Publications by authors named "Ivana Cataldo"

35 Publications

Can Vascular Endothelial Growth Factors and CD34 Expression Implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) Classification in Colorectal Polypoid Lesion Diagnosis?

Eur Surg Res 2020 20;61(2-3):72-82. Epub 2020 Oct 20.

General Surgery Unit, Padova University Hospital, Padova, Italy.

Background: Vascular endothelial growth factor (VEGF) is a subfamily of growth factors involved in angiogenesis; CD34+ cells are normally found in endothelial progenitor cells and endothelial cells of blood vessels. Colonic adenomatous polyps may not always be completely removable endoscopically, and a preoperative diagnosis might still be necessary. The aim of the study was to evaluate whether VEGF-A, VEGF-C and CD34 mRNA expression along colorectal carcinogenesis steps can implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) classification in the diagnosis of malignancy in colorectal polypoid lesions.

Methods: Seventy-one subjects with colonic adenoma or cancer who underwent screening narrow-band imaging (NBI) colonoscopy were prospectively enrolled in the MICCE1 project (Treviso center). Polyps were classified according to the NICE classification. Real-time RT-PCR for VEGF-A, VEGF-C and CD34 mRNA expression was performed. Nonparametric statistics, receiver-operating characteristic curve analysis and logistic multiple regression analysis were used.

Results: VEGF-A and CD34 mRNA expression was significantly higher in sessile adenomas than in polypoid ones (p < 0.001 and p = 0.01, respectively). VEGF-A, VEGF-C and CD34 mRNA expression was significantly higher in adenocarcinoma than in adenoma (p = 0.01, p = 0.01 and p = 0.01, respectively). The accuracy of VEGF-A, VEGF-C and CD34 mRNA expression for prediction of malignancy was 0.79 (95% CI 0.65-0.90), 0.81 (95% CI 0.66-0.91) and 0.80 (95% CI 0.65-0.90), respectively, while the accuracy of the NICE classification was 0.85 (95% CI 0.72-0.94). The determination coefficient R2, which indicates the amount of the variability explained by a regression model, for NICE classification alone was 0.24 (p < 0.001). A regression model that included NICE classification and VEGF-C mRNA expression showed an R2 = 0.39 as well as a model including NICE classification and CD34 mRNA levels.

Conclusions: This study demonstrated that VEGF-C and CD34 mRNA levels might be useful to stratify colorectal polyps in different risk of progression classes by implementing the accuracy of the NICE classification. Studies on in vivo detection of these markers are warranted.
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http://dx.doi.org/10.1159/000510266DOI Listing
October 2020

Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up of Exocrine Pancreatic Ductal Adenocarcinoma: Evidence Evaluation and Recommendations by the Italian Association of Medical Oncology (AIOM).

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Medical Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations.
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http://dx.doi.org/10.3390/cancers12061681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352458PMC
June 2020

Should the search for ganglia in the distal rectal fistula in patients with anorectal malformation be abandoned?

J Pediatr Surg 2020 Oct 1;55(10):2166-2169. Epub 2020 Apr 1.

Pathology, Ca' Foncello Hospital, Treviso, Italy.

Purpose: Occurrence of Hirschsprung's disease in anorectal malformation (ARM) patients is rare, but many surgeons still ask to pathologists to search for ganglia in the terminal rectum/fistula; the histological procedure is time and money consuming and the results confounding. A consecutive series of ARM patients, in which the presence of ganglia in terminal rectum was revised, is herein presented.

Materials And Methods: Rectal specimens of ARM patients who underwent corrective surgery in the last 6 years were retrieved. The histological protocol included H&E staining and calretinin immunohistochemistry. Each specimen is processed until all material is examined if no ganglia are retrieved after the first twelve sections.

Results: Forty cases were examined. Eight patients were younger than 1 month of age at operation. The mean length of the specimen was 1.5cm (range: 1-3 cm). Upon clinical request, ganglia were searched in 15/40 cases (37.5%) and resulted absent in 10/15 (66.5%). All patients have been followed and none developed signs or symptoms suggestive for Hirschsprung.

Conclusions: The practice to search for ganglia in the terminal rectum/fistula in ARM patients should be abandoned, as incidence of associated colorectal diseases is rare. Moreover, the procedure is expensive both in terms of laboratory's reagents and working time of expert pathologists and technicians.

Level Of Evidence: Level IV (Case Series with no Comparison Group).
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http://dx.doi.org/10.1016/j.jpedsurg.2020.03.021DOI Listing
October 2020

DIPLOMA Approach for Standardized Pathology Assessment of Distal Pancreatectomy Specimens.

J Vis Exp 2020 02 1(156). Epub 2020 Feb 1.

Department of Surgery, Southampton University Hospital NHS Foundation Trust;

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant cancers. A minority (20%) of PDACs are found in the pancreatic body and tail. Accurate pathology assessment of the pancreatic specimen is essential for providing prognostic information and it may guide further treatment strategies. The recent 8 edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system for pancreatic tumors has incorporated significant changes to tumor (pT) stage, which is predominantly based on tumor size. This change emphasizes the importance of careful block selection. Owing to the greater prevalence of tumors in the head of the pancreas, efforts are made to standardize the assessment of pancreatoduodenectomy specimens. However, consensus regarding the macroscopic assessment of distal (i.e., left) pancreatectomy specimens is lacking. The DIPLOMA approach includes the standardized measurement of pancreas and other resected organs, inking of relevant surgical margins and anatomical surfaces without removing covering layers of fat, measurement of tumor size (for T-stage), together with assessment of splenic vessel involvement (and other organs if present). All relevant margins are assessed, and relevant blocks are selected to confirm these parameters microscopically. The current protocol describes a standardized approach to the macroscopic assessment of distal pancreatectomy specimens. This approach was developed during several meetings with pathologists and surgeons during the preparation phase for an international multicenter trial (DIPLOMA, ISRCTN44897265), which focuses on radicality of distal pancreatectomy for pancreatic ductal adenocarcinoma. This standardized approach can be instrumental in the design of studies and will uniform reporting on the outcomes of distal pancreatectomy. The described technique is used in the DIPLOMA trial for pancreatic ductal adenocarcinoma but may also be useful for other indications.
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http://dx.doi.org/10.3791/60343DOI Listing
February 2020

The Italian Rare Pancreatic Exocrine Cancer Initiative.

Tumori 2019 Aug 9;105(4):353-358. Epub 2019 Apr 9.

1 Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy.

Introduction: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available.

Methods: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays.

Conclusions: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.
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http://dx.doi.org/10.1177/0300891619839461DOI Listing
August 2019

Dermoscopy of angioleiomyoma: A case report.

Australas J Dermatol 2019 May 4;60(2):e166-e168. Epub 2018 Dec 4.

Department of Dermatology, Ospedale Maggiore, University of Trieste, Trieste, Italy.

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http://dx.doi.org/10.1111/ajd.12962DOI Listing
May 2019

Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis.

Pancreas 2018 07;47(6):759-771

Modena Cancer Center, University of Modena and Reggio Emilia, Azienda Ospedaliera-Universitaria di Modena, Modena, Italy.

Objectives: Two issues were put forth by clinicians in the management of the advanced stages of rare variants of pancreatic ductal adenocarcinoma and other exocrine histotypes with peculiar clinical and pathological features: Do chemotherapy regimens recommended in pancreatic ductal adenocarcinoma patients have a clinical activity in rare pancreatic tumors? Or should other chemotherapy combinations be considered in this subset of patients?

Methods: We conducted a multicenter retrospective study that collected data from 2005 to 2016 at 14 Italian cancer centers with the aim to evaluate tumor response and time to progression for first- and second-line and overall survival.

Results: Of approximately 4300 exocrine pancreatic cancer patients, 79 advanced cases affected by rare histological types were identified, with pancreatic acinar cell cancer (n = 23), pancreatic adenosquamous cancer (n = 16), and mucinous cystic neoplasm with an associated invasive mucinous cystadenocarcinoma (n = 15) most represented. Survival analyses for each subgroup in relation with the different chemotherapy regimens showed the lack of statistical significance correlations.

Conclusions: Because of the lack of clinical trials in patients affected by these rare pancreatic histotypes, only their molecular classification would help clinicians in future therapeutic choice.
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http://dx.doi.org/10.1097/MPA.0000000000001063DOI Listing
July 2018

Angiogenesis in adenosquamous cancer of pancreas.

Oncotarget 2017 Nov 27;8(56):95773-95779. Epub 2017 Sep 27.

Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy.

Adenosquamous carcinoma of the pancreas (ASCP) is an uncommon variant of exocrine pancreatic malignancies, characterized by a histological admixture of adenomatous and squamous cell elements. This cancer is characterized by a poorly differentiated histology and a poorer clinical outcome compared to pancreatic ductal adenocarcinoma (PDAC). Unlike PDAC, that is characterized by a low microvascular density (MVD) and collapsed vasculature, no data are available about angiogenesis in ASPC. Immunohistochemical evaluation of MVD and trypatse-positive mast cells (MCs) were performed on a single case of ASCP compared to PDAC. Moreover, the levels of angiopoietin-1 and -2 (Ang-1, Ang-2), receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie-2), vascular endothelial growth factor A (VEGFA), hypoxia-inducible factor 1 alpha (HIF1A), miR-21-5p, miR-181a-5p, miR-122-5p, and miR-27a-3p were evaluated by real-time PCR. Higher number of tryptase-positive MCs and MVD are observed in the ASCP case compared to PDAC one. Lower levels of miR-122-5p and higher expression of VEGFA, HIF1A and Ang-2 genes were observed in ASCP. Furthermore, lower Ang-1 and Tie-2 transcript levels and higher increases of miR-21-5p, miR27a-3p and miR-181a-5p levels were found in the rarest form of pancreatic carcinoma. Our data demonstrate an important angiogenic activity in ASCP with a putative role of miR-21-5p, miR-181a-5p, miR-122-5p and miR-27a-3p in the regulation of this process.
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http://dx.doi.org/10.18632/oncotarget.21319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707059PMC
November 2017

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

Neurol Sci 2017 Oct;38(Suppl 2):217-224

Laboratory of Neuroimmunology, C. Mondino National Neurological Institute, Via Mondino 2, 27100, Pavia, Italy.

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3034-2DOI Listing
October 2017

Radiofrequency ablation for locally advanced pancreatic cancer: SMAD4 analysis segregates a responsive subgroup of patients.

Langenbecks Arch Surg 2018 Mar 5;403(2):213-220. Epub 2017 Oct 5.

General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.

Purpose: SMAD4 mutational status correlates with pancreatic ductal adenocarcinoma (PDAC) failure pattern. We investigated in a subset of locally advanced patients submitted to radiofrequency ablation (RFA) whether the assessment of SMAD4 status is a useful way to select the patients.

Methods: Clinical, radiological, and follow-up details of patients submitted to RFA for locally advanced pancreatic cancer (LAPC), in whom cytohistological material was available at our institution, were retrospectively retrieved. SMAD4 expression was evaluated by immunohistochemistry (IHC) and considered "negative" or "positive." The survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models.

Results: The study population consisted of 30 patients. Thirteen patients (43.3%) received RFA upfront, whereas 17 (56.7%) after induction treatments. SMAD4 was mutant in 18 out of 30 patients (60%). The overall estimated post-RFA disease-specific survival (DSS) was 15 months (95% CI 11.64-18.35). The estimated post-RFA DSS of patients with wild-type and mutant SMAD4 was 22 and 12 months, respectively (log-rank p < 0.05). At the multivariate analysis, SMAD4 was the only independent predictor of survival (p = 0.05). The pattern of failure was not associated with SMAD4 status (p = 0.4).

Conclusions: Within patients undergoing RFA for LAPC, SMAD4 analysis could segregate a subgroup of subjects with improved survival, who likely benefited from tumor ablation.
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http://dx.doi.org/10.1007/s00423-017-1627-0DOI Listing
March 2018

UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism.

Free Radic Biol Med 2017 12 27;113:176-189. Epub 2017 Sep 27.

Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address:

Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.09.022DOI Listing
December 2017

Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours.

Authors:
Aldo Scarpa David K Chang Katia Nones Vincenzo Corbo Ann-Marie Patch Peter Bailey Rita T Lawlor Amber L Johns David K Miller Andrea Mafficini Borislav Rusev Maria Scardoni Davide Antonello Stefano Barbi Katarzyna O Sikora Sara Cingarlini Caterina Vicentini Skye McKay Michael C J Quinn Timothy J C Bruxner Angelika N Christ Ivon Harliwong Senel Idrisoglu Suzanne McLean Craig Nourse Ehsan Nourbakhsh Peter J Wilson Matthew J Anderson J Lynn Fink Felicity Newell Nick Waddell Oliver Holmes Stephen H Kazakoff Conrad Leonard Scott Wood Qinying Xu Shivashankar Hiriyur Nagaraj Eliana Amato Irene Dalai Samantha Bersani Ivana Cataldo Angelo P Dei Tos Paola Capelli Maria Vittoria Davì Luca Landoni Anna Malpaga Marco Miotto Vicki L J Whitehall Barbara A Leggett Janelle L Harris Jonathan Harris Marc D Jones Jeremy Humphris Lorraine A Chantrill Venessa Chin Adnan M Nagrial Marina Pajic Christopher J Scarlett Andreia Pinho Ilse Rooman Christopher Toon Jianmin Wu Mark Pinese Mark Cowley Andrew Barbour Amanda Mawson Emily S Humphrey Emily K Colvin Angela Chou Jessica A Lovell Nigel B Jamieson Fraser Duthie Marie-Claude Gingras William E Fisher Rebecca A Dagg Loretta M S Lau Michael Lee Hilda A Pickett Roger R Reddel Jaswinder S Samra James G Kench Neil D Merrett Krishna Epari Nam Q Nguyen Nikolajs Zeps Massimo Falconi Michele Simbolo Giovanni Butturini George Van Buren Stefano Partelli Matteo Fassan Kum Kum Khanna Anthony J Gill David A Wheeler Richard A Gibbs Elizabeth A Musgrove Claudio Bassi Giampaolo Tortora Paolo Pederzoli John V Pearson Nicola Waddell Andrew V Biankin Sean M Grimmond

Nature 2017 10 27;550(7677):548. Epub 2017 Sep 27.

This corrects the article DOI: 10.1038/nature21063.
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http://dx.doi.org/10.1038/nature24026DOI Listing
October 2017

Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma.

J Pathol 2017 10 5;243(2):148-154. Epub 2017 Sep 5.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664430PMC
October 2017

Fhit down-regulation is an early event in pancreatic carcinogenesis.

Virchows Arch 2017 Jun 13;470(6):647-653. Epub 2017 Mar 13.

Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.

Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC.
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http://dx.doi.org/10.1007/s00428-017-2105-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568551PMC
June 2017

Multimodal treatment of resectable pancreatic ductal adenocarcinoma.

Crit Rev Oncol Hematol 2017 Mar 4;111:152-165. Epub 2017 Feb 4.

Modena Cancer Center, Policlinico di Modena Università di Modena e Reggio Emilia, Italy. Electronic address:

After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.
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http://dx.doi.org/10.1016/j.critrevonc.2017.01.015DOI Listing
March 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Authors:
Aldo Scarpa David K Chang Katia Nones Vincenzo Corbo Ann-Marie Patch Peter Bailey Rita T Lawlor Amber L Johns David K Miller Andrea Mafficini Borislav Rusev Maria Scardoni Davide Antonello Stefano Barbi Katarzyna O Sikora Sara Cingarlini Caterina Vicentini Skye McKay Michael C J Quinn Timothy J C Bruxner Angelika N Christ Ivon Harliwong Senel Idrisoglu Suzanne McLean Craig Nourse Ehsan Nourbakhsh Peter J Wilson Matthew J Anderson J Lynn Fink Felicity Newell Nick Waddell Oliver Holmes Stephen H Kazakoff Conrad Leonard Scott Wood Qinying Xu Shivashankar Hiriyur Nagaraj Eliana Amato Irene Dalai Samantha Bersani Ivana Cataldo Angelo P Dei Tos Paola Capelli Maria Vittoria Davì Luca Landoni Anna Malpaga Marco Miotto Vicki L J Whitehall Barbara A Leggett Janelle L Harris Jonathan Harris Marc D Jones Jeremy Humphris Lorraine A Chantrill Venessa Chin Adnan M Nagrial Marina Pajic Christopher J Scarlett Andreia Pinho Ilse Rooman Christopher Toon Jianmin Wu Mark Pinese Mark Cowley Andrew Barbour Amanda Mawson Emily S Humphrey Emily K Colvin Angela Chou Jessica A Lovell Nigel B Jamieson Fraser Duthie Marie-Claude Gingras William E Fisher Rebecca A Dagg Loretta M S Lau Michael Lee Hilda A Pickett Roger R Reddel Jaswinder S Samra James G Kench Neil D Merrett Krishna Epari Nam Q Nguyen Nikolajs Zeps Massimo Falconi Michele Simbolo Giovanni Butturini George Van Buren Stefano Partelli Matteo Fassan Kum Kum Khanna Anthony J Gill David A Wheeler Richard A Gibbs Elizabeth A Musgrove Claudio Bassi Giampaolo Tortora Paolo Pederzoli John V Pearson Nicola Waddell Andrew V Biankin Sean M Grimmond

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome.

Oncoimmunology 2016;5(12):e1221556. Epub 2016 Aug 12.

Tumour Immunology and Immunotherapy Unit, Regina Elena National Cancer Institute , Rome, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA, and hMENAΔv6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA isoform only showed strong staining in 26% of PDAC. The absence of hMENA in a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-β1-treated PDAC cell lines. hMENA knock-down in PDAC cell lines affected cell-cell adhesion but not invasion. TGF-β1 cooperated with β-catenin signaling to upregulate hMENA and hMENAΔv6 expression but not hMENA In the absence of hMENA, the hMENA/hMENAΔv6 up-regulation is crucial for SMAD2-mediated TGF-β1 signaling and TGF-β1-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC.
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http://dx.doi.org/10.1080/2162402X.2016.1221556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213039PMC
August 2016

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address:

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Ampulla of Vater Carcinoma: Sequencing Analysis Identifies TP53 Status as a Novel Independent Prognostic Factor and Potentially Actionable ERBB, PI3K, and WNT Pathways Gene Mutations.

Ann Surg 2018 Jan;267(1):149-156

ARC-NET Research Centre, University of Verona, Verona, Italy.

Objective: To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC).

Background: The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders.

Methods: We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma (KRAS), neuroblastoma RAS (NRAS), B rapidly accelerated fibrosarcoma (BRAF), TP53, and 4 membrane erythroblastosis oncogene B (ERBB) receptor tyrosine kinases (EGFR-ERBB1, HER2-ERBB2, HER3-ERBB3, HER4-ERBB4) amenable to pharmacological inhibition. Moreover, we evaluated mutations in 16 key components of rat sarcoma (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein 53 (P53), transforming growth factor beta (TGF-β), and wingless/integrated (WNT) pathways, recently associated to AVC by whole-exome sequencing.

Results: TP53 and KRAS were mutated in 41% and 35% of cases, respectively, and emerged as independent prognostic factors together with tumor stage and regardless of the histotype (TP53: P = 0.0006; KRAS: P = 0.0018; stage IIB: P = 0.0117; stage III-IV: P = 0.0020). ERBB, WNT and PI3K pathway genes were mutated in 37.5% of cases.

Conclusions: KRAS and TP53 mutations are negative predictors of survival in AVCs, regardless of histotype. Potentially actionable mutations in ERBB, WNT, and PI3K signaling pathway genes are present in 37.5% of all cases. These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling.
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http://dx.doi.org/10.1097/SLA.0000000000001999DOI Listing
January 2018

A Novel Nomogram to Predict the Prognosis of Patients Undergoing Liver Resection for Neuroendocrine Liver Metastasis: an Analysis of the Italian Neuroendocrine Liver Metastasis Database.

J Gastrointest Surg 2017 01 8;21(1):41-48. Epub 2016 Aug 8.

General and Hepatobiliary Surgery, Department of Surgery and Oncology, University of Verona, School of Medicine, Verona, Italy.

Even though surgery remains the only potentially curative option for patients with neuroendocrine liver metastases, the factors determining a patient's prognosis following hepatectomy are poorly understood. Using a multicentric database including patients who underwent hepatectomy for NELMs at seven tertiary referral hepato-biliary-pancreatic centers between January 1990 and December 2014, we sought to identify the predictors of survival and develop a clinical tool to predict patient's prognosis after liver resection for NELMs. The median age of the 238 patients included in the study was 61.9 years (interquartile range 51.5-70.1) and 55.9 % (n = 133) of patients were men. The number of NELMs (hazard ratio = 1.05), tumor size (HR = 1.01), and Ki-67 index (HR = 1.07) were the predictors of overall survival. These variables were used to develop a nomogram able to predict survival. According to the predicted 5-year OS, patients were divided into three different risk classes: 19.3, 55.5, and 25.2 % of patients were in low (>80 % predicted 5-year OS), medium (40-80 % predicted 5-year OS), and high (<40 % predicted 5-year OS) risk classes. The 10-year OS was 97.0, 55.9, and 20.0 % in the low, medium, and high-risk classes, respectively (p < 0.001). We developed a novel nomogram that accurately (c-index >70 %) staged and predicted the prognosis of patients undergoing liver resection for NELMs.
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http://dx.doi.org/10.1007/s11605-016-3228-6DOI Listing
January 2017

Extranodal Extension of Nodal Metastases Is a Poor Prognostic Indicator in Gastric Cancer: a Systematic Review and Meta-analysis.

J Gastrointest Surg 2016 10 13;20(10):1692-8. Epub 2016 Jul 13.

Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy.

Introduction: The extranodal extension (ENE) of nodal metastases (the extension of neoplastic cells through the nodal capsule into the perinodal soft tissue) is a histological feature that has been considered a prognostic factor in several cancers, but the role in gastric cancer was not yet investigated. We aimed to investigate the prognostic role of ENE in patients affected by gastric cancer through a systematic review and meta-analysis.

Material And Methods: Two independent authors searched major databases until 09/30/2015 to identify studies providing data on gastric cancer patients' prognostic parameters and comparing patients with ENE (ENE+) vs intra-nodal extension (ENE-). The data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) with 95 % confidence intervals (CI), adjusted for potential confounders.

Results: Nine studies followed up 3250 patients with gastric cancer (1064 ENE+ and 2186 ENE-). ENE+ was associated with a significantly higher risk of all-cause mortality (RR = 1.70; 95 % CI: 1.43-2.03, I (2) = 66 %; HR = 2.14; 95 % CI: 1.66-2.75, I (2) = 0 %), cancer-specific mortality (RR = 1.59; 95 % CI: 1.42-1.79; HR = 1.52; 95 % CI: 1.19-1.96), and disease recurrence (RR = 3.43, 95 % CI: 1.80-6.54, I (2) = 0 %).

Discussion: Judging from our results, ENE in gastric cancer patients should be considered for prognostic purposes from the gross sample to the pathology report.
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http://dx.doi.org/10.1007/s11605-016-3199-7DOI Listing
October 2016

An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients.

Clin Cancer Res 2016 Dec 7;22(24):6164-6175. Epub 2016 Jun 7.

Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.

Purpose: The majority of gastric cancer patients who achieve an initial response to trastuzumab-based regimens develop resistance within 1 year of treatment. This study was aimed at identifying the molecular mechanisms responsible for resistance.

Experimental Design: A HER2-trastuzumab sensitive NCI-N87 gastric cancer orthotopic nude mouse model was treated with trastuzumab until resistance emerged. Differentially expressed transcripts between trastuzumab-resistant and sensitive gastric cancer cell lines were annotated for functional interrelatedness by Ingenuity Pathway Analysis software. Immunohistochemical analyses were performed in pretreatment versus posttreatment biopsies from gastric cancer patients receiving trastuzumab-based treatments. All statistical tests were two-sided.

Results: Four NCI-N87 trastuzumab-resistant (N87-TR) cell lines were established. Microarray analysis showed HER2 downregulation, induction of epithelial-to-mesenchymal transition, and indicated fibroblast growth factor receptor 3 (FGFR3) as one of the top upregulated genes in N87-TR cell lines. In vitro, N87-TR cell lines demonstrated a higher sensitivity than did trastuzumab-sensitive parental cells to the FGFR3 inhibitor dovitinib, which reduced expression of pAKT, ZEB1, and cell migration. Oral dovitinib significantly (P = 0.0006) reduced tumor burden and prolonged mice survival duration in N87-TR mouse models. A higher expression of FGFR3, phosphorylated AKT, and ZEB1 were observed in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatment biopsies.

Conclusions: This study identified the FGFR3/AKT axis as an escape pathway responsible for trastuzumab resistance in gastric cancer, thus indicating the inhibition of FGFR3 as a potential strategy to modulate this resistance. Clin Cancer Res; 22(24); 6164-75. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0178DOI Listing
December 2016

BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing.

Oncotarget 2016 Jan;7(2):1076-83

ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.

BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue.
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http://dx.doi.org/10.18632/oncotarget.6834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811444PMC
January 2016

International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer.

Pancreatology 2016 Jan-Feb;16(1):14-27. Epub 2015 Nov 12.

University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom.

Background: Pancreatic cancer is one of the most devastating diseases with an extremely high mortality. Medical organizations and scientific societies have published a number of guidelines to address active treatment of pancreatic cancer. The aim of this consensus review was to identify where there is agreement or disagreement among the existing guidelines and to help define the gaps for future studies.

Methods: A panel of expert pancreatologists gathered at the 46th European Pancreatic Club Meeting combined with the 18th International Association of Pancreatology Meeting and collaborated on critical reviews of eight English language guidelines for the clinical management of pancreatic cancer. Clinical questions (CQs) of interest were proposed by specialists in each of nine areas. The recommendations for the CQs in existing guidelines, as well as the evidence on which these were based, were reviewed and compared. The evidence was graded as sufficient, mediocre or poor/absent.

Results: Only 4 of the 36 CQs, had sufficient evidence for agreement. There was also agreement in five additional CQs despite the lack of sufficient evidence. In 22 CQs, there was disagreement regardless of the presence or absence of evidence. There were five CQs that were not addressed adequately by existing guidelines.

Conclusion: The existing guidelines provide both evidence- and consensus-based recommendations. There is also considerable disagreement about the recommendations in part due to the lack of high level evidence. Improving the clinical management of patients with pancreatic cancer, will require continuing efforts to undertake research that will provide sufficient evidence to allow agreement.
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http://dx.doi.org/10.1016/j.pan.2015.10.013DOI Listing
December 2016

Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma.

Crit Rev Oncol Hematol 2016 Feb 23;98:309-24. Epub 2015 Nov 23.

Medical Oncology Clinic, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy.

Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed.
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http://dx.doi.org/10.1016/j.critrevonc.2015.11.016DOI Listing
February 2016

Combined inhibition of IL1, CXCR1/2, and TGFβ signaling pathways modulates in-vivo resistance to anti-VEGF treatment.

Anticancer Drugs 2016 Jan;27(1):29-40

aDigestive Molecular Clinical Oncology Research Unit bLaboratory of Oncology and Molecular Therapy, Department of Medicine cDepartment of Computer Science dSection of Anatomy and Histology, Department of Neurological, Neuropsychological, Morphological and Movement Sciences eARC-Net Research Centre and Department of Pathology and Diagnostics, Università degli studi di Verona fMedical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. We recently identified interleukin-1 (IL1), CXC receptors (CXCR)1/2 ligands, and transforming growth factor β (TGFβ) among the proinflammatory factors that were expressed at higher levels in murine models resistant to the antivascular endothelial growth factor (anti-VEGF) antibody bevacizumab. Here, we hypothesized that the combined inhibition of these proinflammatory signaling pathways might reverse this anti-VEGF resistance. Bevacizumab-resistant FGBR pancreatic cancer cells were treated in vitro with bevacizumab, the recombinant human IL1 receptor antagonist anakinra, the monoclonal antibody against TGFβ receptor type II TR1, and a novel recombinant antibody binding CXCR1/2 ligands. The FGBR cells treated with these agents in combination had significantly higher levels of E-cadherin and lower levels of vimentin, IL6, phosphorylated p65, and SMAD2, and showed significantly lower migration rates than did their controls treated with the same agents without bevacizumab or with a single agent bevacizumab as a control. Consistently, the combination of these agents with bevacizumab reduced the FGBR tumor burden and significantly prolonged mice survival compared with bevacizumab in monotherapy. Tumors from mice receiving the combination treatment showed significantly lower expression of IL6 and phosphorylated SMAD2, higher expression of E-cadherin and lower levels of vimentin, and a significantly lower infiltration by CD11b cells compared with bevacizumab-treated controls. This study suggests that inhibition of IL1, CXCR1/2, and TGFβ signaling pathways is a potential therapeutic approach to modulate the acquired resistance to anti-VEGF treatment by reversing epithelial-mesenchymal transition and inhibiting CD11b proangiogenic myeloid cells' tumor infiltration.
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http://dx.doi.org/10.1097/CAD.0000000000000301DOI Listing
January 2016

Genetics and Epigenetics of Pancreatic Neuroendocrine Tumors and Pulmonary Carcinoids.

Front Horm Res 2015 14;44:115-38. Epub 2015 Aug 14.

Department of Endocrine Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.

In this chapter, we give an overview of the genetic and epigenetic background of neuroendocrine tumors (NETs), in particular pancreatic and pulmonary NETs. Studying the mechanism of disease of the inherited syndromes that feature NETs has provided valuable insights that have revolutionized the therapeutic options for these tumor types: both inhibition of mTOR (mammalian target of rapamycin) signaling and inhibition of angiogenesis have become standard treatments. Although sporadic NETs harbor relatively few somatic gene mutations, these somatic mutations often affect genes that encode epigenetic regulators. Restoring the aberrant epigenetic characteristics may be an attractive approach for future treatment.
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http://dx.doi.org/10.1159/000382138DOI Listing
June 2016

Ultra-Sensitive Copeptin and Cardiac Troponin in Diagnosing Non-ST-Segment Elevation Acute Coronary Syndromes--The COPACS Study.

Am J Med 2016 Jan 11;129(1):105-14. Epub 2015 Jul 11.

Institute of Cardiology and Center of Excellence on Aging, "G. d'Annunzio" University, Chieti, Italy. Electronic address:

Objectives: We tested the noninferiority of a fast-track rule-out protocol for the diagnosis of non-ST-segment elevation myocardial infarction vs noncoronary chest pain based on the single-sampling combined assessment of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin compared with the serial assessment of medium-sensitivity cardiac troponin I.

Methods: Ultra-sensitive copeptin and medium-sensitivity cardiac troponin I levels were measured at presentation in 196 consecutive patients admitted to the emergency department for acute nontraumatic chest pain within 6 hours from symptoms onset and without ST-segment elevation on a 12-lead electrocardiogram. The diagnostic performance for non-ST-segment elevation myocardial infarction diagnosis of the dual-marker single-sampling strategy with medium-sensitivity cardiac troponin I and ultra-sensitive copeptin on admission was compared with that of the serial 0- and 3-hour medium-sensitivity cardiac troponin I sampling in reference to the adjudicated postdischarge diagnosis, using both the comparison of area under the curve (AUC) receiver operating characteristic and the McNemar chi-square test.

Results: The diagnosis of non-ST-segment elevation myocardial infarction was adjudicated in 29 patients (14.8%). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin generated an AUC of 0.87 (95% confidence interval, 0.82-0.91), which was noninferior with respect to the 3-hour interval medium-sensitivity cardiac troponin I serial sampling (P = .194 for AUC difference). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin also yielded a numerically higher diagnostic sensitivity (100% vs 89.7%; P = not significant).

Conclusions: A single-sampling strategy of combined ultra-sensitive copeptin and medium-sensitivity cardiac troponin I is noninferior to a 0- and 3-hour serial medium-sensitivity cardiac troponin I sampling in ruling out non-ST-segment elevation myocardial infarction and thus may allow an earlier discharge of patients who are ruled out for non-ST-segment elevation myocardial infarction (ClinicalTrials.gov Identifier NCT01962506).
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http://dx.doi.org/10.1016/j.amjmed.2015.06.033DOI Listing
January 2016

Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation.

Radiol Oncol 2015 Jun 25;49(2):147-54. Epub 2015 Mar 25.

Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells' local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents.

Materials And Methods: The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay.

Results: In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation.

Conclusions: Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma, but has a potentiating effect on cytotoxicity of bleomycin in pancreatic tumour cell lines. Therefore, ECT could be considered as a valid alternative for the local control of non-resectable pancreatic cancer.
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http://dx.doi.org/10.1515/raon-2015-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387991PMC
June 2015

Ezrin expression is an independent prognostic factor in gastro-intestinal cancers.

J Gastrointest Surg 2013 Dec 24;17(12):2082-91. Epub 2013 Oct 24.

Centre for Tumour Biology, John Vane Science Centre, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Background: Ezrin, a member of the ezrin-radixin-moesin (ERM) family of plasma membrane-cytoskeleton linker proteins, has been associated with metastatic behavior.

Methodology: Microarrayed pathological tissues of surgically resected colorectal cancer liver metastasis (CRLM) and whole tissue sections of cancer of the ampulla of Vater (CAV) were analyzed to determine ezrin expression levels and correlation with survival. The requirement of ezrin in invasive capability was assessed using in vitro assays.

Results: Surgically resected CAV showing a low ezrin score have a better 5-year disease-specific survival than those showing a high ezrin score (P < 0.0001). Similarly, high ezrin expression at the invasive front of CRLM resulted in poor disease-free survival (P = 0.05). Multivariate analysis demonstrated high ezrin expression to be an independent adverse prognostic factor for CAV (hazard ratio (HR) 15.22 (95 % confidence interval (CI) 1.98-117.03), P < 0.01) and CRLM (HR 6.42 (95 % CI 1.01-52.43), P = 0.05), among other clinically relevant variables such as lymph node metastasis (for CAV) and the presence of extrahepatic disease, large hepatic metastases (>5 cm), and close surgical resection margins (<5 mm) (all for CRLM). In vitro experiments indicated that ezrin expression was vital for cellular processes such as adhesive and invasive activity.

Significance: High ezrin expression indicates an adverse prognosis in primary CAV and CRLM.
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http://dx.doi.org/10.1007/s11605-013-2384-1DOI Listing
December 2013