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Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.

Aims Contemporary, real-world data on type 2 diabetes mellitus (T2DM) are limited. We analysed prevalence, comorbidities, outcomes and costs of T2DM patients with and without coronary artery disease (CAD) or stroke in >7 million inhabitants. Methods T2DM patients were identified in 2015 (accrual period) from the Ricerca e Salute (ReS) database linking administrative records to demographics. From 2013–2015 information, four cohorts were considered: #1 with CAD and/or stroke; #2 without CAD and/or stroke; #3 with chronic CAD but no myocardial infarction or stroke; #4 with chronic CAD undergoing percutaneous coronary interventions (PCI). Hospitalizations, drugs and other outpatient care were assessed from 2015 to 2017. Results Prevalence of T2DM was 6% (441,085/7,365,954). CAD and/or stroke in the previous 3 years affected 7.5% of T2DM patients (33,153); this cohort was generally older, of male sex, with more comorbidities, prescriptions, and hospital admissions (50% versus 13.4%) compared to cohort #2. Yearly costs were >3-fold for cohort #1 versus #2, main drivers being hospitalizations in the former and drugs in the latter. Unexpectedly, two-year cardiovascular events were significantly higher in cohort #4 compared to any other (Figure). Guideline-recommended therapies were suboptimal in all cohorts. Conclusions The present analysis points to three areas of potential improvement in T2DM management: 1) undertreatment of T2DM patients with recommended drugs; 2) three-fold recurrences and costs in T2DM patients with, compared to those without, prior cardiovascular events; 3) highest risk of events in those with chronic CAD and PCI, warranting specific studies aimed at defining more effective preventive strategies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was partially supported by an unrestricted grant from Astra Zeneca. Astra Zeneca was not involved in data collection, analysis and interpretation, in writing the report, nor in deciding to submit the article for publication.

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II–associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

Diabeticcardiomyopathyreferstoacardiacdysfunctionobservedinpatientswithdiabetesthatoc- curs in absence of other cardiovascular disease, such as coronary artery disease, hypertension, valvular, and congenital heart disease. The main metabolic abnormalities promoting cardiac dysfunction are the resistance to the meta- bolic actions of insulin in heart tissue, compensatory hyperinsulinemia, and the progression of hyperglycemia. Two stages of diabetic cardiomyopathy are described: an early stage characterized by left ventric- ular hypertrophy and impaired diastolic function, and a late stage characterized by cardiac fibrosis and systolic dysfunction. The occurrence of HF in patients affected by DM significantly impacts on quality of life, manifesta- tion of new symptoms and worsening of existing symptoms, and on long-term prognosis. Notargettreatmentshavebeentestedindiabeticcardiomyopathy,thusclinicaltrialsareneededto define the role of available HF therapies or to find new therapeutic targets for this clinical condition.

Background ITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC). Methods Eligible subjects aged 55–69 years, smokers or ex-smokers (at least 20 pack-years in the last 10 years), were randomised to receive an annual invitation for LDCT screening for 4 years (active group) or to usual care (control group). All participants were followed up for vital status and cause of death (at the end of 2014) and LC incidence (at the end of 2013). Pathological and clinical information was collected from the Tuscan Cancer Registry data. Results 1613 subjects were randomly assigned to the active group and 1593 to the control group. At the end of the follow-up period 67 LC cases were diagnosed in the active group and 71 in the control group (rate ratio (RR)=0.93; 95% CI 0.67 to 1.30). A greater proportion of stage I LC was observed in the active group (36% vs 11%, p Conclusions Despite the lack of statistical significance, the ITALUNG trial outcomes suggest that LDCT screening could reduce LC and overall mortality. Moreover, the comparison of the number of LC cases diagnosed in the two groups does not show overdiagnosis after an adequate follow-up period. A pooled analysis of all European screening trials is advocated to assess the benefit-to-harm ratio of LDCT screening and its implementation in public health settings. Trial registration number Results, NCT02777996.

Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. Methods: We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 1010 vp] and MVA-NSmut [2 × 108 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 1010 vp] and MVA.HIVconsv [2 × 108 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 1010 vp] and ChAdV63.HIVconsv [5 × 1010 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 108 pfu]. Immunogenicity was assessed using peptide pools in ex vivo ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. Results: All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728–4,464) and 3,405 (2,307–7,804) spot-forming cells (SFC)/106 PBMC for single and combined HCV vaccinations, respectively (p = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095–4,967) and 1,005 (169–2,482) SFC/106 PBMC for single and combined HIV-1 vaccinations, respectively (p = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4+ and CD8+ T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. Clinical trial registration: https://clinicaltrials.gov, identifier: NCT02362217

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring < 40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter >= 40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule > 5 mm, and MPD diameter > 10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way ‘from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2S) is a gasotransmitter produced from L-cysteine through the enzymatic action of cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase. D-Penicillamine is the d isomer of a dimethylated cysteine and has been used for the treatment of rheumatoid arthritis. AsD-penicillamine is structurally very similar to cysteine, we have investigated whether D-penicillamine, as a cysteine analogue, has an effect on the H2 S pathway. EXPERIMENTAL APPROACH: We tested the effect of D-penicillamine (0.01-1 mM) in mouse aortic rings mounted in isolated organ baths and determined whether it could affect H2 S biosynthesis. In particular, we investigated any possible inhibitor or donor behaviour by using recombinant enzyme-based assays and an in vivo approach. KEY RESULTS: D-Penicillamine, per se, showed little or no vasodilator effect, and it cannot be metabolized as a substrate in place of l-cysteine. However, d-penicillamine significantly reduced L-cysteine-induced vasodilatation in a concentration-dependent manner through inhibition of H2 S biosynthesis, and this effect occurred at concentrations 10 times lower than those needed to induce the release of H2 S. In particular, D-penicillamine selectively inhibited CSE in a pyridoxal-5'-phosphate-dependent manner. CONCLUSIONS AND IMPLICATIONS: Taken together, our results suggest that D-penicillamine acts as a selective CSE inhibitor, leading to new perspectives in the design and use of specific pharmacological tools for H2 S research. In addition, the inhibitory effect of D-penicillamine on CSE could account for its beneficial action in rheumatoid arthritis patients, where H2 S has been shown to have a detrimental effect.

Pancreatic tumors are an increasingly common finding in abdominal imaging. Various kinds of pathologies of the pancreas are well known, but it often remains difficult to classify the lesions radiologically in respect of type and grade of malignancy. Magnetic resonance imaging (MRI) is the method of choice for the evaluation of pancreatic pathologies due to its superior soft tissue contrast. In this article we present a selection of less common malignant and potentially malignant pancreatic neoplasms with their characteristic appearance on established MRI sequences with and without contrast enhancement.

Indications for endoscopic resection of fronto-ethmoidal osteomas have been progressively expanded thanks to optimization of surgical exposure and the development of dedicated instruments. Curved cutting drills are still suboptimal to treat hard osseous neoplasms of the frontal sinus. We present two patients affected by frontal osteoma treated with an endoscopic procedure using an ultrasonic bone curette. The ultrasonic bone curette may be considered an effective tool to reduce soft tissue manipulation, optimize surgical time and accelerate the healing process. However, the technique requires significant shape innovations to reach the lateral recesses and to manage pure intrasinusal lesions.Le indicazioni alla chirurgia endoscopica nel trattamento degli osteomi fronto-etmoidali si sono progressivamente estese grazie all'ottimizzazione dell'esposizione chirurgica ed allo sviluppo di una strumentazione dedicata. Le frese curve sono ancora subottimali nel trattamento di lesioni ossee eburnee del seno frontale. Presentiamo due pazienti affetti da osteoma frontale trattati con procedura endoscopica utilizzando la curette per osso ad ultrasuoni. La curette ad ultrasuoni può essere considerato un efficace strumento chirurgico per ridurre la manipolazione dei tessuti molli e per ottimizzare i tempi chirurgici e del processo di guarigione. Tuttavia è necessario migliorare la forma dello strumento per premettere di raggiungere i recessi più laterali e gestire lesioni localizzate interamente nel seno frontale.

Nearly more than one hundred men and women with massive obesity have been admitted to our clinical unit for the administration of a 6-8 week extremely low calorie diet (300 kcal). Treatment was well tolerated, and led to a weight loss of about 20 kg body weight in men and 15 kg in women. Cardiac, respiratory and orthopedic complications of severe obesity were gradually attenuated with a progressive decrease in the need for hypoglycemic, antihypertensive, analgesic and diuretic drug administrations. This treatment proved to be particularly useful in preparation to bariatric surgery and for improving complications of severe obesity.

Poster-Abstract

Background and Purpose Hydrogen sulfide (H2S) is a gasotransmitter produced from l-cysteine through the enzymatic action of cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase. d-Penicillamine is the d isomer of a dimethylated cysteine and has been used for the treatment of rheumatoid arthritis. As d-penicillamine is structurally very similar to cysteine, we have investigated whether d-penicillamine, as a cysteine analogue, has an effect on the H2S pathway. Experimental Approach We tested the effect of d-penicillamine (0.01-1 mM) in mouse aortic rings mounted in isolated organ baths and determined whether it could affect H2S biosynthesis. In particular, we investigated any possible inhibitor or donor behaviour by using recombinant enzyme-based assays and an in vivo approach. Key Results d-Penicillamine, per se, showed little or no vasodilator effect, and it cannot be metabolized as a substrate in place of l-cysteine. However, d-penicillamine significantly reduced l-cysteine-induced vasodilatation in a concentration-dependent manner through inhibition of H2S biosynthesis, and this effect occurred at concentrations 10 times lower than those needed to induce the release of H2S. In particular, d-penicillamine selectively inhibited CSE in a pyridoxal-5′-phospate-dependent manner. Conclusions and Implications Taken together, our results suggest that d-penicillamine acts as a selective CSE inhibitor, leading to new perspectives in the design and use of specific pharmacological tools for H2S research. In addition, the inhibitory effect of d-penicillamine on CSE could account for its beneficial action in rheumatoid arthritis patients, where H2S has been shown to have a detrimental effect. © 2016 The British Pharmacological Society.

Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO). Binding of NO to ferrous (Fe2+) heme increases its catalytic activity, leading to the production of cGMP from GTP. Hydrogen sulfide (H2S) is a signaling molecule that exerts both direct and indirect anti-oxidant effects. In the present, study we aimed to determine whether H2S could regulate sGC redox state and affect its responsiveness to NO-releasing agents and sGC activators. Using cultured rat aortic smooth muscle cells, we observed that treatment with H2S augmented the response to the NO donor DEA/NO, while attenuating the response to the heme-independent activator BAY58-2667 that targets oxidized sGC. Similarly, overexpression of H2S-synthesizing enzyme cystathionine-γ lyase reduced the ability of BAY58-2667 to promote cGMP accumulation. In experiments with phenylephrine-constricted mouse aortic rings, treatment with rotenone (a compound that increases ROS production), caused a rightward shift of the DEA/NO concentration-response curve, an effect partially restored by H2S. When rings were pre-treated with H2S, the concentration-response curve to BAY 58-2667 shifted to the right. Using purified recombinant human sGC, we observed that treatment with H2S converted ferric to ferrous sGC enhancing NO-donor-stimulated sGC activity and reducing BAY 58-2667-triggered cGMP formation. The present study identified an additional mechanism of cross-talk between the NO and H2S pathways at the level of redox regulation of sGC. Our results provide evidence that H2S reduces sGC heme Fe, thus, facilitating NO-mediated cellular signaling events. © 2016 Elsevier Ltd

The extracellular matrix (ECM) molecule tenascin-C (TNC) promotes tumor progression. This has recently been demonstrated in the stochastic murine RIP1-Tag2 insulinoma model, engineered to either express TNC abundantly or to be devoid of TNC. However, our knowledge about organization of the TNC microenvironment is scant. Here we determined the spatial distribution of TNC together with other ECM molecules in murine RIP1-Tag2 insulinoma and human cancer tissue (insulinoma and colorectal carcinoma). We found that TNC is organized in matrix tracks together with other ECM molecules of the AngioMatrix signature, a previously described gene expression profile that characterizes the angiogenic switch. Moreover, stromal cells including endothelial cells, fibroblasts and leukocytes were enriched in the TNC tracks. Thus, TNC tracks may provide niches for stromal cells and regulate their behavior. Given similarities of TNC rich niches for stromal cells in human insulinoma and colon cancer, we propose that the RIP1-Tag2 model may be useful for providing insights into the contribution of the tumor stroma specific ECM as promoter of cancer progression.

The aim of this survey was to describe the incidence, epidemiology, microbiology, risk factors and outcome of medical care related laboratory-confirmed bloodstream infections (LCBIs) observed during a twelve-month prospective study in a Paediatric Teaching Hospital in Turin, Italy. Inclusion criteria were clinical signs of sepsis and positivity of one or more of the following tests: blood culture, polymerase chain reaction for bacterial and fungal DNA on blood, and culture on intravascular device tips. In all, 140 episodes of sepsis were documented in 131 children: 37 (26.4%) were healthcare outpatient-associated, 91 (65.0%) healthcare-associated and 12 (8.6%) community-acquired. The overall incidence of healthcare-associated LCBIs was 13.6/1,000 hospitalized patients and incidence density 1.4/1,000 inpatient days. The overall mortality was 3.9%. Forty-seven (36.7%) episodes involved newborns and 107 (83.6%) episodes were observed in children with an indwelling central venous catheter. Coagulase-negative staphylococci (26.8%), Staphylococcus aureus (15.2%), Escherichia coli (8.7%) and Candida spp. (7.2%) were responsible for the majority of cases. 9.5% of S. aureus isolates were methicillin-resistant and 6.5% of Gram negatives were extended-spectrum beta-lactamase-producing. Incidence and epidemiology of medical care related LCBIs were similar to the existing literature data. LCBIs caused by antibiotic-resistant microorganisms were fewer and mortality rate was lower. Most of the LCBIs recorded involved newborns and oncological children.

The endocannabinoid system regulates cell proliferation in human breast cancer cells. Recently, we described that a metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide, by activation of CB1 receptors significantly inhibited cell proliferation of human breast cancer cell lines. In this study, we observed that the activation of the CB1 receptor, in two human mammary carcinoma cell lines, MDA MB 231 and MCF7,caused the inhibition of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA)-reductase activity due to a reduction of HMG-CoA reductase transcript levels. The decrease of HMG-CoA reductase activity induced the inhibition of the prenylation of proteins, in particular of the farnesylation of Ras oncogenic protein involved in cell proliferation of these cell lines. We suggest that the inhibitory effect of anadamide analogue on tumor cell proliferation could be related to the inhibition of Ras farnesylation.

Purpose The aim of this study is to compare the results of two multicenter studies of patients with adrenal disease treated with laparoscopic adrenalectomy in the Campania region (Italy) between January 2006 and December 2009 and between January 1992 and December 2005 and to evaluate the differences between the two series. Methods The data regarding 148 patients was obtained using questionnaires mailed or e-mailed in early 2010 to several surgical units operating in the Campania region. Three Units of Endocrine Surgery and 2 Units of General Surgery participated in the audit. The data was analyzed and compared to a previously published series of 250 patients from the same authors. Statistical analysis was performed with SPSS software. Results The definitive histology exams showed that the number of primary adenocarcinomas of the adrenal glands identified preoperatively as incidentalomas < 6 cm in size was smaller (1/68 - 1.4%) than the number reported in the literature. Most of the primary malignant adrenal tumors found were > 6 cm in size (3/4 - 75%). In the second series, intraoperative complications, operative times, and conversion rates were significantly reduced. There was no difference between the two series, in the Endocrine Surgery and General Surgery units, as regards indications for performing an adrenalectomy. Conclusions Laparoscopy can be considered a gold standard for lesions > 10 cm in size, but surgery should not be insisted upon every time an incidentaloma is detected through imaging. The role of the laparoscopic approach to primary adrenal malignancies is still under discussion, but small metastastic lesions < 6 cm in size may be treated with laparoscopy.

Background: Enteric glial cells (EGC) participate to gut homeostasis and are involved in intestinal inflammation. In humans, gut inflammation is characterized by EGC-derived S100B protein up-regulation. Nonetheless, it is still unclear if EGC-response is directly involved in, or it represents an epiphenomenon of inflammation itself. Aims: To investigate: 1) the role of EGC-derived S100B protein in mediating inflammation and nitric oxide (NO) production; 2) the enteroglial activation and responses to inflammatory stimuli in mucosa and in isolated myenteric ganglia and 3) the ability of EGC to stimulate immune cells proliferation. Methods: Rectal biopsies from 30 control subjects were stimulated with exogenous S100B and iNOS expression, NO production, lipid peroxidation and p38MAPkinase activation were evaluated in the presence of anti-RAGE neutralizing antibody, SB203580 (inhibitor of p38MAPkinase), TLCK (inhibitor of Nuclear Factor-kappaB transcription), respectively. Mucosal biopsies and isolated myenteric ganglia (obtained from the ileum of 10 surgical specimens) were stimulated with lipopolysaccharides (LPS)+interferon gamma (IFN-γ); a double labeling immunofluorescence using antibodies to S100B or GFAP was performed to identify EGC expressing c-fos in the nucleus, as a marker of cells activation Similarly, S100B mRNA, protein expression and secretion and iNOS expression and NO production were respectively assessed either in the presence, or absence of anti-RAGE antibody. Proliferation of human peripheral blood mononuclear cells (PBMC) isolated from healthy subjects was also checked by incubation with exogenous S100B. Results: In mucosal biopsies, exogenous S100B increased iNOS expression,NOproduction and lipid peroxidation through p38MAPkinase/Nuclear Factor-kappaB activation and via RAGE. Similarly, the addition of LPS/IFN-γ significantly increased S100B mRNA, protein expression and secretion, accompanied with enhanced iNOS expression and NO production. In isolated myenteric ganglia, LPS/IFN-γ incubation resulted in a consistent EGC's activation (c-fos positive nuclei in S100B/GFAP positive cells), together with S100B up-regulation and increased NO production. Interestingly, exogenous S100B significantly increased PBMC proliferation and activation (increased NO and Tumor Necrosis Factor-alpha production) in a RAGE-dependent manner. Conclusions: EGC are activated by inflammatory stimuli and directly participate to NO production through S100B up-regulation. Increased levels of EGC-derived S100B are able to stimulate immune cells proliferation in a RAGE-dependent pathway.

Introduction: Screening programs for familial pancreatic cancer (FPC) are currently based on endoscopic ultrasonography and / or magnetic resonance imaging. In up to 40% of individuals at risk, cystic lesions are detected, which are suspicious for small intraductal papillary mucinous neoplasms[for full text, please go to the a.m. URL], 131. Kongress der Deutschen Gesellschaft für Chirurgie

Background and aim: Irritable bowel syndrome (IBS) is characterized by disturbed intestinal motility and sensations. Modulation of intestinal microflora has the potential to target both the disturbances but, to date, few studies have evaluated the efficacy and safety of probiotic administration in IBS. The aim of this study was to evaluate the effect of a symbiotic preparation (Bifidobacterium longum W11 5 × 10 9 viable bacteria + fructooligosaccharide –FOS- 2.5 gr per sachet) in IBS patients with constipation. Material and methods: A total of 30 IBS patients with constipation (22 women, age 18-46 years) according to the Roma III criteria were en- rolled. Patients were randomized into 3 groups receiving 2 or 6 sachets of the symbiotic plus 5 g of partially hydrolyzed guar gum (PHGG), or 5 g of PHGG5 alone, respectively. A daily visual analog score-based questionnaire, investigating the severity of abdominal pain, bloating and the feeling of incomplete evacuation, was administered during 2 run-in weeks and 4 treatment weeks, respectively; also, the number of weekly evacuation and the laxative consumption were considered. At baseline and at the end of the treatment the Bristol scale, the colonic transit time and the SF-36 were also evaluated. Results: At the end of the study, none of the patients reported ad- verse effects. Regardless of the treatment there was no significant improvement of abdominal pain or feeling of incomplete evacuation. A significant reduction of bloating severity was observed in subjects receiving 2 sachets of the symbiotic (4 ± 2vs1.6 ± 1 mm, p=0.01) compared to those receiving 6 or fibers alone (3 ± 2vs2 ± 1and2 ± 1 vs 1.5 ± 1 mm, respectively p=NS). The treatment regimens were similarly and significantly effective in improving frequency of defecation, colonic transit time and the stool consistency, as measured by the Bristol scale, whereas no significant improvement of both mental and physical component of the SF-36 questionnaire was observed. Conclusions: Our data demonstrate the utility of symbiotics over fibres in improving the severity of abdominal bloating in patients with IBS with constipation

Gastro-oesophageal reflux disease is a condition in which the reflux of gastric contents into the oesophagus provokes symptoms or complications and impairs quality of life. Typical symptoms of gastro-oesophageal reflux disease are heartburn and regurgitation but gastro-oesophageal reflux disease has also been related to extra-oesophageal manifestations, such as asthma, chronic cough and laryngitis. The pathogenesis of gastro-oesophageal reflux disease is multifactorial, involving transient lower oesophageal sphincter relaxations and other lower oesophageal sphincter pressure abnormalities. As a result, reflux of acid, bile, pepsin and pancreatic enzymes occurs, leading to oesophageal mucosal injury. Other factors contributing to the pathophysiology of gastro-oesophageal reflux disease include hiatal hernia, impaired oesophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Hiatal hernia contributes to gastro-oesophageal reflux disease by promoting lower oesophageal sphincter dysfunction. Impaired oesophageal clearance is responsible for prolonged acid exposure of the mucosa. Delayed gastric emptying, resulting in gastric distension, can significantly increase the rate of transient lower oesophageal sphincter relaxations, contributing to postprandial gastro-oesophageal reflux disease. The mucosal defensive factors play an important role against development of gastro-oesophageal reflux disease, by neutralizing the backdiffusion of hydrogen ion into the oesophageal tissue. While the pathogenesis of oesophageal symptoms is now well known, the mechanisms underlying extra-oesophageal airway manifestations are still poorly understood. Two hypotheses have been proposed: direct contact of gastric acid with the upper airway and a vago-vagal reflex elicited by acidification of the distal oesophagus, leading to bronchospasm. In conclusion, gastro-oesophageal reflux disease can be considered as the result of a complex interplay of factors, all promoting the contact of gastric acidic contents with the oesophageal mucosa, leading to different degrees of oesophageal damage.

Functional dyspepsia and non-erosive reflux disease (NERD) are highly prevalent functional diseases. In both the diseases symptoms overlap can be expected by chance alone, but recent data indicated that acid may be the common factor to explain symptoms generation. Indeed, esophageal acid perfusion has been recently associated with the onset of dyspeptic symptoms in healthy volunteers. Our aim was to study the effect of acid and its suppression, by PPI therapy, on NERD patients with dyspeptic symptoms. Hundred-twenty consecutive patients with reflux-associated symptoms were studied. Sixty-nine of them were selected because they were found to have non-erosive reflux disease during upper GI endoscopy and fulfilled the Rome criteria for functional dyspepsia. A standardized questionnaire, assessing the severity (effect on daily activities, from 0 to 3) of belching, abdominal bloating, early satiety, epigastric pain and burning, nausea, vomiting and postprandial fullness, and an esophagogastric 24hr pHmetry were performed before and at 4th week therapy with esomeprazole 20 mg bid. Intragastric acid inhibition was evaluated as the % of pH >3 and symptoms improvement was considered effective if a reduction of dyspepsia severity score (at least 50%) respect to baseline was obtained. Esophageal basal acid exposure (pH 4%) was pathological in 44 pts, whereas it was normal in 25. No significant difference was observed in the prevalence and the severity of individual dyspeptic symptoms. At baseline the intragastric % pH >3 was similar in subjects with normal and abnormal acid exposure (19±3.8 vs 18±4.5, p=NS). During esomeprazole therapy, reflux-associated symptoms improved in the majority of patients, but 7/69 patients had persistent pathological esophageal acid exposure. Overall PPI therapy significantly improved dyspeptic symptoms in 42/69 patients. Dyspepsia improvement was present in a higher number of patients with abnormal than in those with normal basal acid exposure (31/44 vs 11/25, respectively, p3, p

Objectives The aim of the present study was to assess the effect of previous appendectomy in a series of Crohn’s disease (CD) patients on the clinical characteristics and course of disease. Methods Demographic and clinical data were retrospectively analysed for 129 consecutive outpatients (68 men and 61 women, median age 38 years) with CD. For each patient, information concerning appendectomy, indication for surgery (acute/chronic) and the date of surgery were recorded. The date of the appendectomy in relation to the date of CD diagnosis was carefully assessed in order to evaluate the precise relationship between the two events. A total of 129 CD patients who had not undergone previous appendectomy served as controls. The severity of disease was assessed retrospectively by evaluating the need for systemic steroids, immunosuppressants and surgical treatment for CD, particularly resective procedures. Results Forty-one CD patients (31.8%) underwent appendectomy before the diagnosis of disease. Appendectomy before diagnosis showed a negative association with colonic disease localization and with articular manifestations. In addition, the 41 patients with previous appendectomy had a significantly greater risk of surgery, particularly resective. Multivariate analysis confirmed appendectomy performed before diagnosis as an independent risk factor for surgery; on the contrary, colonic site and inflammatory type of disease were independent factors protecting against surgery. Although current smokers were at an increased risk of surgical treatment, a smoking habit alone did not seem to be relevant at the multivariate analysis. Conclusion The results of this study indicate a worse clinical course of CD in patients appendicectomized before diagnosis.