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Resume Nous rapportons le cas d’un malade de 18 ans, sans antecedent, presentant des ulceres duodenaux hemorragiques recidivant ayant revele un syndrome de Zollinger-Ellison. Les examens realises initialement chez ce malade etaient en faveur d’un gastrinome primitif antral sporadique avec adenopathies satellites ayant conduit a un traitement chirurgical. L’evolution clinique et des tests secretoires, ainsi que l’apparition d’une hyperparathyroidie primaire ont demontre qu’il s’agissait d’un gastrinome dans le cadre d’une neoplasie endocrine multiple de type 1. Il s’agit a notre connaissance du premier cas decrit de gastrinome primitif antral dans le cadre d’une neoplasie endocrine multiple de type 1.

Resume Parmi 408 cas de patients atteints de neoplasie endocrinienne multiple de type 1, 127 cas de gastrinomes ont ete individualises au sein de la cohorte du groupe de tumeurs endocrines (GTE) a la date de juillet 2000 (31,1 %). Le but de cette etude a ete d'evaluer les donnees cliniques, biologiques, chirurgicales, ainsi que leurs tendances sur trois periodes ( 1990). Un syndrome de Zollinger-Ellison (SZE) etait present dans 96 % des cas. L'âge moyen des premiers signes etait de 39,4 ans. Il existait 55,9 % d'hommes, 7,1 % des SZE etaient porteurs de metastases hepatiques synchrones. Les principaux elements evolutifs significatifs ont ete les suivants : diminution de la positivite des quatre tests biologiques diagnostiques pris isolement, meilleure reconnaissance de l'œsophagite (4,5 a 29,7 %), augmentation de la taille des tumeurs resequees (9,9 a 16,8 mm), reconnaissance d'un contexte familial (73,1 a 80 %), utilisation croissante de l'Octreoscan et de l'echoendoscopie contributives dans 81,3 et 92,3 % dans la detection des metastases et des tumeurs pancreatiques apres 1991, diminution des patients operes (96 a 52,5 %), diminution des patients operes du gastrinome (87,5 a 37,5 %), du tractus gastro-intestinal (70,8 a 30 %), augmentation relative des resections pancreatiques majeures enlevant le duodenum et la tete du pancreas (10 a 26,7 %), disparition de la mortalite operatoire. Six des sept patients (85,7 %) ayant eu une resection pancreatique majeure ont normalise la gastrinemie postoperatoire vs 15 % pour les autres techniques. La probabilite de survie etait de 90 ± 4,4 % a cinq ans, legerement amelioree apres 1985 (85 ± 4,8 % vs 95 ± 3,6, p = 0,1). Conclusion. – Les SZE des NEM1 ont ete pris en charge a un stade plus precoce et moins souvent operes. Cependant, l'incidence des metastases hepatiques synchrones n'a pas evolue significativement. Les indications operatoires se sont centrees sur l'urgence et la resection des masses tumorales pour prevenir les metastases et ce sans aucune mortalite apres 1991.

About 25% of patients with ZES have MEN 1. Except diarrhoea, less frequent in patients with ZES-MEN 1 than in sporadic ZES, and specific MEN 1-related signs, clinical characteristics are similar in both ZES types. Acid output and gastrin levels are also similar whether in the basal state or after secretin stimulation. Primary hyperparathyroidism (PHPT) exists in the majority of ZES-MEN 1 patients, 30% have pituitary adenoma (prolactinomas for half), 30% adrenal involvement, 25 to 30% have EC-Lomas; bronchial and thymic carcinoids have probably been underevaluated. Gastrinomas are multiple predominantly located in the duodenal wall, but also in the pancreas in association with clinically silent endocrine tumors. The spread of the disease: metastases to the liver (LM), mediastinum, bones, is evaluated at best by Octreoscan. Endoscopic ultrasonography evaluates the number, size and anatomical characteristics of gastrinomas. Patients without LM have an excellent prognosis. Surgery never cures ZES, but is necessary in case of associated life-threatening condition such as insulinoma and has been advocated to prevent LM development in patients with large pancreatic tumor(s). However although, indeed, the size of the tumor, when located in the pancreas > 3 cm, favours metachronous LM occurrence, surgery, in our experience, has not been able to prevent LM development. Hepatic malignancies remain however the most pejorative prognostic determinant for survival and raise the most difficult therapeutic challenge. Surgery is the best option whenever feasible; specific chemotherapy and chemo-embolisation have not conclusively achieved definite successes. Long-term octreotide treatment, however, has been shown recently to obtain tumour stabilisation. Internal irradiation with 90 Ytrium-labelled octreotide is a new promising option, presently under evaluation (Novartis European trial). Preliminary results are promising.

The incidence of anal cancer is higher in patients with anal canal condyloma, a sexually transmitted disease, than in the general population. We determined the prevalence of anal dysplasia and cancer in patients with anal canal condyloma with respect to human immunodeficiency virus (HIV) status, immunity status, and human papillomavirus types.In 174 consecutive patients (114 HIV positive, 60 HIV negative) with anal canal condyloma, lesions were cured, and the patients were then followed up prospectively. Langerhans cells (LCs) in normal anal mucosa were quantified, and viruses (Epstein-Barr virus, cytomegalovirus, human simplex virus 1, and various human papillomavirus [HPV] types) were characterized on inclusion. During follow-up (median 26 months), relapsed condylomas were resected and examined histologically. HIV load and CD4 T-lymphocyte counts in serum were determined at each visit.Several factors differed significantly between HIV-positive and HIV-negative patients: LCs/mm anal tissue (15 vs. 30), oncogenic HPV (27% vs. 13%), other current anal infections (44% vs. 0%), and sex ratio (93% vs. 73% male). During follow-up, condylomas relapsed in 75% of the HIV-positive patients, with 19 high-grade dysplasias (HGDs) and 1 invasive carcinoma, but in only 6% of HIV-negative patients, with 1 HGD. Male sex, HIV positivity, and15 LCs/mm tissue were independent risk factors for condyloma relapse. HIV positivity, HGD before inclusion, and condyloma relapse were independent risk factors for HGD and cancer. Serum HIV load was associated with relapse, whereas CD4 T-lymphocyte counts were not.The prevalence of HGD and carcinoma is higher in HIV-positive than in HIV-negative patients, probably because of HPV activity. HIV-positive patients with high serum HIV load and/or a history of anal dysplasia should be examined by anoscopy, and condylomas should be analyzed histologically.

The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models.

Transforming growth factor-alpha (TGF-alpha) is overexpressed in colonic carcinomas and promotes mucosal wound healing. It may be implicated in chronic inflammatory bowel disease (IBD). We analyzed the expression of TGF-alpha and its receptor, epidermal growth factor receptor (EGF-r), in the colonic mucosa of patients with Crohn's disease (CD) or ulcerative colitis (UC), in active or inactive stages, as compared with controls. Proteins and mRNA were detected in biopsies from the right and left colon and in surgical colonic specimens. Immunoblot analysis revealed TGF-alpha protein as a 29 kDa band. This band was normally expressed in uninvolved colonic mucosa of patients with CD or UC whether in active or inactive stages, but decreased or absent in involved mucosa of active IBD, even when TGF-alpha mRNA and EGF-r protein were detected. In the unaffected mucosa of CD, the intensity of TGF-alpha immunoreactivity was similar to that of controls in the right colon but stronger (P = 0.05) in the left colon. There was no TGF-alpha overexpression in dysplastic regions. In conclusion, in active IBD disease, the decreased TGF-alpha protein amount seems not only related to epithelial cell loss but reflects a down-regulation at least at the protein level. We speculate that TGF-alpha does not play a role within the active stage but may be implicated later in the repair process.

Background & Aims: Risk factors of metachronous liver metastases and death are not well known in patients with the Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. These factors were retrospectively determined in 77 patients. Methods: Data chart review was performed. Results: Median follow-up was 102 months (range, 12–366). Surgery was performed on 48 patients, including 9 of the 10 patients with large pancreatic tumors (≥3 cm). Liver metastases developed in 4 patients (40%) with large pancreatic tumors, in 3 (4.8%) without, and in 1 of the 4 patients with pancreatic tumors of unknown size; all had previously undergone surgery. The only independent factor associated with development of liver metastases identified by multivariate analysis was large pancreatic tumors (risk ratio, 29.0; 95% confidence interval [CI], 3.2–260.7). Surgery was not selected. The probability of being free of liver metastases in the 63 patients without large pancreatic tumors was 96% (95% CI, 88–100) at 10 and 15 years. Thirteen (16.9%) patients died. The only independent factors of death selected by multivariate analysis were Zollinger–Ellison syndrome diagnosis before 1980 (risk ratio, 8.2; 95% CI, 1.7–40.6) and age at diagnosis (risk ratio/year, 1.08; 95% CI, 1.03–1.14). Conclusions: Large pancreatic tumors are predictive of the development of metachronous liver metastases, and surgery does not seem to prevent them. GASTROENTEROLOGY 1999;116:286-293

Background & Aims: Long-term survival of patients with Zollinger–Ellison syndrome (ZES) is largely determined by the presence or absence of liver metastases. However, because of the lack of precision of these criteria, development of further indicators is still required. Recent evidence showing that autoantibodies directed against the p53 protein could predict poor survival for some types of cancers prompted us to investigate the presence of such antibodies in sera from patients with ZES and their potential value as survival indicator. Methods: Anti-p53 antibodies were detected in the sera of 44 consecutive patients with ZES using both an enzyme-linked immunosorbent assay (ELISA) and Western blotting. The mean follow-up of these patients was 92 months. Results: Anti-p53 antibodies were detected in 7 of the patients with ZES (16%) by both ELISA and Western blotting. Univariate and multivariate analyses showed that the presence of anti-p53 antibodies ( P = 0.0009 and P = 0.017, respectively) and liver metastases ( P = 0.0009 and P = 0.012, respectively) was independently associated with shorter survival. Conclusions: These results suggest that anti-p53 antibodies are an indicator of survival and could be used in combination with staging to determine which patients with ZES have poor prognoses and therefore require reinforced therapy. GASTROENTEROLOGY 1998;114:37-43

Purpose : Hepatic metastases of neuroendocrine tumors are known to mimic hemangiomas on nonenhanced SE MR sequences. The usefulness of MR examination with gadolinium injection to identify lesions was prospectively evaluated. Method : Nine patients with multiple liver metastases of gastrinomas were compared with six patients showing multiple liver hemangiomas. Patients underwent unenhanced T2-weighted SE, T1-weighted SE, and FLASH sequences, followed by enhanced sequential FLASH sequences and a 5 min delayed T1-weighted SE sequence. Results : On T2-weighted SE sequence, all hemangiomas displayed the same typical morphology as a sharply defined, homogeneous, high signal intensity lesion, but this pattern was also observed for some or all of the lesions in seven of nine patients with gastrinoma metastases. Dynamic FLASH sequences were accurate for lesions larger than 2 cm, hemangiomas displaying a nodular peripheral enhancement with centripetal filling in, and metastases displaying either an initial homogeneous or a regular peripheral enhancement. Precise assessment of lesions smaller than 2 cm remained equivocal. Delayed T1-weighted SE sequence (performed at least 5 min after Gd-chelate injection) was the most accurate technique to identify metastases by showing hypo- or isointensity signal, whereas all hemangiomas were hyperintense. Conclusion : Postcontrast delayed T1-weighted sequence is the primary technique to differentiate equivocal cases of hemangiomas from metastases of gastrinoma.

Previous studies have suggested that patients with Barrett's oesophagus may be at increased risk of colorectal neoplasia, though the association is disputed. In a multicentre prospective study we compared the prevalence of colorectal adenomas in patients with Barrett's oesophagus and controls. Barrett's oesophagus patients (n = 104) had histological confirmation of columnar epithelium extending more than 3 cm above the gastro-oesophageal junction. The 537 controls were patients with symptoms suggesting irritable bowel syndrome. No participant had a personal history of colonic neoplasm. Each patient underwent colonoscopy. Histologically proven adenomas were found in 26 Barrett's patients (25%) and 75 controls (14%). Three colorectal cancers were discovered in each group. The prevalence of adenomas was greater in the Barrett's oesophagus group than in the control group (p < 0.01) but the relation became non-significant after adjustment for age and sex and control for other known risk factors by a logistic regression model (odds ratio 1.4 [0.7-2.7]). The relative risk of adenoma was significantly higher in patients older than 59 than in younger patients (2.2 [1.3-3.5]) and in men than in women (3.4 [2.0-5.7]). Other factors contributing significantly to the risk of adenoma were a family history of colorectal cancer (2.3 [1.1-4.8]), rectal bleeding (2.1 [1.1-3.9]), previous colonic investigation (0.3 [0.1-0.7]), and complete as opposed to partial colonoscopy (6.4 [0.8-48.3]). We conclude that Barrett's oesophagus is not an independent risk factor for colorectal neoplasia and, therefore, is not, in itself an indication for colorectal screening.

Background. Preoperative localization of gastrinomas by current imaging techniques such as computed tomography (CT) scan and angiography is still difficult because of the small size of tumor (s) in most patients undergoing operation. This study evaluated the diagnostic value of endoscopic ultrasonography. Methods. Twenty-two patients presenting with Zollinger-Ellison syndrome underwent exploratory laparotomy after preoperative attempts to identify the gastrinoma (s) by CT scan, upper gastrointestinal endoscopy, and endoscopic ultrasonography. Surgery included intraoperative ultrasonography and duodenal transillumination in all cases. The sensitivity and specificity of imaging techniques were then evaluated. Results. At least one tumor was found in 19 patients (four had two tumors and one had multiple tumors). Duodenal, lymph node, and pancreatic gastrinomas were found in 42%, 38%, and 17% of the patients, respectively. Sensitivity of endoscopic ultrasonography was 50% for duodenal wall tumors (conventional endoscopy, 40%), 75% for pancreatic tumors (CT scan, 25%), and 62.5% for tumoral lymph nodes (CT scan, 0%). The specificity of all techniques was excellent. Correct diagnosis was made by endoscopic ultrasonography alone in 41% of the patients. The combination of conventional endoscopy and endoscopic ultrasonography provided correct diagnosis in 60% of the patients. Conclusions. Endoscopic ultrasonography should be considered as a first-choice imaging technique for preoperative detection of gastrinomas. Although small duodenal gastrinomas are still obviously difficult to detect, an accurate exploration of the pancreatic area was provided by this technique.

In patients with the Zollinger-Ellison syndrome, which is either sporadic or integrated into multiple endocrine neoplasia type 1, accurate localization of all the tumours is difficult and may have therapeutic implications. In an attempt to improve this localization, somatostatin receptor scintigraphy using [111In-DTPA-D-Phe1]-octreotide was performed prospectively in 48 consecutive patients with the Zollinger-Ellison syndrome. Thirty of them had the sporadic type of this disease. Scintigraphic data were compared with data obtained by conventional imaging methods, and also, in 32 selected patients, with those obtained by endoscopic ultrasonography. Somatostatin receptor scintigraphy showed abnormal tracer uptake in 39 patients (81%), in whom it correctly identified 50 of the 60 tumoral sites (83%) previously localized by the other imaging methods. In 17 patients (35%) somatostatin receptor scintigraphy disclosed abnormal tracer uptake at 18 different tumoral sites: 14 were located in the abdomen, including four in the liver and eight in the duodenopancreatic area, and four outside the abdomen, including two in the mediastinum. Six of the ten tumoral sites which were not correctly identified by somatostatin receptor scintigraphy were located in the duodeno-pancreatic area. However, in the 20 patients for whom conventional techniques failed to visualize any tumour in the duodenopancreatic area, somatostatin receptor scintigraphy was positive in ten (50%) whereas endoscopic ultrasonography was only positive in five (25%). In our patients with the Zollinger-Ellison syndrome, somatostatin receptor scintigraphy appeared to be a useful new addition to the battery of tests used for tumour detection.

The authors report first on the current status of liver transplantation in France and underline its exponential development. The main indications for this procedure are outlined for adults as well as for children. The modalities of distribution of livers harvested by strictly controlled university teams are also briefly described. The specificities of French ethical attitudes towards liver transplantation are discussed. They concern the donor, the recipient and the society. Legal dispositions stipulating the presumed consent of the donor and accrediting the notion of "cerebral death" have eased the development of liver transplantation in France. Despite these measures shortage in liver available for grafts results in still too large waiting list and fosters nation-wide campaign to encourage organ donation. There is, in France, a strong consensus for a strict sticking to the absolute principles of gratuity of organ donation and non-marketing of excised organs available for graft. As stated recently by Thomas Starzl, liver transplantation has become the second most commonly performed solid organ transplant after kidney transplant. In the latin Europe, the idea of organ transplantation is in the mind of people for a long time as illustrated from paintings or carvings that can still be seen in several roman catholic churches of the Middle Age. Although, liver transplantation in man developed only after the pioneer work of Thomas Starzl in Pittsburg, it is fair to recall that Alexis Carrel (1908, Noble Prize), from France, opened the way to organ transplantation by performing in animals the first vascular sutures and organ auto- or homografts.(ABSTRACT TRUNCATED AT 250 WORDS)

This study reports the effects of 4 and 5-year treatment with octreotide (200 micrograms sc bid) in the Zollinger-Ellison syndrome (ZES). No symptoms related to acid hypersecretion were observed in the four patients throughout the study, and upper GI endoscopy was normal. Basal acid output (BAO) measured 12 h after injection, was below 10 mmol h-1 in three to four patients and previous ranitidine treatment was discontinued. In the fourth case (pretreatment BAO value: 115 mmol h-1), BAO progressively decreased to 42 mmol h-1 after 5 years of octreotide treatment. At the end of the study, serum gastrin levels were 58.5% (30-68) of the pretreatment values and two patients had normal gastrin levels. Peak acid output (PAO) decreased markedly after 2, 4 and 5 years, by 68% (35-89) suggesting that octreotide had exerted an antitrophic effect on parietal cell mass. Diffuse hyperplasia of fundic argyrophil cells present in two patients before octreotide, decreased during the treatment. Mean argyrophil cell density for all patients was not significantly modified. Antral gastrin-cell density was in the normal range. No long-term side effect of octreotide treatment was observed. Although octreotide may not be considered as a substitute for benzimidazoles in the treatment of ZES, its specific properties may be of therapeutic benefit in some ZES patients.

Summary The clinical evolution of type I multiple endocrine neoplasia (MEN I) was studied in 45 patients among a consecutive series of 172 with Zollinger-Ellison syndrome (ZES). These 172 patients were seen in our hospital between 1959 and 1989. Diarrhea was half as frequent in ZES-MEN I as in sporadic ZES cases. At diagnosis, mean basal acid output and serum gastrin levels in MEN I patients (28.8 ± 6.6 mmoVh and 587 ± 487 pg/ml, respectively) were not different from those observed in the others with sporadic ZES. Laparotomy was performed in all 36 patients with no diffuse liver involvement to attempt the removal of gastrinomas. Twenty-nine patients had adenomas, located in the pancreas in 21, in the duodenal wall in 3, and in both in 5. Adenomas were multiple in 23 cases (78%). No tumor was found in seven patients. Twenty-nine of the 36 operated patients were tumor-free after surgery; 7 died in the postoperative period between 1959 and 1970. Median follow-up of the 38 other patients was 95 months (range 17–278 months). Among the 24 patients without residual tumor at discharge (group I), biological and or morphological evidence of a persistent or recurrent source of gastrin was obtained in 22. Among the 14 patients with residual tumor (group II), an increase in tumor size was seen in 5 after a median of 27 months (range 9–36 months), while no change occurred in 9 after 54 months (3-100 months). Actuarial survival curves were not different, either in group I versus group I1 patients (67 and 72% at 5-year follow-up, respectively) or in MEN I versus sporadic ZES patients. Apparently, complete resection of primary tumor did not reduce the incidence of subsequent liver metastases. In all, 21 of the 45 patients had malignant gastrinomas (47%), consisting of liver metastases in 14 (31%), metastatic lymph nodes in 11 (24%), and lung metastases in 2 (4%). Monitoring of fundic argyrophil cells disclosed hyperplasia in 13 of the 14 MEN I patients (92%), and 5 had invasive carcinoid tumors. Taken together, these results prompt us to recommend that in ZES-MEN I patients, surgery should be avoided and oxyntic mucosa regularly monitored.

Gastrin and pancreastatin-like immunoreactivity were determined by radioimmunoassay methods and chromogranin A was determined by enzyme-linked immunoassay in sera from 18 patients with gastrinomas (Zollinger-Ellison syndrome) and in 20 age and sex matched controls. Gastrin serum levels in the gastrinoma patients were in the range 26-80,000 pmol/l, and in the controls 5-31 pmol/l. Chromogranin A serum levels in the gastrinoma group were in the range 6-2,700 ng/ml (mean +/- SEM: 400 +/- 147 ng/ml). The mean value of chromogranin A was significantly higher than in the control group (8 +/- 2 ng/ml, p = 0.008). The serum levels of pancreastatin-like immunoreactivity in the gastrinoma patients were in the range 23-1,994 pg/ml (597 +/- 123 pg/ml). The mean value of pancreastatin-like immunoreactivity in the gastrinoma group was significantly higher than in the control group (104 +/- 25 pg/ml, p = 0.0002). The levels of chromogranin A and pancreastatin-like immunoreactivity were significantly higher in patients with verified metastatic disease (p = 0.04, p = 0.01 respectively). There was a significantly positive correlation between levels of gastrin and pancreastatin-like immunoreactivity (r = 0.7, p = 0.002), while no correlation was found between gastrin and chromogranin A levels or between levels of chromogranin A and pancreastatin-like immunoreactivity. The study demonstrates an elevation of both chromogranin A and pancreastatin-like immunoreactivity in serum of gastrinoma patients. The lack of correlation between gastrin and chromogranin A, however, gives an indication that the gastrinoma cells are not the main source of serum chromogranin A elevation.

Platelet-activating factor (PAF) has been implicated in the pathogenesis of acute inflammatory and ulcerative diseases of the upper gastrointestinal tract. In the present study, we compared the gastric output of PAF and its precursors with gastric acid output, in patients with various upper gastrointestinal tract diseases and healthy controls. PAF and precursors were also extracted from gastric biopsies from subjects with chronic gastritis and/or gastric colonization by Helicobacter pylori. Under basal conditions, hourly gastric PAF output increased in esophagitis and erosive gastritis, but not in duodenal ulcer or Zollinger-Ellison syndrome. In the gastric juice of duodenal ulcer patients, PAF output rose after secretin, but in patients with Zollinger-Ellison syndrome, PAF was only detected when gastric acid secretion had been reduced by antisecretory drugs and no concurrent changes were observed in serum gastrin levels. After pentagastrin, patients and controls exhibited a significant decrease in PAF output and a negative correlation was found between PAF and acid outputs (r = -0.57, p0.01). When PAF was incubated with gastric juice in vitro, it underwent degradation irrespective of the medium pH. We found no relation between the outputs of PAF and precursors and the severity of gastritis or gastric colonization by H. pylori. Overall, these results suggest that PAF might be released in the stomach by gastric epithelial cells and could be responsible for mucosal injury of the upper gastrointestinal tract.

The biologic gastrin activity in serum from 14 patients with the Zollinger-Ellison syndrome was assessed by the stimulation of histamine release and acid secretion from the isolated vascularly perfused rat stomach and compared with the immunologic activity as determined by radioimmunoassay using an antibody directed towards the active site of the gastrin molecule. Biologic gastrin activity assessed by the stimulation of histamine release was more closely correlated to immunologic gastrin activity than biologic activity assessed by the stimulation of gastrin acid secretion. This study does not contradict the concept that gastrin stimulates acid secretion at least partly by releasing histamine and also shows that the immunologic gastrin activity determined with the help of an antibody directed towards the active site reflects biologic activity.

Mil neuf cent cinquante-cinq, annee essentielle pour l’endocrinologie digestive, alors naissante. C’est en effet a cette date que deux auteurs americains, Robert M. Zollinger et Edwin H. Ellison [1], tous deux chirurgiens et physiologistes digestifs a l’Universite de Colombus, etat de l’Ohio, decrivent deux cas d’une maladie ulcereuse severe duodeno-jejunale avec hypersecretion gastrique caricaturale et rebelle a toutes les actions therapeutiques iteratives entreprises : medicales (mais on ne disposait que d’atropiniques a l’epoque !) comme chirurgicales (toutes, helas, partielles de la gastrectomie des 2/3 a la vagotomie) sauf, en tout dernier, avec le recours a une gastrectomie totale dont le second patient, heureusement, beneficie ! ; cette ese ereuse severe etait associee dans les deux cas a une tumeur du pancreas endocrine a cellules non-s, c’est-a-dire non insulino-secretantes mais elaborant une substance gastro-secretagogue, comme Zollinger et Ellison le proposerent des 1955.

We report the case of a 45-yr-old white man, investigated for chronic diarrhea, malabsorption and weight loss associated with sicca syndrome. Endoscopic and x-ray examinations showed normal macroscopic mucosa in gastrointestinal tract (GIT). Immunohistochemistry showed diffuse polyclonal T cell lymphocytes infiltrating either epithelium and lamina propria in GIT. There was no villous atrophy in the jejunum and ileum. Corticosteroids, azathioprine, and cyclosporine failed to improve symptoms. Monthly intravenous cyclophosphamide administered over 1 yr, stopped the diarrhea and weight loss. The patient is free of symptoms up to a 5-yr follow-up.

Summary Appropriate indication for upper gastrointestinal endoscopy (UGE) may be facilitated by referring to qualifying criteria such as those devised by the European Panel (EPAGE) and French Experts (ANAES). This prospective study evaluates the applicability and efficacy of these criteria in clinical practice. Patients and methods A total of 522 patients was included (55% inpatients, 57% male, mean age 55 years). Appropriateness of referral was evaluated using EPAGE and ANAES criteria sets by a single independent expert. Results EPAGE criteria were applicable in 71% of cases. Indications for UGE were appropriate, inappropriate and uncertain in 62%, 27% and 11% respectively; 74%, 16% and 10% of clinically significant lesions detected by UGE were disclosed in patients having appropriate, inappropriate and uncertain indications respectively. ANAES criteria were applicable in 81% of cases. Indications for UGE were appropriate in 74%, inappropriate in 26%; 76% and 24% of clinically significant lesions detected by UGE were disclosed in patients having appropriate and inappropriate indications respectively. Whatever the criteria set used, all cancers and most of the severe lesions were observed in patients with appropriate indications: those patients were more often in-patients and were significantly older than patients belonging to the inappropriate group. Conclusion Reference to EPAGE and ANAES qualifying criteria facilitates patient selection for UGE. Final decision must however rely upon practitioner advice. ANAES criteria are significantly more often applicable than EPAGE ones. However EPAGE referential when applicable is more predictive of the UGE findings.

We report the case of an 18-year-old man, with no previous medical history, presenting with recurrent hemorrhagic duodenal ulcers revealing a Zollinger-Ellison syndrome. The initial diagnosis of sporadic gastrinoma of the antrum associated with satellite lymph nodes led to surgical treatment. The evolution of clinical and secretory tests associated with the outbreak of a primary hyperparathyroïdism demonstrated that the patient had a type I multiple endocrine neoplasia. To our knowledge, this is the first described case of primitive gastrinoma of the antrum occurring in a type I multiple endocrine neoplasia.

Therapeutic options in patients with advanced-stage gastroenteropancreatic (GEP) neuroendocrine tumors are limited. We compared the efficacy of radionuclide therapy with 111In-pentetreotide and 131I-metaiodobenzylguanidine (MIBG) in 20 patients (group A) with the outcome of similar patients who could not be treated for nonmedical reasons (group B, n = 12). The intent was to treat all patients because of uncontrolled tumor disease (n = 21), contraindication to chemotherapy or surgery (n = 7), or uncontrolled and badly tolerated clinical symptoms (n = 4).Group A patients received 3 monthly administrations of 3.7-7.4 GBq of 131I-MIBG (n = 5) or 7 GBq of 111In-pentetreotide (n = 15), according to the best tracer uptake. Clinical evaluation, biologic tests, and conventional imaging were performed at 3, 6, 12, 18, and 24 mo. Therapy was considered beneficial if clinical status improved, laboratory tests for secreting tumors improved by20%, tumor progression was halted, the size of the most significant localization had decreased by25%, and the dosage of analgesic and cold somatostatin therapy could be lowered. Pejorative events were defined as side effects due to therapy, relapse in clinical symptoms, tumor progression, tumor laboratory marker increase, and death.The overall survival rate at 3 mo was significantly higher in group A (P = 0.05). Radionuclide therapy was beneficial in 14 patients (73% of group A), with only 1 significant side effect. The average time before relapse was 16.1 +/- 7.8 mo. The overall Kaplan-Meier survival rate and cumulative progression-free and cumulative event-free survival rates during the first 15 mo were significantly higher in patients receiving radionuclide therapy (P = 0.019, P = 0.024, and P = 0.019, respectively).Radionuclide therapy is feasible and safe and significantly defers the occurrence of fatal and nonfatal events in patients clinically uncontrolled by conventional therapy.

About 25% of patients with ZES have MEN 1. Except diarrhoea, less frequent in patients with ZES-MEN 1 than in sporadic ZES, and specific MEN 1-related signs, clinical characteristics are similar in both ZES types. Acid output and gastrin levels are also similar whether in the basal state or after secretin stimulation. Primary hyperparathyroidism (PHPT) exists in the majority of ZES-MEN 1 patients, 30% have pituitary adenoma (prolactinomas for half), 30% adrenal involvement, 25 to 30% have EC-Lomas; bronchial and thymic carcinoids have probably been underevaluated. Gastrinomas are multiple predominantly located in the duodenal wall, but also in the pancreas in association with clinically silent endocrine tumors. The spread of the disease: metastases to the liver (LM), mediastinum, bones, is evaluated at best by Octreoscan. Endoscopic ultrasonography evaluates the number, size and anatomical characteristics of gastrinomas. Patients without LM have an excellent prognosis. Surgery never cures ZES, but is necessary in case of associated life-threatening condition such as insulinoma and has been advocated to prevent LM development in patients with large pancreatic tumor(s). However although, indeed, the size of the tumor, when located in the pancreas3 cm, favours metachronous LM occurrence, surgery, in our experience, has not been able to prevent LM development. Hepatic malignancies remain however the most pejorative prognostic determinant for survival and raise the most difficult therapeutic challenge. Surgery is the best option whenever feasible; specific chemotherapy and chemo-embolisation have not conclusively achieved definite successes. Long-term octreotide treatment, however, has been shown recently to obtain tumour stabilisation. Internal irradiation with 90 Ytrium-labelled octreotide is a new promising option, presently under evaluation (Novartis European trial). Preliminary results are promising.

The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, 99mTc-P829, compared with that of 111In-pentetreotide.Forty-three patients (32 men, 11 women; age range, 24-78 y; mean age, 56 y) with biologically or histologically proven neuroendocrine tumors were prospectively included: 11 patients with Zollinger-Ellison syndrome, 16 patients with carcinoid tumors, and 16 patients with other types of functioning (n = 6) or nonfunctioning (n = 10) endocrine tumors. 111In-Pentetreotide planar images (head, chest, abdomen, and pelvis) were obtained 4 and 24 h after injection of 10 microg somatostatin analog labeled with 148 +/- 17 MBq 111In, and SPECT was performed 24 h after injection. Similar (99m)Tc-P829 planar images were obtained at 1, 4-6, and 24 h after injection of 50 microg peptide labeled with 991.6 +/- 187.59 MBq 99mTc. Abdominal SPECT was performed 4-6 h after injection.111In-Pentetreotide detected 203 tumoral sites in 39 (91%) of 43 patients, whereas 99mTc-P829 detected 77 sites in 28 (65%) of 43 patients (P0.005). In the liver, 129 sites (in 24 patients) were detected by 111In-pentetreotide scintigraphy and 34 sites (in 10 patients) were detected by 99mTc-P829 scintigraphy.In patients with endocrine tumors, the detection rate of 99mTc-P829 scintigraphy was lower than that of 111In-pentetreotide scintigraphy, which appeared to be more sensitive, especially for liver metastases.

In this open prospective study, the efficacy of pantoprazole in reducing gastric acid secretion in Zollinger-Ellison syndrome patients was compared to that obtained previously with other proton pump inhibitors.Eleven male patients previously treated with omeprazole (n=7, mean dosage: 63 mg/day; range: 20-100 mg/day) or lansoprazole (n=4, mean dosage: 75 mg/day; range: 30-120 mg/day) were included. These patients underwent a 24-hour intragastric pH-metry, measurement of basal acid output and of serum gastrin first while receiving their usual therapy and second after 7 to 10 days of pantoprazole treatment at a mean dosage of 116 mg/day (range: 40-200 mg/day). Basal acid output was evaluated after each intragastric pH-metry, one hour before the next intake of proton pump inhibitor and a serum gastrin curve was determined according to 9 fixed time points.One patient dropped out before the second intragastric pH-metry due to an adverse event (varicella) unrelated to pantoprazole and was reinvestigated thereafter. The median 24-h intragastric pH with pantoprazole was not significantly different than that with the other proton pump inhibitors (5.3 versus 4.6, respectively; P=0.90). Neither the median basal acid output values nor the median serum gastrin levels were significantly different between pantoprazole and the other proton pump inhibitors.In these patients with the Zollinger-Ellison syndrome, pantoprazole was well tolerated and equally effective to the other proton pump inhibitors in terms of antisecretory potency.

PURPOSE: Thrombosed external hemorrhoids and anal fissures are common and are responsible for severe discomfort during childbirth. However, the real incidence of these lesions is unknown. The aim of our study was to evaluate their incidence and the risk factors for these lesions during childbirth. METHODS: A prospective study with proctologic examination during the last 3 months of pregnancy and after delivery (within 2 months) was performed in 165 consecutive pregnant females. RESULTS: Fifteen females (9.1 percent) with anal lesions (13 thrombosed external hemorrhoids and 2 anal fissures) were observed during pregnancy. Fifty-eight females (35.2 percent) with anal lesions (33 thrombosed external hemorrhoids and 25 anal fissures) were observed during the postpartum period. Ninety-one percent of thrombosed external hemorrhoids were observed during the first day after delivery, whereas anal fissures were distributed, with no peak, over the two months after delivery. The 2 independent risk factors for anal lesions (among obstetric, baby’s, and mother’s information) were dyschezia, with a 5.7 odds ratio (95 percent confidence interval, 2.7–12), and late delivery, with a 1.4 odds ratio (95 percent confidence interval, 1.05–1.9). Furthermore, many thrombosed external hemorrhoids were observed after superficial perineal tears and heavier babies (P < 0.05). Only 1 of the 33 patients with thrombosed external hemorrhoids who were observed underwent a cesarean section. CONCLUSION: One third of females have thrombosed external hemorrhoids or anal fissures in the postpartum period. The most important risk factor is dyschezia. Traumatic delivery appears to be associated with thrombosed external hemorrhoids.

Helicobacter pylori may increase or inhibit gastric acid. We studied acid variations and plasma gastrin in cats harboring Helicobacter felis, harboring H. pylori, or free of gastric pathogens with reference to thioperamide (H3receptor antagonist) and SR-27417A (PAF receptor antagonist). In cats harboring H. felis, gastric mucosa were histologically normal. After H. feliseradication, pentagastrin-stimulated acid secretion was increased (40%) compared with the situation before eradication. Thioperamide abolished this inhibitory effect of H. felis, whereas SR-27417A did not. Basal and meal-stimulated plasma gastrin levels were not affected by eradication therapy. Acid secretion was inhibited (−80%) in week 3, increased from weeks 5 to 9, and remained constant for up to 42 weeks after H. pylori infection. SR-27417A had no effect on acid secretion before week 8 but inhibited it thereafter, and thioperamide increased it (20%) only before week 7 in those cats. Helicobacter inhibits gastric acid via an H3receptor pathway. Inflammatory mediators are thus involved in adaptation to the inhibitory effects of H. pylori on acid secretion.

In 1998 and 1999, a delphi consensus procedure was performed to establish guidelines for standardised diagnostic imaging of neuroendocrine tumours. The procedure included four consecutive workshops of a European group of experts in neuroendocrine tumours as well as feedback given by specialists from the departments of radiology, nuclear medicine, surgery and internal medicine of the according home institutions. Diverging approaches among the centres, which became apparent during the discussion, reflect a lack of controlled studies specifically for rare subgroups of neuroendocrine tumours. This paper summarises the standards for diagnostic imaging as developed during the delphi process. In particular, the diagnostic workflows as well as the technical properties of different imaging modalities are described in detail.

Neuroendocrine enteropancreatic tumors (NEEPTs) include tumors developing from the pancreatic islets and the duodenal loop, and those developing from gut serotonin-secreting cells (mid-gut carcinoids). When functioning, they are rare tumors with frequently inconsistant clinical and biological characteristics. Provocative dynamic tests are very useful. Their natural history, with the exception of insulinomas and mid-gut carcinoids, is still incompletely known due to their rarity, relatively recent description, slow evolution and the absence of definitive reliable markers for prognosis. The following factors affect the natural history of NEEPTs. (1) Inclusion or not within the spectrum of multiple endocrine neoplasia type-1 (MEN1), such an integration often dramatically modifies the management strategy. In patients with MEN1, NEEPTs are often multiple, diffusely spread in the duodenopancreatic area and of small size. Definite cure by surgery is then very scarce. Mid-gut carcinoid tumors are the most protean NEEPTs. In contrast to appendiceal carcinoids, usually with a benign course, mid-gut carcinoids have a more malignant course and are very common indeed: local transmural invasion, early metastasis to lymph nodes and/or liver, and symptoms from hormone oversecretion. Carcinoid syndrome is usually well controlled by long-acting somatostatin analogs. (2) Disease spreading, i.e. liver and bone metastases, are the major causes of death in patients with NEEPTs. Liver metastases (LMs) are synchronous in about 75% of the patients with LMs but may develop during follow-up (about 25% of the patients with LMs were without LMs at the initial evaluation). Development of bone metastases has a very poor prognosis accompanying LM progression.

PURPOSE: Anal incontinence affects approximately 10 percent of adult females. Damage to the anal sphincters has been considered as the cause of anal incontinence after childbirth in the sole prospective study so far available. The aims of the present study were to determine prospectively the incidence of anal incontinence and anal sphincter damage after childbirth and their relationship with obstetric parameters. METHODS: We studied 259 consecutive females six weeks before and eight weeks after delivery. They were asked to fill in a questionnaire assessing fecal incontinence. Anal endosonography (7–10 MHz) was then performed. Two independent observers analyzed internal and external anal sphincters. RESULTS: A total of 233 patients (90 percent) were assessed, of whom 31 had cesarean section.De novo sphincter defects were observed in 16.7 percent (14 percent external, 1.7 percent internal, and 1 percent both) in the postpartum period only after vaginal delivery. These disruptions occurred with the same incidence after the first and the second childbirth. Independent risk factors (odds ratio; 95 percent confidence interval) for sphincter defect were forceps (12; 4–20), perineal tears (16; 9–25), episiotomy (6.6; 5–17), and parity (8.8; 4–19) as revealed by multivariate analyses. The overall rate of anal incontinence was 9 percent and independent risk factors (odds ratio; 95 percent confidence interval) involved forceps (4.5; 1.5–13), perineal tears (3.9; 1.4–10.9), sphincter defect (5.5; 5–15), and prolonged labor (3.4; 1–11). Among these patients only 45 percent had sphincter defects. CONCLUSION: Anal incontinence after delivery is multifactorial, and anal sphincter defects account for only 45 percent of them. Primiparous and secundiparous patients have the same risk factors for sphincter disruption and anal incontinence. Because external anal sphincter disruptions are more frequent than internal anal sphincter damage, surgical repair should be discussed in symptomatic patients.

PURPOSE: The case of a human immunodeficiency viruspositive patient with rectal stenosis caused by a tumor that completely regressed in response to gancyclovir is presented. METHODS: Several biopsies from the tumoral mass failed to show any stigmata of non-Hodgkin's lymphoma, adenocarcinoma, or Kaposi sarcoma. No parasites could be detected in rectal biopsies. Viral inclusions showing both Epstein-Barr virus and cytomegalovirus on immunostained sections suggested an unusual form of viral infection. RESULTS: Antiviral therapy (gancyclovir 10 mg/kg/day) had a dramatic effect on pain and discharge of blood, and suppressed rectal difficulties within three days of therapy. The antiviral treatment was stopped at Day 10 because of leukopenia. Endoscopic and histologic examinations revealed normal rectal mucosa after 3, 6, 9, 12, and 18 months of follow-up. CONCLUSION: This is the first case of complete and long-term regression of a rectal stenosis secondary to a tumoral mass in response to antiviral therapy in patients with human immunodeficiency virus.

In 1996 a consensus workshop on the preoperative diagnosis and surgical treatment of neuroendocrine tumor disease took place in Berlin. Although there was a consensus on the diagnosis and surgical treatment by world experts in neuroendocrine surgery in some areas, it became clear that certain management policies vary among centers. In large part, diverging policies reflect a lack of controlled studies. This paper summarizes the various opinions brought forward during this conference and emphasizes consensus approaches for the diagnosis and therapy of neuroendocrine neoplasms.

Barry J. Marshall, Australien, est ne le 30 septembre 1951 a Kalgoorlie (Western Australia ). Medecin, chef de clinique en gastroenterology au Royal Perth Hospital de 1977 a 1984, il accede par la suite a la chaire de medecine interne en 1997, puis devient Professeur de microbiologie en 1999 a l’University of Western Australia . Il recoit en 1995 le Prix Albert Lasker et en 1999, a Philadelphie, la Benjamin Franklin Medal for Life Sciences .J. Robin Warren, Australien, est ne le 11 juin 1937 a Adelaide (South Australia ). Medecin, chef de clinique, en hematologie en 1962 a l’Institute of Medical Science d’Adelaide puis en anatomopathologie en 1964 au Royal Melbourne Hospital , il est laureat (conjointement avec Barry J. Marshall) des Prix Warren Alpert (1994) et Paul Ehrlich (1997).

BACKGROUND Peritoneal carcinomatosis (PC) in patients with digestive endocrine tumors (DET) is considered rare but its prevalence is unknown. The objectives of this study were to assess the prevalence and prognostic implications of PC in patients with various types of DET. METHODS One hundred and sixteen consecutive patients with DET seen over a 3-year period were studied. Fifty-nine had gastrinomas, 30 had carcinoid tumors, and 27 had other types of endocrine tumors, mainly nonfunctioning ones. Diagnosis of PC was based on clinical symptoms (ascites and Konig's syndrome), findings of computed tomography scans that were performed at least yearly, and pathologic confirmation of tumor nodules or positive cytology in the peritoneal fluid. Factors associated with PC were investigated and the influence of PC on patients' survival was assessed. RESULTS PC was found in 11 patients (overall PC prevalence: 10%; with 27% in patients with carcinoid tumors, 11% in those with nongastrinoma pancreatic endocrine tumors, and 0% in patients with gastrinomas). Nine of 11 patients with PC also had liver metastases. PC was metachronous to detection of the primary tumor in 7 of 11 patients, occurring 54 months (range, 23–273 months) after the diagnosis. In addition to the nature of the primary tumor, a greatest dimension of more than 5 cm was associated with the presence of PC in two of three patients with pancreatic endocrine tumors. In patients with carcinoid tumors, an ileal primary tumor occurred more frequently in patients with PC (87.5%) than in those without PC (50%). Prevalence of liver and other metastases was not significantly increased in patients with PC. Although five patients died of their disease, no deaths were related to PC. Actuarial survival rates at 5 years were 64% and 84% in patients with and without PC, respectively (P = not significant), whereas they were 73% and 93% in patients with and without liver metastases, respectively (P < 0.02). CONCLUSIONS PC is not a rare event in the course of DET, especially in patients with carcinoid tumors. It did not occur in the patient population with gastrinomas, which are less often malignant but may also differ from the other types of DET by several cell characteristics. In contrast to liver metastases, PC is not associated with a significant decrease in life expectancy. Cancer 1996;78:1686-92.

In an open phase III study, octastatin was given as a continuous subcutaneous (s.c.) infusion to 35 patients (mean age 62 years) with malignant neuroendocrine gastro-intestinal tumours and the carcinoid syndrome. The wash-out was often incomplete because of the advanced stage of disease. The starting dose of 1.5 mg/24 h was increased up to 3.0 mg/24 h at 3 months in some patients. The carcinoid syndrome disappeared in 20% of patients at 3 months and in 23% at 6 months, with 43 and 45% of patients, respectively, experiencing an improvement. The mean Karnovsky index increased by10% in 40% of patients at 3 and 6 months. Urinary 5-hydroxyindoleacetic acid (U-5-HIAA) levels at 3 months normalised in 1 patient, fell in 20% (by50%; p = 0.0021) and stabilised in 66%. The respective values at 6 months were 1, 17% (p = 0.023) and 60%. There was also a significant decrease in plasma chromogranin levels at 3 months (p = 0.042), which did not persist at 6 months. Tumour size fell (by50%) in 1 patient by 6 months but this patient had undergone chemoembolisation one month prior to the start of the study. Most patients had tumour size stabilisation (76 and 68%) or progression (20 and 24%) at 3 and 6 months, respectively. Dose escalation from 1.5 to 3.0 mg did not significantly improve clinical, biochemical or tumour responses. The treatment was well tolerated with minor adverse events. In an open pilot phase II study of 19 patients (mean age 58 years), patients were given high dose somatuline with a maintenance dose of 12,000 mg/day in 4 divided s.c. injections. U-5-HIAA, which was elevated in 13 patients with a mean of 444 mumol/day before the start, was reduced to 58% of baseline at 3 months, 68% at 6 months (p = 0.04), 66% at 9 months and 75% at 12 months (p = 0.14). P-chromogranin was elevated in 18 patients, with a mean of 5,300 micrograms/l before the start, and was reduced to 52, 55, 63 and 64% of the baseline at 3, 6 (p = 0.039), 9 and 12 (p = 0.013) months, respectively. In the responding patients, apoptosis was induced.

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors occur almost exclusively in the small subgroup of patients who also have multiple endocrine neoplasia type 1. In these patients, tumor development seems related to the same genetic alterations as those observed in other endocrine tumors related to multiple endocrine neoplasia type 1. We report here the second detailed case of a patient with sporadic Zollinger-Ellison syndrome who developed an argyrophil carcinoid tumor in nonatrophic fundic mucosa, suggesting that chronic hypergastrinemia may lead to fundic carcinoid development in non-genetically predisposed patients.

Inflammatory pseudotumors (IPT) of the liver are rare benign tumors of unknown origin. Most previously reported cases were initially misdiagnosed and treated surgically; thus, their course under medical treatment remains unclear. We report an additional case of hepatic IPT with a favorable outcome under medical treatment without surgical resection. New imaging and pathologic features of this disease are presented that may facilitate preoperative recognition and appropriate treatment.

Pouchitis is an increasing drawback to patients who undergo ileal pouch-anal anastomosis for ulcerative colitis; complication overshadows the overall good functional results of this sphincter-saving operation. There is a need for cooperative, multicenter, and longitudinal studies of patients undergoing ileal pouch-anal anastomosis, to unravel the etiology and pathophysiology of pouchitis. Because of the absence of a mucosal inflammation before pouch construction, patients operated on for familial adenomatous polyposis are the perfect control group. Thus, it may be possible to elucidate and define the sequence that leads to pouchitis, including overgrowth of a colonic type flora, transformation of the histology to an epithelium with colonic features, an altered biochemical milieu in the lumen (volatile fatty acids, secondary bile acids), and changes in mucosal defense mechanisms.

Fifteen patients with unresectable liver metastases of endocrine tumors (nine carcinoid tumors and six gastrinomas) were treated with an intraarterial emulsion of iodized oil and adriamycin followed by gelatin sponge particles. Therapeutic efficacy was evaluated in terms of hormone levels and tumor size as measured with computed tomography. Six patients showed a reduction in tumor size, and 4 a response in tumor marker levels. All these metastases were derived from primary carcinoid. All cancer-related syndromes disappeared. There were two major complications. The response in these 6 patients lasted from 2 to 39 months. Metastasis from primary gastrinomas did not respond to CE. These results indicate that chemoembolization is useful palliative therapy for patients with hormone-secreting tumors of the liver, particularly in carcinoids

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors have been described only in the small genetically defined subgroup of patients who have the multiple endocrine neoplasia type 1 syndrome (MEN-1). Allelic losses on 11q13, on which MEN-1 gene has been localized, have been noted in parathyroid and pancreatic tumors of patients with MEN-1, suggesting that the MEN-1 gene could act as a recessive tumor suppressor gene. One fundic argyrophil carcinoid tumor from a patient with the Zollinger-Ellison syndrome and MEN-1 was studied. Loss of heterozygosity in the tumor DNA at loci close to MEN-1 locus was looked for using Southern technique with six DNA probes. Segregation of alleles was examined in relatives. In the tumor DNA, we found the loss of one allele with PYGM, the closest probe to the MEN-1 locus. The allele lost in the tumor had been transmitted by the unaffected parent. This suggests that in patients with the Zollinger-Ellison syndrome and MEN-1, the promotion of fundic argyrophil carcinoid tumors results from the inactivation of the two copies of MEN-1 gene and that fundic argyrophil carcinoid tumors may be included in the spectrum of MEN-1-related tumors.

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (ror = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

The difficult and controversial diagnostic and therapeutic management of patients having gastrinoma or insulinoma with multiple endocrine neoplasia type I (MEN-I) has been discussed by reference to the literature and a personal series of 45 gastrinoma/MEN-I patients followed consecutively at Bichat Hospital. In both gastrinoma/ and insulinoma/MEN-I patients, anatomic distribution and morphology of tumoral process(es) are usually multiple, diffuse, of small size, and associated with endocrine cell hyperplasia and even nesidioblastosis. These features enhance the difficulty of tumor localization and eradication. Despite the dramatic development of modern medical imagery and surgical experience, the real possibility, on a long-term basis, of curing the patients from their disease remains limited, especially in the gastrinoma/MEN-I patients. In the latter group, according to our experience, persistence or recurrence of the disease after surgery is usual, and metachronous hepatic metastasis development is frequently observed when the follow-up is long enough. Patients with liver metastases, however, seem to undergo a more indolent course than sporadic gastrinoma cases. In insulinoma/MEN-I patients, removal of the functionally dominant islet cell area(s) is essential. Various preoperative and intraoperative localization techniques allow efficacious selective pancreatic surgery in many cases. The latter refinements and the promises of long-acting somatostatin analogs, if confirmed, might restrict to exceptional circumstances the indication of near-total or total pancreatectomy.