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Malabsorption of thyroxine has been described in patients treated with drugs that modify an acidic environment. We determined whether there is an increased need for thyroxine in patients with euthyroid multinodular goiter and impaired secretion of gastric acid.We assessed the dose of thyroxine required to obtain a low level of thyrotropin (0.05 to 0.20 mU per liter) in 248 patients with multinodular goiter. Of these 248 patients, 53 also had Helicobacter pylori-related gastritis and 60 had atrophic gastritis of the body of the stomach (31 with evidence of H. pylori infection and 29 without such evidence). The reference group comprised 135 patients with multinodular goiter and no gastric disorders. In addition, variation in the level of serum thyrotropin was prospectively studied in 11 patients treated with thyroxine before and after H. pylori infection and both before and during treatment with omeprazole in 10 patients treated with thyroxine who had gastroesophageal reflux.The daily requirement of thyroxine was higher (by 22 to 34 percent) in patients with H. pylori-related gastritis, atrophic gastritis, or both conditions than in the reference group. In prospective studies, the occurrence of H. pylori infection in the 11 patients treated with thyroxine led to an increase in the level of serum thyrotropin (P=0.002), an effect that was nearly reversed on eradication of H. pylori infection. In a similar way, omeprazole treatment was associated with an increase in the level of serum thyrotropin in all 10 patients treated with thyroxine, an effect that was reversed by an increase in the thyroxine dose by 37 percent.Patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine.

Peanut-like 1 (PNUTL1) is a septin gene which is expressed at high levels in human brain. There it plays a role in the process of membrane fusion during exocytosis by interacting with syntaxin and synaptophysin. As the secretory apparatus of pancreatic islet cells closely resembles that of neurons, we decided to study the expression of PNUTL1 in the human endocrine pancreas, both in normal islets and in pancreatic endocrine tumors (PETs). Normal pancreatic tissue, purified islets, 11 PETs and two cell lines were used to evaluate the presence of PNUTL1 by RT-PCR and Western blot. The expression of the PNUTL1 protein was also evaluated by immunohistochemistry on normal pancreas, additional 26 PETs, eight pancreatic adenocarcinomas, one mixed endocrine-exocrine pancreatic neoplasm, a specimen of solid papillary pseudomucinous tumor, an adult islet cell hyperplasia and a case of neonatal nesidioblastosis. In addition, a tissue array (LandMark High Density Cancer Tissue MicroArray) comprising 280 various tumor and matched normal specimens was utilized. In PETs, the expression of pancreatic hormones, chromogranin-A, synaptophysin and Ki-67 were also evaluated. In the normal pancreas PNUTL1 expression is almost exclusively confined to the islet cells, weak expression was occasionally seen in some acinar cells, while immunoreactivity was completely absent in the ductal epithelia. PNUTL1 expression is maintained at similar high levels in hyperplastic and neoplastic islet cells, but this did not correlate with any of the clinicopathological data nor with proliferation status in PETs. Weak immunoreactivity was also noted in a proportion of exocrine neoplasms. Our findings describe for the first time the high expression levels of PNUTL1 in human pancreatic endocrine cells that suggests a similar role of this protein in islet cells to that demonstrated in neuronal tissues, and warrants further functional studies of this protein.

Background. Detection of Helicobacter pylori infection in atrophic body gastritis (ABG) is difficult, as during progression of body atrophy, H. pylori disappears. Aim. To increase the diagnostic yield of detection of active H. pylori infection in atrophic body gastritis patients by using noninvasive tests such as 13C-Urea Breath Test (13C-UBT) and H. pylori stool antigen test (HpSA) would be useful. Patients. 27 consecutive patients with newly-diagnosed atrophic body gastritis (19F/7M, age 27–73 years). Methods. Gastroscopy with biopsies (antrum n = 3, body n = 3) and histology according to updated Sydney system, H. pylori IgG serology, 13C-UBT, and HpSA. Results. All tests used in the diagnosis of H. pylori infection were in agreement in 9/27 atrophic body gastritis patients (33.3%), being all positive in four (14.8%) and all negative in five patients (18.5%). Ten of the 27 (37%) patients were Giemsa stain-positive and serology-positive (group I). Seventeen of the 27 (63%) patients were Giemsa stain-negative: 5/17 with positive serology (group II) and 12/17 with negative serology (group III). In group I, 5/10 (50%) were 13C-UBT positive and 4/10 (40%) HpSA positive. In group II, two patients were 13C-UBT positive, but all were HpSA negative. Also in group III, all patients were HpSA negative, but one had a positive 13C-UBT. Conclusions. In atrophic body gastritis patients, neither 13C-UBT nor HpSA per se add useful information regarding active H. pylori infection, but these noninvasive tests may be important in combination with histology and serology to define the H. pylori status in some atrophic body gastritis patients.

Introduction: Several studies have correlated the diabetic status with increased cancer risk and worse cancer prognosis, while metformin (MET) use is associated with a better prognosis. MET could display antitumor effects by modifying systemic metabolism, e.g. by decreasing of blood glucose, insulin and IGF1 levels, or by affecting cancer cell metabolism and proliferation, e.g. through AMPK activation and inhibition of protein/lipid synthesis. Preliminary findings of the PRIME-net retrospective study, conducted on 445 Italian pts, suggested that the addition of MET to EVE and/or SSAs provides clinical benefit in diabetic patient with advanced pancreatic NETs. Methods: To exclude the possibility that the “time-on-treatment bias” could affect our results, with the risk that an early interruption of EVE or SSA-therapy due to early disease progression may result in lower pt exposure to these drugs and a consequently lower incidence of diabetes in poor responders, a sensitivity analysis on the PRIME-net study population was performed. The analysis considered only diabetics at baseline (BD), thus excluding pts who developed on-treatment diabetes as an adverse event (AE). All statistical tests were two-tailed and p-values Results: Out of 445 pts, 237 were diabetics. Of them, 179 had baseline diabetes (BD) while 57 developed on-treatment diabetes as an adverse event. Among pts with BD, 80 (44.7%) received MET, while 99 (55.3%) were not treated with MET, but received other treatments including insulin. mPFS was 24.7 mo in pts with BD and 15.1 mo in normoglycemic ones (HR 0.70, 95%CI 0.55-0.91; p=0.007). In pts on MET therapy, mPFS was 43.7 mo (HR vs normoglycemic pts 0.52, 95%CI 0.36-0.76, p=0.0006), while it was 20.8 mo in pts not receiving MET (HR vs normoglycemic pts 0.87, 95%CI 0.65-1.17, p=0.37). Conclusions: This sensitivity analysis confirms results emerged from the main analysis, thus demonstrating a mPFS advantage in diabetic patients with advanced pNETs patients receiving MET in combination with EVE and/or SSAs. Prospective investigations are ongoing to test the antitumor activity of MET in combination with everolimus and SSAs in normoglycaemic pts with advanced pNETs. Protocol number INT 85/15, approved by Ethical committee of fondazione IRCCS Istituto Tumori Milano on 15 June 2015. Citation Format: Sara Pusceddu, Claudio Vernieri, Massimo Di Maio, Femia Daniela, Natalie Prinzi, Riccardo Marconcini, Francesca Spada, Sara Massironi, Alberto Bongiovanni, Maria Pia Brizzi, Davide Campana, Antongiulio Faggiano, Dario Giuffrida, Gianfranco Delle Fave, Sara Cingarlini, Francesca Aroldi, Lorenzo Antonuzzo, Rossana Berardi, Laura Catena, Roberto Buzzoni, Filippo de Braud. Impact of metformin on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNETs) receiving everolimus and/or somatostatin analogues: A sensitivity analysis of the PRIME-NET (pancreatic multicentric, retrospective, italian metformin) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2017-LB-256

Hepatitis B virus (HBV) reactivation (HBVr) in patients undergoing immunosuppressive therapy is still a hot topic worldwide. Its prevention and management still represents a challenge for specialists dealing with immunosuppressed patients. Aim of this paper is to provide a critical review of the relevant information emerged in the recent literature regarding HBV reactivation following immunosuppressive treatments for oncohematological tumors. A computerized literature search in MEDLINE was performed using appropriate terms arrangement, including English-written literature only or additional relevant articles. Articles published only in abstract form and case reports not giving considerable news were excluded. Clinical manifestation of HBVr can be manifold, ranging from asymptomatic self-limiting anicteric hepatitis to life-threatening fulminant liver failure. In clusters of patients adverse outcomes are potentially predictable. Clinicians should be aware of the inherent risk of HBVr among the different virological categories (active carriers, occult HBV carriers and inactive carriers, the most intriguing category), and classes of immunosuppressive drugs. We recommend that patients undergoing immunosuppressive treatments for hematological malignancies should undergo HBV screening. In case of serological sign(s) of current or past infection with the virus, appropriate therapeutic or preventive strategies are suggested, according to both virological categories, risk of HBVr by immunosuppressive drugs and liver status. Either antiviral drug management and surveillance and pre-emptive approach are examined, commenting the current international recommendations about this debated issue.

In recent decades, the prominent role of endoscopy in the management of ulcerative colitis (UC) has been translated into the concept of mucosal healing (MH) as a fundamental therapeutic end-point. This is partially the consequence of growing evidence of a positive prognostic role of MH on the disease course and partially due to market cues indicating a higher rate of MH in patients treated by novel potent biologic agents. The aim of the present review is to clarify the current knowledge of MH in UC, analyzing the definition, the putative prognostic role and the association of MH with the current drugs used to treat UC patients. Because solid data about the management of UC patients based solely on the healing of the mucosa are not yet available, a tailored approach for individual patients thatconsiders the natural history of UC and the presence of prognostic indicators of aggressive disease is desirable. Consequently, unnecessary examinations and treatment would be avoided and restricted to UC patients who require the maximum amount of effort to affect the disease course in the short and long term.

Hepatitis E virus (HEV) is the most important causative agent of acute hepatitis in developing countries. The disease is usually characterized by a self-limiting, benign course. However, when particular conditions coexist (pregnancy, old age, pre-existing liver disease) it may run an unfavourable course. To date, 4 HEV genotypes have been described. Historically, in the Western world, HEV infection was considered a travel-related disease, however in the last 2 decades a great number of non-travel-related autochthonous cases have been described, more often related to genotype 3 or 4 and in the context of zoonosis. We report the case of an elderly Italian man with an acute fulminant HEV infection genotype 3e that developed in the context of pre-existing liver disease; this is the first case of an unfavourable outcome associated with subgenotype 3e. The potential pathogenicity of this subgenotype together with the influence of host-related risk factors are discussed.

The aim of our study was to evaluate the diagnostic accuracy of gadoxetic acid-enhanced magnetic resonance (MR) imaging both in the detection of hepatocellular carcinoma (HCC) and precancerous lesions and in the assessment of their evolution. A retrospective study was undertaken on 56 patients with chronic liver disease and suspected liver lesions. We evaluated the number, size and signal intensity of the nodules on dynamic and hepatobiliary MR images. Follow-up studies were carried out every 3 months. Statistical analysis was performed using the Fisher’s exact test. A total of 120 nodules were identified in 41 patients. Of these, 92/120 nodules (76.6 %; mean diameter 18.4 mm) showed the typical HCC vascular pattern: 90/92 nodules appeared hypointense and 2/92 were hyperintense on hepatobiliary phase images. An additional 28/120 hypointense, nonhypervascular nodules (23.3 %; mean diameter 11 mm) were detected on hepatobiliary phase images, 15 of which showed hypointensity also on the equilibrium phase images. During the 3- to 12-month follow-up, 14/28 nodules (mean diameter 13.3 mm) developed the typical vascular pattern of HCC. Gadoxetic acid-enhanced MR imaging is useful for detecting HCC as well as hypovascular nodules with potential progression to HCC. Lesions measuring more than 10 mm in diameter are at higher risk of developing into HCC (p = 0.0128).

In the presence of somatostatin-14 or some of its receptorial agonists, the uptake of large neutral amino acids by isolated brain microvessels was found to be inhibited up to 50%, no other transport system being affected. Although the luminal and abluminal sides of brain endothelial cells are both capable of taking up large neutral amino acids, only uptake from the abluminal side appears to be inhibited by somatostatin. The involvement of a type-2 somatostatin receptor was suggested by assays with a series of receptor-specific somatostatin agonists, and was confirmed by the release of inhibition caused by a specific type-2 receptor antagonist. A type-2-specific mRNA was indeed shown to be present in both bovine brain microvessels ex vivo and primary cultures of endothelial cells from rat brain microvessels.

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53. p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors. p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling ( P =.02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases. Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors. HUM PATHOL 32:1094-1101. Copyright © 2001 by W.B. Saunders Company

Background. Helicobacter pylori is involved in the induction of atrophic body gastritis (ABG). During the progression of atrophic gastritis the disappearance of H. pylori has been documented and in time serology is the only sign that indicates a previous infection. It has been shown that a positive serology, in ABG patients without histological evidence of infection, indicates an active H. pylori infection. Aim. To investigate in a population of patients with ABG the prevalence of H. pylori infection on the basis of histology and serology. Patients. A total of 150 consecutive outpatients with atrophic body gastritis were diagnosed on the basis of a screening system. Methods. All patients had a detailed assessment including measurement of specific anti-H. pylori antibodies, parietal cell antibodies, and fasting gastrin, gastroscopy with biopsies from gastric antrum and body. Results. 24.6% of patients were histologically and serologically negative (Group A). 52.7%H. pylori was not detected on histology but IgG to H. pylori were in all these patients elevated (Group B). 22.6% of patients were found to be positive at histology in the corpus mucosa; all but one of these patients had elevated circulating IgG to H. pylori (Group C). Mean corporal atrophy score in Group B patients was statistically lower than in Group A patients (2.43 ± 0.08 vs. 2.75 ± 0.09; p

To investigate the optimum number of biopsy specimens to be obtained for enterochromaffin-like (ECL) cell monitoring in hypergastrinemic patients and ECL cell regional variations potentially influencing the results, qualitative ECL cell changes were assessed in 149 patients with Zollinger-Ellison syndrome using jumbo biopsy specimens and a systematic sampling procedure of 4 areas each from the lesser or greater curvature of the gastric body. Of 1,176 specimens examined, 1,101 were adequate. The correlation was excellent between different sites within the greater or lesser curvature. In contrast, a normal ECL cell pattern was more frequent in the lesser curvature, whereas linear hyperplasia was more frequent in the greater curvature. Dysplastic lesions and carcinoid tumors in endoscopically unremarkable mucosa were detected in 3.4% and 1.2% of biopsy specimens, respectively, and were equally distributed between the lesser and greater curvature. Their chances of being diagnosed were related to the number of specimens examined. Extensive sampling of both the lesser and greater curvature is recommended for early diagnosis of dysplastic and/or carcinoid lesions in patients at risk. In contrast, limited sampling in the greater curvature seems to be adequate in patients with no risk for carcinoid development.

The aim of the present study was to evaluate the correspondence of the classification of non-antral endocrine cell growths proposed by Solcia and co-workers with clinical features and non-endocrine mucosal changes. For this purpose, 94 cases of newly diagnosed atrophic body gastritis were investigated using endoscopic biopsies and compared with 18 control subjects. The patients were subdivided into the following four groups according to the most severe pattern of endocrine cell proliferation found in the body mucosa, as shown by chromogranin A immunostaining: group 1, normal pattern (7 cases, 7.5 per cent); group 2, simple hyperplasia (6 cases, 6.5 per cent); group 3, linear hyperplasia (24 cases, 25.8 per cent); group 4; micronodular hyperplasia (56 cases, 60.2 per cent). Adenomatoid hyperplasia was found in only one case, thus precluding further analysis. Patients in groups 1 and 2 had lower acid secretion, higher gastrin level, and higher mean scores in all histopathological variables of chronic gastritis considered by the Sydney system when compared with controls, but did not differ among them in any parameter investigated. When compared with groups 1 and 2, patients of groups 3 and 4 showed higher values of circulating gastrin, higher scores of glandular atrophy, and lower values of acid secretion and of mononuclear and neutrophil inflammatory cell infiltration. Moreover, group 4 patients differed significantly from those of group 3 in their higher gastrin levels and atrophy scores, and lower scores of neutrophil cell infiltration. On the basis of these results, it is proposed that for practical purposes the normal and the simple hyperplasia patterns may be incorporated into a single group. It is concluded that this classification in its simplified form, based on a qualitative histological approach, shows clinical relevance without the need to perform expensive, time-consuming morphometric evaluations.

Dear Sir, We thank Ezziddin et al. for their comments [1] on our article [2]. The aim of our study was to determine the time to progression of patients treated with radiolabelled somatostatin analogues and to identify the prognostic factors related to treatment response. Regarding the prognostic factors related to treatment response [2] and in accordance with the report by Ezziddin et al., we did not find any correlation between the response rate at 6 months after radiolabelled somatostatin analogue treatment (PRRT) and either the WHO2010 classification [3] or Ki67 as a continuous variable. On the contrary, we reported the role of the WHO 2010 classification in terms of progression-free survival after PRRT. Moreover, our data confirm that Ki67 is a major prognostic factor in neuroendocrine tumours (NETs) [4–6]. In addition, both our study and that of Ezziddin et al. showed that Ki67 does not influence the PRRT response in terms of the RECIST criteria but is a crucial prognostic factor for progression-free survival. Our results, in accordance with those of many other studies, indicate the key role of Ki67 as a prognostic factor. Concerning this key role, neither Kwekkeboom et al. [7] nor Imhof et al. [8] evaluated Ki67 in their large series. Imhof et al. reported the prognostic factors regarding overall survival and severe kidney toxicities after PRRTwith Y, but, despite being large, the series included a wide spectrum of neuroendocrine neoplasms (gastroenteropancreatic NETs, bronchial carcinoids, rare NETs, unknown primary NETs) [8]. However, in a large and more homogeneous series of patients (with gastroenteropancreatic NETs and unknown primary NETs), Kwekkeboom et al. investigated the presence of bone metastases, the extent of liver involvement, and gastrinoma, insulinoma or VIPoma tumour types as prognostic factors for tumour progression in a multivariate analysis [7]. Our series, with respect to the two previous studies, evaluated the role of major prognostic factors [9, 10] in patients treated with PRRT in a smaller but even more homogeneous series (only pancreatic and gastrointestinal NETs). In this study, the more recent classifications in terms of TNM [11, 12] and WHO [3] were used to update the findings regarding prognostic factors. We agree with Ezziddin et al. as far as the need for caution in the use of multivariate analyses with a large number of variables in a relatively small number of patients is concerned. However, in order to reduce the impact of too many variables, the forward stepwise method was used. We also agree that prospective and comparative studies in larger homogeneous series are obviously necessary to better assess the value of the data reported. D. Campana : P. Tommassetti Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

This is a medical position statement developed by the Exocrine Pancreatic Insufficiency collaborative group which is a part of the Italian Association for the Study of the Pancreas (AISP). We covered the main diseases associated with exocrine pancreatic insufficiency (EPI) which are of common interest to internists/gastroenterologists, oncologists and surgeons, fully aware that EPI may also occur together with many other diseases, but less frequently. A preliminary manuscript based on an extended literature search (Medline/PubMed, Cochrane Library and Google Scholar) of published reports was prepared, and key recommendations were proposed. The evidence was discussed at a dedicated meeting in Bologna during the National Meeting of the Association in October 2012. Each of the proposed recommendations and algorithms was discussed and an initial consensus was reached. The final draft of the manuscript was then sent to the AISP Council for approval and/or modification. All concerned parties approved the final version of the manuscript in June 2013.

Celiac Disease and CFTR Mutations in Patients With Chronic Asymptomatic Pancreatic Hyperenzymemia

a b s t r a c t Background: There are few data on the outcome of patients with intraductal papillary mucinous neoplasms of the pancreas meeting criteria for resection (Sendai-positive), and not operated. Aim: To evaluate outcome of patients with a resectable, Sendai-positive intraductal papillary mucinous neoplasm, and not operated. Methods: Multicentre, retrospective analysis of prospectively enrolled patients, with resectable Sendai- positive, not-operated intraductal papillary mucinous neoplasm. Overall-survival and disease-specific survival were the primary end-point, and progression-free survival secondary. Results: Thirty-five patients (60% male, median age 77) enrolled: 40% main-duct, 60% branch-duct intra- ductal papillary mucinous neoplasms. In 19 patients surgery was ruled out due to comorbidities, in 7 because aged > 80, 9 refused surgery. Twelve (34.3%) patients died after a mean of 32.5 months, 8 due to disease progression, 4 due to comorbidities. The median overall, disease-specific and progression-free survival were 52, 55, and 44 months respectively. Main duct involvement and age at diagnosis were associated with worse overall and progression-free survival, only main duct involvement with worse disease-specific survival (52 months main duct vs. 64 branch duct; P = 0.04). Conclusion: These results suggest that in elderly and comorbid patients with Sendai-positive intraductal papillary mucinous neoplasms, especially of the branch duct, a conservative approach could be reason- able, as associated with a relatively good outcome, and should be carefully discussed with the patients.

Risk Factors for Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas: A Multicentre Case–Control Study

Gastric acid secretion is an important factor in iron absorption in humans. Chronic corporal atrophic gastritis (CAG) is a pathologic condition characterized by oxyntic mucosal atrophy and hypochlorhydria that may cause unexplained iron-deficiency states that are difficult to treat with standard oral iron therapy. The molecule ferrous acetyl transferrin (FAT) displays a high degree of homology with human transferrin and may thus use the same transferrin receptor-mediated iron absorption system on ileal and duodenal crypts. We tested this oral iron preparation in nine achlorhydric CAG patients to evaluate its absorption in the total absence of gastric acid secretion. FAT 40 mg was administered twice daily by mouth for 7 days. Blood samples for determination of serum iron, ferritin, and transferrin levels were collected and calculation of the transferrin saturation index was performed before drug administration at 8 am on the first day of the study (when patients had been fasting), on day 8 (13 hours after the last dose of FAT), and on day 15 (7.5 days after the last dose of FAT). Serum iron levels on day 15 (median, 65 μg/dL) were significantly increased over pretreatment levels (median, 32.5 μg/dL) and over the levels observed on day 8 (median, 47.0 μg/dL). A similar increase in median transferrin saturation index was observed (17.52% on day 15 vs 7.33% before treatment and 11.53% on day 8). Serum transferrin levels decreased significantly from day 8 (median, 281.5 mg/dL) to day 15 (median, 264.5 mg/dL). The study shows that in CAG patients with achlorhydria, iron in the form of FAT administered by mouth can be absorbed, resulting in increases in serum iron level and transferrin saturation index, during short-term treatment.

To evaluate the involvement of the apoptosis-suppressing protein BCL-2 in the gastrin-dependent mechanism of induction of gastric enterochromaffin-like (ECL) cell carcinoids, the endocrine cell of the oxyntic mucosa were immunohistochemically investigated in (a) 10 normogastrinemic subjects with histologically normal gastric mucosa; (b) 22 patients with endocrine cell hyperplasia and affected by hypergastrinemic conditions with different risk of gastric carcinoid development, such as sporadic Zollinger-Ellison syndrome (sZES; n = 9), ZES associated with multiple endocrine neoplasia-1 (MEN-1; n = 4), and atrophic fundal gastritis (AFG; n = 9); (c) 14 patients with ECL gastric carcinoids accounting for a total of 31 tumors investigated. In the normal oxyntic mucosa, BCL-2 was consistently expressed by a subset of endocrine cells accounting for 50.0% (median; range, 24.6-74.0%) of the total number of endocrine cells immunostained for chromogranin A (CgA) in consecutive sections. BCL-2 immunoreactive cells were located mostly in the middle mucosal layer, suggesting a role for the protein during downward migration of maturing endocrine cells. No BCL-2 immunoreactivity was found in other specialized gastric epithelial cells. Expression of BCL-2 by hyperplastic oxyntic endocrine cells (mostly ECL cells) varied in parallel with the risk of carcinoid development. In fact, the ratio of BCL-2- to CgA-immunoreactive cells was reduced (median, 4.6%; p less than 0.0001; range, 0.9-42.0%) in sZES, a condition showing virtually no risk, unchanged (median, 55.6%; range 29.4-83.8 %) in cases of MEN-1/ZES with intermediate risk, and increased (median 87.6%; p less than 0.014; range, 48.8-199.4%) in cases of AFG, a condition at the highest risk of carcinoid. In ECL cell carcinoids, BCL-2 expression varied markedly from one tumor to another even in the same patient and was low or absent in most cases. In both hyperplastic and neoplastic ECL cells, an inverse relation between BCL-2 expression and CgA immunoreactivity, that is, the cell granule content, was found. These results suggest that BCL-2 expression by hyperplastic ECL cells is independent of the influence of serum gastrin and may contribute to the development of ECL cell carcinoid tumors by extending cell exposure to oncogenic factors. Once a carcinoid tumor is established, BCL-2 expression becomes inconsistent.

4094Background: Surgery with radical intent is the only curative option for digestive neuroendocrine neoplasms (DNENs), but clinical practice shows disease-free patients recurring even after years....

219 Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), which can be detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to evaluate, in metastatic DNENs FU, the diagnostic yield of FITs associated to Computed Tomography scan (CT) in terms of detecting new distant metastases (primary outcome) and of clinical usefulness (secondary outcome). Methods: Retrospective analysis of stage IV DNENs expressing SSTRs and with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), subsequently it was 68Ga-DOTA- PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-“units”, in which each patient had faced at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathological findings collected for each patient during FU. Clinical usefulness was defined as “appropriate changes” in management (indication to further imaging tests, surgery, biopsy, change in therapy) due to CT and/or FITs. Results: Interim analysis of 381 units (median 3 per patient, range 2-7) obtained from 121 patients included so far (67.8% metastatic since diagnosis). New lesions were detected by CT alone in 82.3% of cases; adding OCT, the diagnostic yield was 9.6%, while adding GaPET 21.7% (P

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment modality for patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs). The aim of this study was to determine the time to progression of patients treated with PRRT and to identify the prognostic factors related to treatment response. METHODS: Patients with sporadic GEP NETs prospectively treated with PRRT were retrospectively analysed. The primary end point was progression-free survival (PFS). RESULTS: A total of 69 patients (37 men and 32 women; 45 with pancreatic and 24 with gastrointestinal lesion; 22 NET G1 and 41 NET G2) were treated with 90Y or 177Lu. The objective response rate was 27.5 % (partial response, PR), while 50.7 % had stable disease and 23.2 % had progressive disease. Significant differences in PFS were observed in relationship to the stage of the disease (44 months for stage III, 23 months for stage IV), the evidence of a PR 6 months after the end of the PRRT (39 months in patients with a PR, 22 months in patients without a PR) and previous transarterial chemoembolization (TACE, yes 13 months vs no 31 months). Stage IV, NET G2 and previous TACE were found to be significant factors for tumour progression at multivariate analysis. CONCLUSION: Low tumour burden and a low proliferation index represent independent prognostic factors for long PFS, while previous chemoembolization techniques represent independent prognostic factors for early tumour progression and shorter PFS. Our data suggest that chemoembolization techniques to reduce the hepatic tumour burden should be avoided.

The small intestine is one of the distant organs that become damaged during severe acute pancreatitis, due to microcirculation disturbance associated with loss of fluids in the "third space," hypovolemia, splanchnic vasoconstriction, and finally an ischemia-reperfusion injury. In this scenario, the gut acts as the starter for severe systemic complications, as the failure of the intestinal barrier is associated with translocation of bacteria and inflammatory and toxic products produced in the intestinal wall, which can be responsible for sepsis and infection of the necrotic pancreas and for systemic inflammatory response. Therefore, one of the main goals of treatment in the early phases of severe acute pancreatitis should be to maintain the integrity of the gut barrier in the small intestine. These strategies include appropriate fluid resuscitation to limit the damage due to the relative hypovolemia and early enteral feeding. The role of intravenous antibiotics to prevent infection of the pancreatic necrosis is controversial and the role of probiotics, which seemed a promising tool in vitro and in early clinical trials, needs to be further investigated to better understand the effects of the single specific strains at various doses and timing before designing new clinical trials.

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n = 86), chronic pancreatitis (n = 272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.

Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel–Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.