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Pancreatic Neoplasms: HELP
Articles by Stefania Beghelli
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, S. Beghelli wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Autoantibodies to Ezrin are an early sign of pancreatic cancer in humans and in genetically engineered mouse models. 2013

Capello, Michela / Cappello, Paola / Linty, Federica Caterina / Chiarle, Roberto / Sperduti, Isabella / Novarino, Anna / Salacone, Paola / Mandili, Giorgia / Naccarati, Alessio / Sacerdote, Carlotta / Beghelli, Stefania / Bersani, Samantha / Barbi, Stefano / Bassi, Claudio / Scarpa, Aldo / Nisticò, Paola / Giovarelli, Mirella / Vineis, Paolo / Milella, Michele / Novelli, Francesco. ·Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy. franco.novelli@unito.it. ·J Hematol Oncol · Pubmed #24010981.

ABSTRACT: BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy with only a 5% 5-year survival rate. Reliable biomarkers for early detection are still lacking. The goals of this study were (a) to identify early humoral responses in genetically engineered mice (GEM) spontaneously developing PDAC; and (b) to test their diagnostic/predictive value in newly diagnosed PDAC patients and in prediagnostic sera. METHODS AND RESULTS: The serum reactivity of GEM from inception to invasive cancer, and in resectable or advanced human PDAC was tested by two-dimensional electrophoresis Western blot against proteins from murine and human PDAC cell lines, respectively. A common mouse-to-human autoantibody signature, directed against six antigens identified by MALDI-TOF mass spectrometry, was determined. Of the six antigens, Ezrin displayed the highest frequency of autoantibodies in GEM with early disease and in PDAC patients with resectable disease. The diagnostic value of Ezrin-autoantibodies to discriminate PDAC from controls was further shown by ELISA and ROC analyses (P < 0.0001). This observation was confirmed in prediagnostic sera from the EPIC prospective study in patients who eventually developed PDAC (with a mean time lag of 61.2 months between blood drawing and PDAC diagnosis). A combination of Ezrin-autoantibodies with CA19.9 serum levels and phosphorylated α-Enolase autoantibodies showed an overall diagnostic accuracy of 0.96 ± 0.02. CONCLUSIONS: Autoantibodies against Ezrin are induced early in PDAC and their combination with other serological markers may provide a predictive and diagnostic signature.

2 Article Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. 2018

Bauer, Andrea S / Nazarov, Petr V / Giese, Nathalia A / Beghelli, Stefania / Heller, Anette / Greenhalf, William / Costello, Eithne / Muller, Arnaud / Bier, Melanie / Strobel, Oliver / Hackert, Thilo / Vallar, Laurent / Scarpa, Aldo / Büchler, Markus W / Neoptolemos, John P / Kreis, Stephanie / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany. · Genomics and Proteomics Research Unit, Luxembourg Institute of Health, Luxembourg City, Luxembourg. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom. · Life Sciences Research Unit, University of Luxembourg, Luxembourg City, Luxembourg. ·Int J Cancer · Pubmed #28983920.

ABSTRACT: Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

3 Article Somatic mutations in exocrine pancreatic tumors: association with patient survival. 2013

Rachakonda, P Sivaramakrishna / Bauer, Andrea S / Xie, Huaping / Campa, Daniele / Rizzato, Cosmeri / Canzian, Federico / Beghelli, Stefania / Greenhalf, William / Costello, Eithne / Schanne, Michaela / Heller, Anette / Scarpa, Aldo / Neoptolemos, John P / Werner, Jens / Büchler, Markus / Hoheisel, Jörg D / Hemminki, Kari / Giese, Nathalia / Kumar, Rajiv. ·Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. s.rachakonda@dkfz.de ·PLoS One · Pubmed #23565280.

ABSTRACT: KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.

4 Article Targeting gemcitabine containing liposomes to CD44 expressing pancreatic adenocarcinoma cells causes an increase in the antitumoral activity. 2013

Dalla Pozza, Elisa / Lerda, Carlotta / Costanzo, Chiara / Donadelli, Massimo / Dando, Ilaria / Zoratti, Elisa / Scupoli, Maria Teresa / Beghelli, Stefania / Scarpa, Aldo / Fattal, Elias / Arpicco, Silvia / Palmieri, Marta. ·Department of Life and Reproduction Sciences, University of Verona, Verona, Italy. ·Biochim Biophys Acta · Pubmed #23384419.

ABSTRACT: Pancreatic adenocarcinoma is often diagnosed when metastatic events have occurred. The early spread of circulating cancer cells expressing the CD44 receptor may play a crucial role in this process. In this study, we have investigated the cellular delivery ability and both in vitro and in vivo anti-tumoral activity of liposomes conjugated with two different low molecular weight hyaluronic acids (HA 4.8kDa and HA 12kDa), the primary ligand of CD44, and containing a lipophilic gemcitabine (GEM) pro-drug. By confocal microscopy and flow cytometry analyses, we demonstrate that the cellular uptake into a highly CD44-expressing pancreatic adenocarcinoma cell line is higher with HA-conjugated (12kDa>4.8kDa) than non-conjugated liposomes. Consistently, in vitro cytotoxic assays display an increased sensitivity towards GEM containing HA-liposomes, compared to non-conjugated liposomes. Conversely, CD44 non-expressing normal cells show a similar uptake and in vitro cytotoxicity with both HA-conjugated and non-conjugated liposomes. Furthermore, we demonstrate that the HA-liposomes are taken up into the cells via lipid raft-mediated endocytosis. All the liposome formulations containing GEM show a higher antitumoral activity than free GEM in a mouse xenograft tumor model of human pancreatic adenocarcinoma. The 12kDa HA-liposomes have the strongest efficiency, while non-conjugated liposomes and the 4.8kDa HA-liposomes are similarly active. Taken together, our results provide a strong rationale for further development of HA-conjugated liposomes to treat pancreatic adenocarcinoma.

5 Article ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. 2013

Campos, M Luisa / Sánchez-Arévalo Lobo, Víctor J / Rodolosse, Annie / Gottardi, Cara J / Mafficini, Andrea / Beghelli, Stefania / Scardoni, Maria / Bassi, Claudio / Scarpa, Aldo / Real, Francisco X. ·Grupo de Carcinogénesis Epitelial, Programa de Patología Molecular, CNIO-Spanish National Cancer Research Center, 28029 Madrid, Spain. ·Biochem J · Pubmed #23339455.

ABSTRACT: The PTF1 (pancreas transcription factor 1) complex is a master regulator of differentiation of acinar cells, responsible for the production of digestive enzymes. In the adult pancreas, PTF1 contains two pancreas-restricted transcription factors: Ptf1a and Rbpjl. PTF1 recruits P/CAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] which acetylates Ptf1a and enhances its transcriptional activity. Using yeast two-hybrid screening, we identified ICAT (inhibitor of β-catenin and Tcf4) as a novel Ptf1a interactor. ICAT regulates the Wnt pathway and cell proliferation. We validated and mapped the ICAT-Ptf1a interaction in vitro and in vivo. We demonstrated that, following its overexpression in acinar tumour cells, ICAT regulates negatively PTF1 activity in vitro and in vivo. This effect was independent of β-catenin and was mediated by direct binding to Ptf1a and displacement of P/CAF. ICAT also modulated the expression of Pdx1 and Sox9 in acinar tumour cells. ICAT overexpression reduced the interaction of Ptf1a with Rbpjl and P/CAF and impaired Ptf1a acetylation by P/CAF. ICAT did not affect the subcellular localization of Ptf1a. In human pancreas, ICAT displayed a cell-type-specific distribution; in acinar and endocrine cells, it was nuclear, whereas in ductal cells, it was cytoplasmic. In ductal adenocarcinomas, ICAT displayed mainly a nuclear or mixed distribution and the former was an independent marker of survival. ICAT regulates acinar differentiation and it does so through a novel Wnt pathway-independent mechanism that may contribute to pancreatic disease.

6 Article Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma. 2012

Laghi, Luigi / Beghelli, Stefania / Spinelli, Antonino / Bianchi, Paolo / Basso, Gianluca / Di Caro, Giuseppe / Brecht, Anna / Celesti, Giuseppe / Turri, Giona / Bersani, Samantha / Schumacher, Guido / Röcken, Christoph / Gräntzdörffer, Ilona / Roncalli, Massimo / Zerbi, Alessandro / Neuhaus, Peter / Bassi, Claudio / Montorsi, Marco / Scarpa, Aldo / Malesci, Alberto. ·Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. luigi.laghi@humanitas.it ·PLoS One · Pubmed #23029359.

ABSTRACT: BACKGROUND AND AIMS: Pancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS. METHODS: MS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338 consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers. RESULTS: Only one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one. CONCLUSIONS: MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.

7 Article Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. 2012

Corbo, V / Beghelli, S / Bersani, S / Antonello, D / Talamini, G / Brunelli, M / Capelli, P / Falconi, M / Scarpa, A. ·ARC-NET Center for the Applied Research on Cancer-Networking, Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. ·Ann Oncol · Pubmed #21447618.

ABSTRACT: BACKGROUND: Kinases represent potential therapeutic targets in pancreatic endocrine tumours (PETs). PATIENTS AND METHODS: Thirty-five kinase genes were sequenced in 36 primary PETs and three PET cell lines: (i) 4 receptor tyrosine kinases (RTK), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tyrosine-protein kinase KIT (KIT), platelet-derived growth factor receptor alpha (PDGFRalpha); (ii) 6 belonging to the Akt/mTOR pathway; and (iii) 25 frequently mutated in cancers. The immunohistochemical expression of the four RTKs and the copy number of EGFR and HER2 were assessed in 140 PETs. RESULTS: Somatic mutations were found in KIT in one and ATM in two primary neoplasms. Among 140 PETs, EGFR was immunopositive in 18 (13%), HER2 in 3 (2%), KIT in 16 (11%), and PDGFRalpha in 135 (96%). HER2 amplification was found in 2/130 (1.5%) PETs. KIT membrane immunostaining was significantly associated with tumour aggressiveness and shorter patient survival. PET cell lines QGP1, CM and BON harboured mutations in FGFR3, FLT1/VEGFR1 and PIK3CA, respectively. CONCLUSIONS: Only rare PET cases, harbouring either HER2 amplification or KIT mutation, might benefit from targeted drugs. KIT membrane expression deserves further attention as a prognostic marker. ATM mutation is involved in a proportion of PET. The finding of specific mutations in PET cell lines renders these models useful for preclinical studies involving pathway-specific therapies.

8 Article MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. 2010

Corbo, Vincenzo / Dalai, Irene / Scardoni, Maria / Barbi, Stefano / Beghelli, Stefania / Bersani, Samantha / Albarello, Luca / Doglioni, Claudio / Schott, Christina / Capelli, Paola / Chilosi, Marco / Boninsegna, Letizia / Becker, Karl-Friedrich / Falconi, Massimo / Scarpa, Aldo. ·ARC-NET Research Center Department of Pathology, University of Verona, Policlinico G.B. Rossi c/o Piastra Odontoiatrica, Piazzale L.A. Scuro 10, Verona, Italy. ·Endocr Relat Cancer · Pubmed #20566584.

ABSTRACT: Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.

9 Article Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. 2010

Scarpa, Aldo / Mantovani, William / Capelli, Paola / Beghelli, Stefania / Boninsegna, Letizia / Bettini, Rossella / Panzuto, Francesco / Pederzoli, Paolo / delle Fave, Gianfranco / Falconi, Massimo. ·Department of Pathology, University of Verona, Verona, Italy. aldo.scarpa@univr.it ·Mod Pathol · Pubmed #20305616.

ABSTRACT: Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS-TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS-TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases.

10 Article Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy. 2010

Monsurrò, Vladia / Beghelli, Stefania / Wang, Richard / Barbi, Stefano / Coin, Silvia / Di Pasquale, Giovanni / Bersani, Samantha / Castellucci, Monica / Sorio, Claudio / Eleuteri, Stefano / Worschech, Andrea / Chiorini, Jay A / Pederzoli, Paolo / Alter, Harvey / Marincola, Francesco M / Scarpa, Aldo. ·Department of Pathology, University of Verona Medical School, Verona, Italy. ·J Transl Med · Pubmed #20113473.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested. METHODS: We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines. RESULTS: The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6. CONCLUSION: Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials.

11 Article Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. 2010

Missiaglia, Edoardo / Dalai, Irene / Barbi, Stefano / Beghelli, Stefania / Falconi, Massimo / della Peruta, Marco / Piemonti, Lorenzo / Capurso, Gabriele / Di Florio, Alessia / delle Fave, Gianfranco / Pederzoli, Paolo / Croce, Carlo M / Scarpa, Aldo. ·Departments of Pathology and Surgical and Gastroenterological Sciences, University of Verona, Verona, Italy. ·J Clin Oncol · Pubmed #19917848.

ABSTRACT: PURPOSE: We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome. PATIENTS AND METHODS: Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays. RESULTS: Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines. CONCLUSION: Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.

12 Article Expression pattern of claudins 5 and 7 distinguishes solid-pseudopapillary from pancreatoblastoma, acinar cell and endocrine tumors of the pancreas. 2009

Comper, Fabrizio / Antonello, Davide / Beghelli, Stefania / Gobbo, Stefano / Montagna, Licia / Pederzoli, Paolo / Chilosi, Marco / Scarpa, Aldo. ·Dipartimento di Patologia, Universita'e Azienda Ospedaliera di Verona, Verona, Italy. ·Am J Surg Pathol · Pubmed #19194274.

ABSTRACT: Solid-pseudopapillary tumor (SPT) of the pancreas is characterized by a discohesive appearance of the neoplastic cells. This has been linked to the displacement of E-cadherin and beta-catenin from their normal membrane location, which prevents adherens junctions to form. The nuclear localization of beta-catenin is also a feature of SPT that helps in differential diagnosis. This latter includes pancreatic endocrine tumor (PET) as SPT may show neuroendocrine differentiation, and pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma (PB) that may often show nuclear beta-catenin staining. However, the role of additional cell-cell adhesion systems remains to be elucidated in SPT, particularly that of claudins that are essential components of tight junctions showing modulated expression in diverse tumor types. We studied 20 SPT, 20 nonfunctioning PET, 7 ACC, 2 PB, and their matched normal pancreas for the immunohistochemical expression of claudin family members 1, 2, 3, 4, 5, and 7, beta-catenin and E-cadherin. All SPT showed intense membrane claudin 5 and cytoplasmic claudin 2 staining, lack of claudins 3 and 4, and positive cytoplasmic claudins 1 and 7 in few cases. Conversely, PET, ACC, and PB showed strong membrane expression of claudin 7 and lack of claudin 5, whereas claudins 1, 2, 3, and 4 showed variable expression among samples. All SPT showed nuclear beta-catenin and lack of E-cadherin membrane staining, whereas PET, ACC, and PB only showed nuclear beta-catenin in 1, 2, and 2 cases, respectively. SPT shows a peculiar claudin expression profile and the highly specific pattern of claudins 5 and 7 differentiates SPT from PET, ACC, and PB.