months in the other group. Among the 39 evaluable patients, two objective responses were obtained, giving an objective response rate of 5% (one in the group with symptomatic tumors and one in the other group). Nineteen patients had no significant increase in their tumor size for a mean of 9.5 months.CONCLUSIONS:Lanreotide is safe and well tolerated in patients with carcinoid tumors. It seems to have both symptomatic and antitumoral effects in this setting.

Epidemiology and course of acute upper gastro-intestinal haemorrhage in four French geographical areas

Objective To compare incidence rates and epidemiological characteristics of acute upper gastrointestinal haemorrhage (AUGIH) in France with those of other European studies. Design Population‐based multi‐centre prospective survey. Setting 29 public hospitals and 96 private specialists in gastroenterology in four administrative areas in France during 1996. Subjects A total of 2133 AUGIH patients 18 years and over were included in the six‐month study. Outcome measures Incidence and mortality. Results The overall incidence in France was 143 cases per 100 000 persons per year, classified as out‐patients (16%), emergency admissions (59%) and in‐patients (25%). The incidence rates increased with age except for in‐patients, and were higher in males. Peptic ulcer (36.6%), varices (13.7%) and erosive disease (12.3%) were the most frequent diagnoses. In 677 patients (31.7%), aspirin, antiinflammatory drugs or corticosteroids were taken on the 7 days before bleeding. The overall mortality (out‐patients excluded) was 14.3% (10.7% for emergency patients and 23% for in‐patients). Mortality was associated with comorbidities (especially malignancies, cirrhosis, asthma or respiratory deficiency), was lower in emergency patients using non‐steroid anti‐inflammatory drugs, and higher in in‐patients using corticosteroids. Conclusions In France, patients with AUGIH are frequently managed as out‐patients. Gastrotoxic drug use is frequently associated with AUGIH and constitutes a strategic opportunity for preventive treatment. Discrepancies between countries are not clearly explained either by demographic factors or by drug use, but this may be related to the emphasis on AUGIH in in‐patients. Eur J Gastroenterol Hepatol 12:175‐181

Factors associated with liver steatosis and fibrosis in chronic hepatitis C patients.

UNLABELLED Liver steatosis is a common finding in patients infected with hepatitis C virus (HCV). Host and viral factors have been associated with steatosis, but their relative contributions have not been clearly addressed. It has been suggested that steatosis plays a role in the progression of liver fibrosis. AIMS To assess: a) factors associated with steatosis in patients infected with hepatitis C virus; b) their impact on liver fibrosis. PATIENTS AND METHODS Three hundred and fourteen untreated patients were included. Lifetime alcohol consumption was estimated. Liver fibrosis, inflammation and necrosis were assessed using the METAVIR score. Body mass index (BMI) was determined. The scoring system for steatosis was as follows: 0, no steatosis; 1, less than 10%; 2, 10% to 30%; 3, 30% to 70%; 4, more than 70% of hepatocytes affected. RESULTS In univariate analysis, steatosis was associated with elevated BMI (P=0.001), excessive alcohol intake (P=0.005), genotype 3 (P<0.001) and moderate to severe histological activity (P=0.01). Multivariate analysis showed that steatosis correlated with two independent factors: genotype 3a (OR=60.7; 95% CI: 7.6-483.4) (P<0.001) and BMI (OR=4.86; 95% CI: 1.8-13.15) (P=0.002). In univariate analysis, severe fibrosis (F2-F3-F4) was associated with older age (P<10(-5)), male gender (P=0.001), disease duration (P<0.006), BMI (P<10(-4)), alcohol intake (P<10(-6)), severity of histological activity (P<10(-5)) and steatosis (P<10(-6)). In multivariate analysis, three independent factors were associated with severe fibrosis: disease duration > 10 years (OR=3.17; 95% CI: 0.65-15.4) (P=0.015), presence of steatosis (OR=3.17; 95% CI: 1-9.99) (P<0.049) and genotype 3a (OR=5.56; 95% CI: 1.4-22.1) (P=0.015). CONCLUSION In patients with chronic hepatitis C, steatosis is significantly associated with genotype 3 infection and high BMI. Steatosis is an independent risk factor associated with severe fibrosis. These results have major implications for the management of patients with chronic hepatitis C.

Epidemiology and long term survival of gastric carcinoma in the French district of Finistere between 1984 and 1995.

OBJECTIVES The aims of this study were to evaluate trends in incidence, clinical characteristics, treatment regimen and prognosis of gastric carcinoma in the area of Finistere (France) during a 12-year period. METHODS Between 1984 and 1995, the Finistere Registry of GastroIntestinal Tract Tumors listed 2 139 patients with gastric carcinoma in a population of 838 627 inhabitants. Curative resection and operative mortality were analyzed by logistic regression. Prognostic factors were determined using the Kaplan-Meier method and the Cox model. RESULTS When comparing the second period (1990-1995) to the first period (1984-1989) we observed: a) a decrease of standardized incidence (13.2 vs. 15.6/100 000 inhabitants/year in males and 5.4 vs. 7.0/100 000 inhabitants/year in females); b) a significant increase of linitis plastica (21.4% vs. 10.9%) and infiltrative tumors (53.1 vs. 31.2%) (P<0.0001); c) no variation in tumor stage at diagnosis; d) a significant increase in curative resection (65.7% vs. 45.0%; P<0.0001); e) no variation in operative mortality; f) the absence of improvement of survival rate; the latter was 29% at 2 years, 19% at 5 years and 11% at 10 years during the second period. Multivariate analysis showed that the main prognostic factors of gastric carcinoma were age, tumor stage and the type of surgical procedure. CONCLUSION This study showed a decrease in the incidence of gastric carcinoma over time and an increase of linitis plasticia and infiltrative forms. Despite improvement in management of patients, the global prognosis of gastric carcinoma did not improve significantly over a 12-year period of observation.

Antibody response of patients with Helicobacter pylori-related gastric adenocarcinoma: significance of anti-cagA antibodies.

ABSTRACT The aim of this study was to search for a specific antibody pattern in sera from patients suffering from Helicobacter pylori-related gastric adenocarcinoma (GAC). The serological response of 22 patients suffering from GAC, 31 patients with gastroduodenal ulcer, and 39 asymptomatic subjects was analyzed using immunoblotting performed with three H. pylori strains: strain ATCC 43579; strain B110, isolated from a patient with ulcers; and strain B225, isolated from a patient with GAC. In addition, the latex agglutination test Pyloriset Dry was used to analyze ambiguous sera. H. pylori seropositivity was 75% in the GAC group, 61.3% in the ulcer group, and 56.4% in the asymptomatic group. Anti-CagA antibodies were found more often in the GAC group (48.8%) and in the ulcer group (47.3%) than in the asymptomatic group (21.2%). These percentages depended on the strain used as an antigen: in the GAC group, the anti-CagA frequencies were 93.3, 40, and 13.3% with strains B225, B110, and ATCC 43579, respectively. Thus the presence of anti-CagA antibodies was increased in patients suffering from H. pylori-related GAC, in particular when the CagA antigen was from a GAC strain. These data suggest the existence of a CagA protein specifically expressed by H. pylori strains isolated from GAC patients.

Flow-Cytometric DNA Content Analysis of Esophageal Squamous Cell Carcinomas

To better understand the mechanisms of esophageal carcinogenesis, abnormalities in DNA content of esophageal squamous cell carcinomas were studied. Cellular DNA content was determined by flow cytometric study of 70 endoscopic biopsy specimens obtained from 26 patients with esophageal squamous carcinoma. High-quality histograms were obtained for 23 patients. Twenty-one patients had at least one aneuploid population in their tumor. In 7 patients, multiple aneuploid peaks were detected. Specimens from 2 patients were diploid. The interpretation of the DNA histograms was difficult in 3 patients; an aneuploid population of cells was probable in 2 of them. A statistically significant relationship was found between the degree of differentiation and DNA content abnormalities in the regions of the tumors that could be evaluated by endoscopic biopsies: well-differentiated carcinomas had diploid or small aneuploid populations containing less than 15% of the cells, whereas DNA histograms of moderately or poorly differentiated carcinomas were characterized by large aneuploid peaks representing 25%-90% of the cells and a higher proliferative fraction. No relationship was found between the size or the stage of the tumor and the DNA content detected in endoscopic biopsy samples. The frequency and the multiplicity of abnormal clones in esophageal squamous carcinomas indicates that this cancer, like esophageal adenocarcinoma, develops an association with an acquired genomic instability that produces abnormal clones of cells, according to the multistep model of neoplastic progression.

Epidemiology of hepatocellular carcinoma in Finistère. Prospective study from June 2002 to May 2003.

OBJECTIVES The aims of this prospective study were to evaluate the incidence of hepatocellular carcinoma (HCC) in Finistère, an administrative district of western France, and to highlight epidemiological characteristics. METHODS From June 1st 2002 to May 31st 2003, all cases of HCC in Finistère were registered prospectively. Standardized incidence rates were calculated. RESULTS One hundred and six cases of HCC were registered. Standardized incidence rates were 13.8/100000 among men and 0.8/100000 among women. Among the incident cases of HCC, 52% were discovered in patients consulting for symptoms, and 28% in patients undergoing screening. The new non-invasive diagnostic criteria of HCC were used in 60% of cases. HCC was associated with cirrhosis in 89 patients (84%). Excessive alcohol intake was the main cause of cirrhosis. In all, 27 patients (25.5%) received potentially curative treatment. CONCLUSION Incidence of HCC is high in Finistère. The proportion of patients given potentially curative treatment is still low, illustrating how difficult screening can be when alcoholic cirrhosis predominates in the target population.

Coexistence of annular pancreas with carcinoma in the dorsal part of pancreas divisum: diagnostic value of magnetic resonance cholangiopancreatography

We report on the incidental observation of a pancreas divisum coexistent with an annular pancreas in a 88-year-old woman presenting with jaundice due to a pancreatic carcinoma. This case report discusses the embryologic hypotheses underlying this peculiar association, highlights the capacities of imaging techniques to depict them, and enhances the performance of magnetic resonance imaging.

Prevalence and topography of intestinal metaplasia in columnar lined esophagus.

OBJECTIVES Barretts mucosa is considered as a mosaic of three epithelial types but little is known about the topography of intestinal metaplasia in columnar lined esophagus. The aims of the study were to determine the prevalence of intestinal metaplasia within long and short segments of columnar lined esophagus and to analyze the distribution of the intestinal metaplasia within long segments of Barretts esophagus. PATIENTS AND METHODS The study was performed on the initial endoscopy carried out among 112 patients enrolled in an endoscopic surveillance program. Seventy-two patients with columnar mucosa extending more than 3 cm into the esophagus (group I) and 40 patients with a short segment of columnar mucosa (group II) had multiple biopsies according to a standardized protocol. 1163 biopsies were analyzed on the whole: 949 biopsies in group I and 214 biopsies in group II. RESULTS Intestinal metaplasia was identified among 650 (68.5%) and 50 (23.4%) biopsies in groups I and II respectively (P<10-7). The proportion of biopsies with foci of intestinal metaplasia increased significantly with the length of the columnar mucosa. The diagnosis of Barretts esophagus was confirmed in 100% of the patients in group I and in 45% of the patients in group II. In long segments of Barretts esophagus, intestinal metaplasia was more frequently observed in the 2 upper thirds of the columnar mucosa that in the lower third (P<10-7). Detailed mapping of the distribution of epithelial types within the columnar lined esophagus identified three patterns of distribution of intestinal metaplasia within long segments of Barretts esophagus: unifocal, multifocal and diffuse, in 5%, 56% and 39% of the patients respectively. Dysplasia was present in 15% of patients with long segments of Barretts esophagus and 11% of patients with short segments (NS). CONCLUSION The distribution of intestinal metaplasia within columnar lined esophagus is heterogeneous and three distinct patterns can be identified: unifocal, multifocal and diffuse. Considering the risk of sampling error, the current recommendations concerning the biopsy protocols are mandatory until the validation of new techniques such as chromoendoscopy or magnifying endoscopy.

Infrequent p16/CDKN2 alterations in squamous cell carcinoma of the oesophagus.

Loss of heterozygosity (LOH) on chromosome 9 and p16 (MTS1/CDKN2) gene mutations have been reported in various human cancers. The present study aimed to determine the prevalence of LOH in 100 oesophageal squamous cell carcinomas (OSCCs) by typing microsatellite loci and mutations of the p16 gene. The methods used included denaturing gradient gel electrophoresis (DGGE) and DNA sequencing of exon 2. LOH was found in 14.7% of the OSCC cases. Six gene alterations were identified in exon 2. They consisted of three deletions and the same polymorphism in three samples. The relatively low rate of p16 mutation compared with the frequency of LOH suggests the possible involvement of another tumour suppressor gene located on chromosome 9 in oesophageal carcinogenesis.