Philippe Pages

sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1). Evidence for the role of SHP-1.

Activation of the somatostatin receptor sst2 inhibits cell proliferation by a mechanism involving the stimulation of the protein-tyrosine phosphatase SHP-1. The cell cycle regulatory events leading to sst2-mediated growth arrest are not known. Here, we report that treatment of Chinese hamster ovary cells expressing sst2 with the somatostatin analogue, RC-160, led to G1cell cycle arrest and inhibition of insulin-induced S-phase entry through induction of the cyclin-dependent kinase inhibitor p27 Kip1 . Consequently, a decrease of p27 Kip1 -cdk2 association, an inhibition of insulin-induced cyclin E-cdk2 kinase activity, and an accumulation of hypophosphorylated retinoblastoma gene product (Rb) were observed. However, RC-160 had no effect on the p21 Waf1/Cip1 . When sst2 was coexpressed with a catalytically inactive mutant SHP-1 in Chinese hamster ovary cells, mutant SHP-1 induced entry into cell cycle and down-regulation of p27 Kip1 and prevented modulation by insulin and RC-160 of p27 Kip1 expression, p27 Kip1 -cdk2 association, cyclin E-cdk2 kinase activity, and the phosphorylation state of Rb. In mouse pancreatic acini, RC-160 reverted down-regulation of p27 Kip1 induced by a mitogen, and this effect did not occur in acini from viable motheaten (me v /me v) mice expressing a mutant SHP-1 with markedly deficient enzymes. These findings provide the first evidence that sst2 induces cell cycle arrest through the up-regulation of p27 Kip1 and demonstrate that SHP-1 is required for maintaining high inhibitory levels of p27 Kip1 and is a critical target of the insulin, and somatostatin signaling cascade, leading to the modulation of p27 Kip1 .

Role of EUS in the management of pancreatic and ampullary carcinoma: a prospective study assessing resectability and prognosis☆☆☆

BACKGROUND Endoscopic ultrasonography (EUS) is highly accurate for the staging of tumors, but its role in the management of periampullary carcinoma is still being defined. METHODS Seventy-nine patients with pancreatic (n = 73) or ampullary (n = 6) carcinoma underwent prospective evaluation by means of assessment of resectability and survival according to the following three-step staging algorithm: (1) ultrasonography and computed tomography; (2) if tumor appears resectable, EUS; (3) if criteria of resectability are found at EUS, laparotomy for curative resection. RESULTS The first step of the algorithm helped predict unresectability of tumors and need for palliative treatment for 36 patients. Among the other 43 patients EUS revealed signs of unresectability in 20 additional patients who then underwent palliative surgical or medical treatment (median survival time 7 to 8 months). Twenty-three carcinomas were considered resectable according to EUS findings: Palliative surgery was performed in 9 cases (survival time 6 months), and 14 tumors could be resected in a curative way with a median survival period of 15 (pancreatic) to 16 months (ampullary). In evaluation of resectability, EUS had a 50% sensitivity (positive examination), 100% specificity, 100% positive predictive value, 61% negative predictive value, and 72% accuracy. CONCLUSIONS EUS is accurate for evaluating resectability of ampullary and pancreatic cancer. EUS staging can prevent unnecessary surgery, and the findings correlate well with prognosis. The management of ampullary and pancreatic cancer could be improved with EUS.

Annexin 1 is secreted in situ during ulcerative colitis in humans.

Although annexin l exerts extracellular anti-inflammatory properties, little is known about its release in inflammatory diseases. Here, we characterized annexin 1 secretion in ulcerative colitis (UC) patients. Annexin 1 was detected by immunoblotting, in tissue homogenates and supernatants of colonic biopsies incubated in culture media, and in luminal colonic perfusates of UC patients. Annexin 1 was released by inflamed colonic biopsies from patients having severe UC but not by biopsies from healthy colon of the same patient or by biopsies from non-UC patients or from patients with slight or moderate UC. Annexin 1 was detected in luminal colonic perfusates of patients having moderate or slight UC but not in perfusates from control patients. The level of annexin 1 expression and secretion was unrelated to long-term glucocorticoid treatment, but annexin 1 secretion in perfusates was induced, in some patients, by short-term glucocorticoid exposure. These results show that annexin 1 is secreted endogenously in the colon of patients with UC. This secretion, which occurs both in vitro and in vivo, depends on the severity of inflammation. Given the anti-inflammatory effects of annexin 1, this protein may serve to down-regulate the inflammatory response in the course of inflammatory bowel disease.

7031 Clinical impact of upper and lower enteroscopy.

Aim: To assess the clinical benefit of gastrointestinal tract enteroscopy. Methods: Between august 98 and october 99, 28 patients (16 men, 12 women), mean age: 51.5 (20-81 years) were admitted for upper and lower enteroscopy. In these 28 patients, indications were the followings: Iron deficiency anemia (n=20, mean rate of hemoglobina: 6.6 g/dl (4-11)) with (n=8; hematemesis n=1, melena n=7) or without macroscopic haemorrhages (n=12), abdominal pain (n=8). Results: Upper enteroscopy was performed in 25/28 patients (89%) and considered as sufficient by operator in 23 cases (92%). Twenty patients underwent lower enteroscopy (71.4%): satisfactory progression in 13 patients (65%), incomplete in 4 (20%) and no progression beyond caecum due to an irreducible loop in 3 cases (15%). Enteroscopy was normal in 15 cases (53.6%). In the 13 remaining patients (46.4%), findings were: angiomatous lesions (n=5: jejunal (n=2), colonic (n=3)), malignant tumours (n=2: jejunal adenocarcinomas including a HNPCC syndrom), jejunal benign tumours (n=2: moderate dysplasiaadenomas including one patient with Gardner syndrom), ulcerative gastric lesion (n=3: fundus ulcer (n=2), antral erosion (n=1)) missed by gastrocopy, intestinal lipomatosis (n=1). Lesions were diagnosed in 4/8 (50%) and 9/12 (75%) patients who had respectively anemia with or without macroscopic haemorrhages. Enteroscopy showed lesion strictly limited to the small intestine only in 6 cases (21.4%). A treatment was performed in 9 cases (32.1%): jejunal carcinoma resection (n=1), polypectomy (n=2), endoscopic electrocoagulation (n=3), antisecretory treatment without bleeding recurrence (n=3). Conclusion: Enteroscopy is useful for exploration of occult gastrointestinal bleeding. A therapeutic management was performed in one third of patients.

7247 Impact of endoscopic treatment in painful chronic pancreatitis.

Aim: To assess endoscopic treatment in hyperalgic chronic pancreatitis (CP). Patients and methods: Between 2/95 and 3/99, 21 patients (M: 17,W: 4), mean age 42 years (range: 22-69) with painful CP requiring dialy analgesic treatmentwith: central analgesic (such as dextropropoxyphen or codeine) or opioods,were admitted in our unit for endoscopic retrograde cholangio-pancreatography (ERCP). Endoscopic treatment consisted to pancreatic sphincterotomy +/- pancreatic stent insertion. Follow-up was performed including clinical (pain score, weight) and therapeutic evaluation (nature and dose of analgesic medication). Patients were classified into 3 groups according to follow-up: Group I (pain disappearance no analgesic treatment), Group II (pain and analgesic treatment decreased), Group III (no modification or increased pain and analgesic treatment). Results: All patients had ERCP with pancreatic sphincterotomy in each cases (morbidity 14.3%: acute pancreatitis (n=2), sepsis (n=1)). Sixteen patients underwent pancreatic stent (5 to 11.5 French; mean: 1.6 stent). Three patients with ductal pancreatic stones were totally healthed after pancreatic sphincterotomy and stones extraction. The median duration of treatment with pancreatic stent was 6.9 months (1-17). The median followup was 38 months (6-48). Distribution of patients after endoscopic treatment were: Group I (n=18), Group II (n=1), Group III (n=2).Weight variations were +5.3 Kgs, -3 Kgs and 4.5 kgs respectively for groups I, II and III. Patients in Group II and Group III had distal pancreatic duct stricture. Conclusion: After mean follow-up of 3 years, 86% of patients stopped analgesic treatment and a ponderal increase is observed in 3/4 of cases. Endoscopic treatment of painful PC with pancreatic stent insertion is a reliable, efficient and reproducible method.

7018 Endoscopic ultrasonography in diagnosis and staging of ampullary carcinoma: a comparative study with surgical resection.

Aim: Prospective evaluation of endoscopic ultrasonography (EUS) for diagnosis and staging of ampullary tumors surgically resected. Patients and methods: Between may 95 and september 99, 16 consecutive patients (mean age: 62,2 years (44-74), sex-ratio: 0,5) admitted in our unit for diagnosis and pre-therapeutic staging of ampullary underwent bilio-pancreatic EUS (radial probe EUM3 et EUM20 7,5-12 MHz and miniprobe 20 MHz Olympus®) and following curative surgical resection. Diagnosis of ampulloma was suspected according to following criterias: jaundice (n=6), abdominal pain (n=1), acute pancreatitis (n=5), biological cholestastic syndrom (n=4). Results: EUS was performed in all patiens without complications. Dilatation of main pancreatic duct and/or main biliary duct were visualized at abdominal ultrasonography (US) and/or CT-scan (n=6). Ampullary lesion in CT-scan (n=4) showed an ampullary tumoral lesion in 4 cases (25%), all visualized in EUS. An ampullary tumor was revealed by EUS in 14 patients (87,5%), hypoechogenic (n=10), isoechogenic (n=2) or heterogenous (n=2). Two patients had a dilatation of main bile duct (n=1) and Wirsung duct (n=1). No vascular invasion or peritoneal metastasis were detected. A curative surgery was performed in all patients (Whipple resection (n=15), ampullectomy n=1) which showed ampullary carcinoma without vascular involvement in 14 cases (87,5%) including two tumors that had been not visualized by EUS. In the two remaining patients, a cholangiocarcinoma and an odditis was diagnosed. Correlation between EUS staging and surgical/pathological findings were: 6/10, 0/1 and 3/4 for ampullomas respectively classified T1, T2 and T3 - 12/13 and 3/1 for N staging. Conclusion: EUS is useful for the diagnosis of ampullary tumours not showed by classical morphologic exams (71.4%). EUS represents the most accurate imaging technique for detecting ampulloma potentially resectable.

⁎4559 Long term follow-up of early chronic pancreatitis diagnosed at endoscopic ultrasonography.

Aim : The diagnosis of early chronic pancreatitis (ECP) remains difficult and endoscopic ultrasonography (EUS) features are still controversial. The aim of this study was to evaluate the long term follow-up of patients with ECP diagnosed at EUS. Methods : Between 1994 and 1998, 37 patients were diagnosed to have ECP at EUS. All experienced at least one episode of non biliary acute pancreatitis. None had evidence of pancreatic stone on plain film of the abdomen or on CTscanner. The ECP were classified as group A (possible ECP with either parenchymal signs or ductal signs), as group B (probable ECP with both parenchymal and ductal signs) and as group C (certain ECP with pancreatic stones). Results : 11 patients were lost to follow-up, 26 men with median age of 46.5 (23-70) years and median alcohol consumption of 76 ( 0-150) g per day, have been followed for a median duration of 37 (1-94).months. - At the initial examination, 10 patients belonged to group A, 4 to group B and 12 to group C. The pancreatographies (n=24) according to the Cambridge classification were 7 cases in stage 0, 4 cases in stage 1 , 4 cases in stage 2 and 9 cases in stage 3. - At the end of the follow-up, 4 patients underwent surgery (pseudotumorous chronic pancreatitis in 2 cases, duodenal cystic dystrophy in 1 case, and pancreatic cancer complicating chronic pancreatitis in 1 case). 26 patients had clinical evaluation : 12 remained unchanged, 12 had improved health status and 2 still experienced clinical disorders (pain, weight-loss). The final diagnosis of certain ECP was yeldied in 6 out of 10 patients of the group A, in 3 out of 4 patients of the group B and in 9 out of the 12 patients of the group C. Conclusion : The positive predictive value of EUS signs of ECP was 64% in case of possible or probable ECP and 75% in case of certain ECP.