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Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted. © 2017 The Author(s).

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favour the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, up-regulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to up-regulation of PTBP1 and modulation of PKM alternative splicing in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.

and moderate-severe steatosis (OR 2.1; 95%CI, 1.1-4.1; p=0.03). SVR rates were not related to HOMA in the overall population [63% (220/351) vs 60% (29/48), p=0.75], nor in subgroup analysis by virus genotype [genotype 1: 43% (61/143) for ≤ 2 HOMA vs 53% (9/17) for > 2 HOMA (p=0.45); genotype 2 and 3: 83% (143/173) vs 80% (20/25), p=0.78, respectively]. In SVR patients, baseline and follow up HOMA values were similar (1.12±0.82 vs 1.17±1.1, p=0.25). Conversely, nonresponders had increased HOMA values trough 18 months follow up (from 1.17±0.7 to 1.49±1.3, p=0.007); IR de-novo occurred more frequently in non-SVR than in SVR patients [24% (25/106) vs 8% (16/198), p=0.0003]. Conclusions: While the outcome of Peg-IFN/Rbv therapy is not influenced by IR, the latter is prevented once SVR is achieved.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6 mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

Pancreaticoduodenectomy is the standard care for invasive ampullary adenocarcinomas. However, endoscopic snare papillectomy (ESP) might play a curative role in very selected patients. We studied a series of 15 patients with T1 ampullary adenocarcinoma who were treated by ESP alone and followed up for a mean of 29.6 ± 21.9 months (range 8 - 81 months). ESP was curative for eight patients (57.1 %). No tumor-related death was observed in patients with a cancer infiltration depth of ≤ 4 mm. According to this preliminary experience, we suggest that this measurable variable threshold should be considered as a possible basis for future large-scale studies.

Background The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. Patients and methods We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. Results Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17–3.96), renal cell carcinoma (6.00; CI 95% 2.74–11.39) and thyroid carcinoma (5.56; CI 95% 1.80–12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. Conclusion We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

International audience; Background: Long-term observational studies assessing the incidence of Type I Gastric Carcinoid (GC) in patients with chronic atrophic gastritis are few. The aim of the present study was to evaluate the occurrence at diagnosis and during follow-up and to identify patient features associated with the presence of TypeIGC in a cohort of chronic atrophic gastritis patients. Methods: 367 chronic atrophic gastritis patients (245 females, age 54[18-79]years) underwent regular follow-up by gastroscopy. The incidence of TypeIGC was determined in chronic atrophic gastritis patients with at least 2 years of follow-up (n=214). Baseline clinical and histological features were analysed as factors associated with the presence of TypeIGC by univariate analysis. Results: TypeIGC was diagnosed in 9(2.4%) patients at the moment when chronic atrophic gastritis was diagnosed. After 1463 person-years, 6 patients developed TypeIGC with an annual incidence rate (person-year) of 0.4 %. Patients with TypeIGC had significantly higher levels of gastrin, chromogranin A and more frequently the presence of body polyps and ECL-dysplasia compared with chronic atrophic gastritis patients without TypeIGC. Conclusion: This cohort study shows that TypeIGC is a rare complication in patients with chronic atrophic gastritis and the presence of body polyps and ECL-dysplasia at gastroscopic/histologic evaluation are strongly associated with the presence of TypeIGC.

Background: Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined.

Aliment Pharmacol Ther 31, 1042–1050 Summary Background Atrophic gastritis, involving the gastric body mucosa, predisposes to gastric neoplastic lesions (GNL). However, regular gastroscopic-histological follow-up for GNL is not recommended for patients with atrophic gastritis. Aim To evaluate risk factors for the progression to GNL in a cohort of patients with atrophic gastritis. Methods A total of 300 patients with atrophic gastritis [205 women, aged 54 (18–78) years] underwent gastroscopy with six gastric antrum and body biopsies. All patients had at least one follow-up gastroscopy/histology at an interval of at least 1 year after the atrophic gastritis diagnosis. Baseline clinical and histological features were analysed as risk factors for the development of GNL by Cox-regression. Results During a median follow-up of 4.3 (1–16.5) years, 15 GNL were detected in 14 of the 300 patients with atrophic gastritis: three were gastric cancer, whereas 12 were non-invasive neoplasia. The annual incidence for GNL was 1%. Cox-regression analysis identified the following risk factors: age over 50 years (HR 8.8, 95%CI 1.2–68.4), atrophic pangastritis (HR 4.5, 95% CI 1.5–14.1) and severe intestinal metaplasia in the gastric body (HR 4.0, 95% CI 1.3–11.8). Conclusions Atrophic pangastritis, severe body intestinal metaplasia and/or age over 50 years increase the risk for developing GNL in patients with atrophic gastritis. In this subset of patients, an endoscopic-histological follow-up for GNL surveillance may be worthwhile.

This medical position statement has been developed by the board of ProInf AISP (Computerized Project on Acute Pancreatitis) Study Group. The evidence and key recommendations were discussed at a dedicated meeting held in Milan on September 2007 and during this meeting the main clinical and therapeutic medical topics were extensively discussed. Each of the proposed recommendations was discussed and an initial consensus was reached. Acute pancreatitis in Italy is a disease of increasing annual incidence. The diagnosis of the disease should be established within 48hours of admission. Early identification of patients at risk of developing a severe attack of acute pancreatitis is of great importance because rapid therapeutic interventions improve outcome. The endoscopic approach seems to be most beneficial measure in patients with acute pancreatitis with jaundice and in those with cholangitis. The development of infected necrosis should be assessed using fine-needle aspiration and the sample should be cultured for germ isolation and characterization. The role of early ERCP in all patients with severe acute pancreatitis of biliary origin is still controversial. The data supporting the efficacy of antibiotic prophylaxis to prevent infection of necrosis are conflicting. The refeeding is a crucial topic in patients who have recovered from an acute episode of mild acute pancreatitis, but there are very few studies on this issue.

Vasoactive intestinal peptide (VIP) relaxes smooth muscle by interacting with receptors coupled to cAMP- or cGMP-signalling pathways. Their relative contribution to human gastric relaxation is unknown. This study aimed at investigating, in terms of biological activity, receptor expression and related signalling pathways, the action of VIP separately on the human fundus and the antrum. VIP caused greater relaxation of smooth muscle cells (SMC) and strips of the antrum presenting on the former a higher efficacy and potency (ED(50): 0.53 +/- 0.17 nmol L(-1)) than on the fundus (ED(50): 3.4 +/- 1.4 nmol L(-1)). On both fundus and antrum strips, its effect was tetrodotoxin insentitive. Reverse transcriptase-polymerase chain reaction analysis showed the sole expression of VPAC2 and natriuretic peptide clearance receptors, with VPAC2 being more abundant in the antrum. Functional regional differences in receptor-related signalling pathways were found. Activation of the cAMP-pathway by forskolin or its inhibition by adenylate cyclase (2'5'-dideoxyadenosine) or kinase (Rp-cAMPs) inhibitors had more pronounced effects on antrum SMC. Activation of the cGMP-pathway by sodium nitroprusside or its inhibition by guanylate cyclase (LY83583) or kinase (KT5823) inhibitors had more effects on fundus SMC, on which a higher expression of endothelial nitric oxide synthase was found. In conclusion, regional differences in VIP action on human stomach are related to distinct myogenic properties of SMC of the antrum and the fundus.

The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.

Summary Background : Long-term outcome of atrophic body gastritis has not yet been defined. Aim : To investigate at long-term follow-up the behaviour of atrophy and intestinal metaplasia and the occurrence of neoplastic lesions in atrophic body gastritis patients. Methods : Overall 106 atrophic body gastritis patients with ≥ 4-year follow-up were studied; 38 were Helicobacter pylori-positive at histology + serology and cured of infection (group A), 36 were positive at serology and not treated (group B) and 32 were H. pylori-negative (group C). Patients underwent gastroscopy with antral (n = 3) and body (n = 3) biopsies for histology according to the Sydney System. Results : At 6.7-year follow-up body atrophy and intestinal metaplasia remained unchanged in all 106 patients irrespective of H. pylori status. Antral atrophy was significantly increased at follow-up only in group C, whereas antral intestinal metaplasia was unchanged in all three groups. During follow-up eight (8%) patients developed neoplastic lesions (one adenocarcinoma, one adenoma with low-grade dysplasia and six low-grade dysplasia without endoscopic lesions). Antral atrophic gastritis was present at baseline in all but one (88%) of the eight patients with neoplastic lesions, but only in 15 (15%) of the 98 patients without (P

Background. Inherent properties of gastrointestinal smooth muscle can be assessed using isolated cell suspensions. Currently available isolation techniques, based on short 2-h enzymatic digestion, however, present the disadvantage of low cellular yield with brief viability. These features are an important limiting factor especially in studies in humans in which tissue may not be available daily and mixing of samples is not recommended. Aims. To optimise the isolation procedure of cells from human colon to obtain a richly pure primary smooth muscle cell preparation. Methods. Slices of circular muscle layer, obtained from surgical specimens of human colon, were incubated overnight in Dulbecco's modified eagle's medium supplemented with antibiotics, foetal bovine serum, an ATP-regenerating system and collagenase. On the following day, digested muscle strips were suspended in HEPES buffer, and spontaneously dissociated smooth muscle cells were harvested and used either immediately or maintained in suspension for up to 72 h. Cell yield, purity, viability, contractile responses, associated intracellular calcium signals and RNA and protein extraction were evaluated and compared to cell suspensions obtained with the current short digestion protocol. Results and conclusion. The overnight isolation protocol offers the advantage of obtaining a pure, homogeneous, long-life viable cell suspension that maintains a fully differentiated smooth muscle phenotype unchanged for at least 72 h and that allows multiple functional/biochemical studies and efficient RNA extraction from a single human specimen.

Somatostatin analogues are considered first-line therapy in patients with digestive endocrine tumours. Indeed, several studies have investigated their efficacy in the control of specific symptoms and in the decrease of tumour markers. However, randomised controlled trials are needed in order to better define their role in non functioning tumours and their effect on tumour growth, which have seldom been assessed. Several new drugs have been developed over the last few years such as, for example, new long-acting formulations, universal analogues binding to all five somatostatin receptors subtypes, and cytotoxic analogues, all of which offer a promising therapeutic tool in the near future, even if further studies are needed to determine their efficacy and safety in man.

Background. Colorectal cancer is a frequent cause of mortality in Western countries, including Italy, where a definite screening policy has not yet been adopted. It is likely that most patients with colorectal cancer refer, first of all, to their primary care physician at onset of symptoms. Aim. To perform a survey on the approach, of primary care physicians, to patients with symptoms suggesting the presence of colorectal cancer. Methods. A total of 280 consecutive symptomatic patients without previous diagnosis of organic colon disease or recent colon investigation in whom, after consulting, 159 primary care physicians in Lazio (Italy) prescribed colonoscopy or double-contrast barium enema. Results. Most frequent presenting symptoms were lower abdominal pain (79.6%), bloating (59.6%), constipation (47.8%), diarrhoea (30.3%), iron deficiency anaemia (24.6%), change in bowel habits (20.3%) and weight loss (15%). Colonoscopy and barium enema were equally advised by physicians to rule out the presence of cancer (56% versus 44%, P =ns). Cancer was found in 14.6% of patients. Age >50 years and iron deficiency anaemia were the only independent variables associated with colorectal cancer (Odds ratios 9.0 and 8.8 at multivariate analysis, respectively). Conclusion. The symptom-based selection criteria used by primary care physicians have been shown to be scarcely effective. Colonic investigation should be requested, irrespective to the symptoms, in patients aged >50 years with iron deficiency anaemia.

In premenopausal women, iron-deficiency anaemia is common and menstrual flow is often held responsible, but it is not clear whether these women should be submitted to gastrointestinal (GI) evaluation. We aim to prospectively investigate whether premenopausal women with iron-deficiency anaemia benefit from GI evaluation regardless of menstrual flow.The study population comprised 59 consecutive premenopausal women with iron-deficiency anaemia. Excluded were women with obvious or suspected causes of anaemia and thoseor = 21 years. Heavy menstrual loss was not considered an exclusion criterion. All subjects had: complete blood count, ferritin, non-invasive testing by faecal occult blood (FOB), 13C-urea breath test (13C-UBT), anti-tissue transglutaminase antibodies (tTG) and gastrin levels. Gastroscopy with antral (n = 3), corporal (n = 3) and duodenal (n = 2) biopsies was performed in women with positive 13C-UBT or tTG titre or hypergastrinaemia.Heavy menstrual loss was present in 50.8%. Non-invasive tests were positive in 40/59 (67.8%): 30 had positive 13C-UBT, 12 had hypergastrinaemia, 7 had positive tTG and 3 had positive FOB. Women tested positive were similar to those tested negative as far as concerned age, haemoglobin and ferritin levels and heavy menstrual flow (55% versus 42.1%). All 40 women tested positive underwent gastroscopy with biopsies. Four (10%) had bleeding-associated lesions and 34 (85%) had non-bleeding-associated lesions. As regards upper GI findings, no differences were observed between women with normal and those with heavy menstrual flow. No lower GI tract lesions were detected in the three women with positive FOB.Our data suggest that premenopausal women with iron-deficiency anaemia benefit from endoscopic evaluation of the upper GI tract irrespective of menstrual flow.

We read with interest the paper by Whiting et al ( Gut 2002; 50 :378–81) regarding the surveillance of premalignant gastric lesions. The authors reported that over 10 years, 12 cancers (11.5%) were diagnosed in 104 patients with intestinal metaplasia and/or atrophic gastritis. Therefore, they suggest that these patients have an increased risk of developing gastric cancer, and benefit from annual endoscopic follow up. Although we agree with the major conclusions of the study, our experience is somehow different. In fact, we have recently investigated the timing of first endoscopic-histological follow up of patients with body predominant atrophic gastritis and demonstrated that four years seems a satisfactory interval for the first follow up of these patients.1 The timing of surveillance …

The optimal dosage of somatostatin analogs for the long-term control of carcinoid tumors has not yet been established. Receptor alterations induced during long term treatment with somatostatin analogs have lead to consecutive drug dosage increases in order to control carcinoid disease. In this report, we describe the rapid and effective control of tumor in a patient with metastatic carcinoid treated for nine years with a single daily dose of octreotide based on tumor marker levels. Tumoral somatostatin receptor (sst) subtype analysis by RT-PCR amplification showed the expression of sst2 subtype only. We suggest that a single daily dose of octreotide strictly related to tumor marker secretion, could have played a role in the effective long-term therapy by avoiding the phenomenon of somatostatin receptor desensitisation. Furthermore, the exclusive presence of sst2 subtype supports the high affinity of octreotide to tumoral cells.

Gastrin levels have been reported to be often increased in patients with primary hyperparathyroidism (PHPT) considered to be caused by hypercalcemia. To determine the prevalence of increased basal gastrin and to investigate its causes, 52 consecutive patients with PHPT were studied prospectively, undergoing a clinical, biochemical, and gastric morphofunctional assessment before any parathyroid surgical procedure. This included evaluation of basal and secretin-stimulated gastrin, basal and pentagastrin-stimulated gastric acid secretion, upper gastrointestinal endoscopy, with histological evaluation for gastritis and Helicobacter pylori infection. Twenty of the 52 PHPT patients (38.5%) had increased fasting gastrin. Further investigation allowed us to clearly demonstrate the causes of hypergastrinemia in 16 of these 20 patients. In 7 of 20 (35%), hypergastrinemia was caused by gastric fundus atrophy; in 3 patients (15%), Zollinger-Ellison syndrome with Multiple Endocrine Neoplasia type I was diagnosed; whereas in another 20% of patients, mild hypergastrinemia was ascribed to Helicobacter pylori gastritis. Finally, in 2 patients, additional clinical history revealed an occasional use of the gastric antisecretory drug omeprazole a few days before the serum gastrin determination. This study shows that the hypercalcemic status per se is not sufficient to produce an increase in fasting gastrin levels. Furthermore, gastric fundus atrophy, and not gastrinoma, is the major cause of relevant (160 pg/mL) hypergastrinemia.

Helicobacter pylori has been proposed as a major determinant in multiple gastric disorders. We describe the case of a young adult with a long-standing medical history of sideropenic anaemia and of oral iron consumption dependence with a chronic superficial H. pylori-positive gastritis. All other causes of sideropenic anaemia were carefully excluded. Histology showed a peculiar pattern of non-active H. pylori-positive gastritis. The bacterium was a non-VacA-producing strain. The first attempt at eradication caused a reduction in bacterial load and led to a partial normalization of haematologic variables without improving the ferritin level. A successful second course of eradication therapy completely reversed the anaemia and restored the iron deposit, which persisted at the 29-month follow-up. H. pylori infection can be involved in unexplained cases of iron deficiency anaemia in adults, and its cure can normalize the haematologic picture.

Antral gastrin cell hyperfunction (AGCH) is a rare syndrome characterized by persistent hypergastrinemia and important peptic symptoms in the absence of a gastrin-producing tumor. The pathogenesis of AGCH is still unknown and debated. Helicobacter pylori (Hp) infection has been reported as a possible cause of sustained hypergastrinemia. To assess the relevance of Hp infection in pediatric AGCH patients, Hp status, G cell function, acid secretion, and antral G and D cell populations were investigated in six children presenting with gastrointestinal bleeding of unknown origin, sideropenic anemia, and variable abdominal symptoms. All patients had moderate high basal gastrinemia with abnormally increased peak values after meals and elevated values of basal acid output (BAO), maximal acid output (MAO), and pentagastrin-stimulated acid output (PAO). Circulating pepsinogen I was also significantly increased. Three children had Hp infection, as assessed by enzyme-linked immunosorbent assay, urease test, and histology. Endoscopy showed duodenal erosions in three children, with ulcer in two Hp-positive cases. At histology, moderate gastritis was observed only in the three Hp-positive cases. In all patients, quantitative assessment of antral gastrin and somatostatin cells gave significantly elevated G cell counts; D cells were at the lower reference limit and the G/D cell ratio was significantly elevated. These data indicated a diagnosis of AGCH, possibly due to the elevated G/D cell ratio, and suggest HP infection as an overlapping factor complicating the clinical picture in some cases.

The effect of somatostatin-14 (SST) and the SST analogues SMS and RC160 on human natural killer (NK) activity mediated by large granular lymphocytes (LGL), as well as on IL-2-and/or anti-CD16 monoclonal antibody (mAb)-induced activation of these cells, was investigated. The NK activity of LGL was studied by the release of 51Cr by the erythroleukemia-derived cell line K562, whereas 51Cr release by the P815 murine mastocytoma-derived cell line, for which lysis was redirected by the use of an anti-CD16 mAb, was used to study the cytolytic potential of these cells. IL-2 was used at the final concentration of 100 IU and was incubated overnight with LGL. SST and the analogues, added to these systems at final doses ranging from 10−12 to 10−5 M , were inhibitory of the NK cell activity to K562, with a dose-response curve starting from 10−8 M and reaching a significant level at 10−6 M . On the contrary, no effect was observed on the redirected killing assay to P815 and on the IL-2-induced activation of NK cells. These results provide additional evidence for the immunomodulatory action of somatostatin.

Duodenal ulcer disease is a heterogenous condition characterized by episodes of recurrence and remission. Recurrences are often painful and may result in gross duodenal scarring and pyloric stenosis; bleeding and perforation can complicate the disease, requiring operative treatment and increasing mortality. Treatment should therefore maintain remission after ulcer healing, prevent possibly lethal complications, be safe and maintain efficacy over time. Maintenance treatment with H2 receptor antagonists reduces the rate of symptomatic relapse, but there is no evidence that it affects the complication rate. Tolerance develops in a subgroup of patients and seems to contribute to their poor response to long-term H2 antagonist therapy. It seems wise to prescribe maintenance treatment for 3 years following initial healing in patients with severe relapsing disease, or smokers with recurrent symptoms, and to continue it for life in selected individuals at increased risk of acute complications or of complication-related mortality.

SUMMARY Thirteen patients with Zollinger-Ellison syndrome were investigated: 8 without, and 5 with, previous gastric surgery. After 7–34 months of treatment with famotidine, 8 out of 13 patients were resistant to this drug. Omeprazole 60 mg/day was administered to these 8 patients; after one month, the dose was reduced to 40 mg/day, and after another month to 20 mg/day. Basal acid secretion was inhibited by every dose of omeprazole. The patients were then treated with a low dose (20 mg/day) of omeprazole for a longer period. Periodic clinical and endoscopic assessments, and measurement of basal acid secretion showed the efficacy of this low dose of omeprazole in our Zollinger-Ellison syndrome patients. The drug was discontinued after 12–32 months of omeprazole treatment, and gastric acid recovery was evaluated. Four patients recovered 50% of their ‘initial basal acid secretion’ after 5 days, while two patients who had been treated with omeprazole for a longer time (30–32 months) recovered only 38 and 40%, respectively, of their ‘initial basal acid secretion’ at the tenth day. Our results indicate that the omeprazole dosage to be used in the treatment of Zollinger-Ellison syndrome must be chosen principally on the basis of basal acid secretion determination. A low daily dose of omeprazole is able to control acid secretion in Zollinger-Ellison syndrome for a long period (10–30 months). The slow recovery of gastric secretory function demonstrates the prolonged inhibitory effects of omeprazole.

We assessed the effect of long-lasting inhibition of gastric acid secretion on basal and meal-stimulated serum gastrin and gastric acid secretion in 37 patients on long-term maintenance treatment with H2 antagonists for severe relapsing and/or complicated duodenal ulcer disease. After a mean of 142 weeks (range, 28-324 weeks) of continuous treatment, gastric acid secretion, basal plasma gastrin, and gastrin response to a test meal were evaluated. All tests were performed a week after drug discontinuation to exclude rapidly reversible hypergastrinemia. Gastrin levels were above the normal range in seven patients (18.9%). After H2 antagonist were stopped for 6 weeks, basal gastrin returned to normal levels in all cases [from a median of 180 (range, 130-350) pg/ml to 58 (25-90) pg/ml] and peak meal-stimulated gastrin significantly decreased from a median of 500 pg/ml to 245 pg/ml (p = 0.02). In patients with hypergastrinemia, the discontinuation of H2 antagonists for 6 weeks led to a significant decrease of gastric acid secretion. Patients who developed hypergastrinemia spent more weeks on full-dose treatment and had more recurrences during therapy. The results of the present investigation demonstrate that a long-lasting inhibition of gastric acid secretion can induce, in a small percentage of patients, a reversible sustained hypergastrinemia and a consequent increase of acid secretion, which conceivably could lead to more frequent relapses of duodenal ulcer disease.

In this article some of the actions of amphibian skin peptide Bombesin (BBS) on human gastrointestinal and pancreatic functions are reviewed. BBS causes increases of lower esophageal sphincter pressure, delay of gastric emptying, inhibition of mechanical activity of duodenum and jejunum and gallbladder emptying. BBS also releases in man gastrin and stimulates gastric acid secretion. BBS administration induces release of insulin, glucagon and pancreatic polypeptide from human Islet of Langerhans and causes secretion of pancreatic bicarbonates and enzymes in duodenal juice and release of pancreatic enzymes in blood stream.

The effect of sham feeding upon gastric acid secretion and pancreatic polypeptide release was investigated in 28 patients with duodenal ulcer in order to evaluate whether high basal vagal activity is the cause of basal acid hypersecretion in patients with duodenal ulcer and basal secretion higher than 30% of their peak acid output. The patients were divided into two groups based on the ratio of basal/pentagastrin stimulated peak acid output (BAO/PAO) was higher or lower than 0.30: group A n = 19 (BAO/PAO less than or equal to 0.30) and group B n = 9 (BAO/PAO greater than 0.30). Gastric acid response to sham feeding (SAO) was significantly higher than basal level in group A (SAO: 11.4 mEq/h (2.5-20.1) vs BAO: 5.2 mEq/h (0.8-22.9), p less than 0.01, median (range)) while in group B the acid secretion did not increase with sham feeding (SAO: 9.6 mEq/h (4.5-13.6) vs BAO: 8.8 mEq/h (6.3-13.8) ns, median (range)). A negative correlation (r= -0.6118226, p less than 0.01) was found between acid increase expressed as basal subtracted sham feeding response (SAO-BAO) and BAO/PAO ratio of the entire group of duodenal ulcer patients (n = 28) suggesting that the greater is basal acid secretory capacity the smaller is acid increase in response to residual vagal activation. Pancreatic polypeptide response to sham feeding was higher in group A than in group B but no correlation (r = 0.20, n = 28) nor individual covariation was found between acid and pancreatic polypeptide secretions during vagal stimulation. sham feeding did not change serum gastrin. It is concluded that an increased vagal stimulation seems to be the cause of basal hypersecretion in a subgroup of patients with duodenal ulcer. The lact of correlation between the pancreatic polypeptide and acid responses to vagal stimulation interferes with the reliability of pancreatic polypeptide as indicator of vagal tone on gastric parietal cells.

Methanol extracted skins from 84 species of amphibia were screened, measuring by RIAs: gastrin-CCK, VIP, calcitonin, GIP, PP and motilin. G-CCK-like immunoreactivity was found in 97.6%; VIP-like immunoreactivity in 41%; CT-like immunoreactivity in 34%; GIP-like immunoreactivity in 10%; PP-like immunoreactivity in 40% and MT-like immunoreactivity in 60% of the samples. The use of a sequence-specific radioimmunoassay and of gel-chromatography confirmed the caerulein-CCK-8-like nature of the immunoreactive material. Detected amounts of the other peptides (VIP, CT, GIP, PP, MT) were too low for bioassay or chromatographic studies, thus leaving the question open if they are due to some kind of unspecific interferences or, most likely, to species-specificity differences of the used antisera.