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Pancreatic Neoplasms: HELP
Articles by Daniela Campani
Based on 20 articles published since 2010
(Why 20 articles?)
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Between 2010 and 2020, D. Campani wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Robotic pancreatoduodenectomy with vascular resection. 2016

Kauffmann, Emanuele F / Napoli, Niccolò / Menonna, Francesca / Vistoli, Fabio / Amorese, Gabriella / Campani, Daniela / Pollina, Luca Emanuele / Funel, Niccola / Cappelli, Carla / Caramella, Davide / Boggi, Ugo. ·Division of General and Transplant Surgery, University of Pisa and Azienda Ospedaliero Universitaria Pisana, Via Paradisa 2, 56124, Pisa, Italy. · Division of Anesthesia and Intensive Care, University of Pisa and Azienda Ospedaliero Universitaria Pisana, Pisa, Italy. · Division of Pathology, University of Pisa and Azienda Ospedaliero Universitaria Pisana, Pisa, Italy. · Division of Radiology, University of Pisa and Azienda Ospedaliero Universitaria Pisana, Pisa, Italy. · Division of General and Transplant Surgery, University of Pisa and Azienda Ospedaliero Universitaria Pisana, Via Paradisa 2, 56124, Pisa, Italy. u.boggi@med.unipi.it. ·Langenbecks Arch Surg · Pubmed #27553112.

ABSTRACT: PURPOSE: This study aims to define the current status of robotic pancreatoduodenectomy (RPD) with resection and reconstruction of the superior mesenteric/portal vein (RPD-SMV/PV). METHODS: Our experience on RPD, including RPD-SMV/PV, is presented along with a description of the surgical technique and a systematic review of the literature on RPD-SMV/PV. RESULTS: We have performed 116 RPD and 14 RPD-SMV/PV. Seven additional cases of RPD-SMV/PV were identified in the literature. In our experience, RPD and RPD-SMV/PV were similar in all baseline variables, but lower mean body mass and higher prevalence of pancreatic cancer in RPD-SMV/PV. Regarding the type of vein resection, there were one type 2 (7.1 %), five type 3 (35.7 %) and eight type 4 (57.2 %) resections. As compared to RPD, RPD-SMV/PV required longer operative time, had higher median estimated blood loss, and blood transfusions were required more frequently. Incidence and severity of post-operative complications were not increased in RPD-SMV/PV, but post-pancreatectomy hemorrhage occurred more frequently after this procedure. In pancreatic cancer, RPD-SMV/PV was associated with a higher mean number of examined lymph nodes (60.0 ± 13.9 vs 44.6 ± 11.0; p = 0.02) and with the same rate of microscopic margin positivity (25.0 % vs 26.1 %). Mean length or resected vein was 23.1 ± 8.08 mm. Actual tumour infiltration was discovered in ten patients (71.4 %), reaching the adventitia in four patients (40.0 %), the media in two patients (20.0 %), and the intima in four patients (40.0 %). Literature review identified seven additional cases, all reported to have successful outcome. CONCLUSIONS: RPD-SMV/PV is feasible in carefully selected patients. The generalization of these results remains to be demonstrated.

2 Review Critical role of laser microdissection for genetic, epigenetic and proteomic analyses in pancreatic cancer. 2011

Funel, Niccola / Giovannetti, Elisa / Pollina, Luca E / del Chiaro, Marco / Mosca, Franco / Boggi, Ugo / Campani, Daniela. ·Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy. niccolafunel@blu.it ·Expert Rev Mol Diagn · Pubmed #21902531.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and molecular studies to unravel novel biomarkers and therapeutic targets are warranted. However, PDAC is characterized by different precursor lesions, as well as by an intense desmoplastic reaction, with islet of neoplastic cells often representing a minor population. Moreover, normal ductal cells, which are considered to be the normal counterpart of pancreatic adenocarcinoma cells, comprise approximately 5% of the total population of cells making up this organ. For all these reasons, molecular techniques to identify critical mutations, as well as the pattern of altered mRNA/microRNA/protein expression should be performed on selected pancreatic cell subpopulations. Therefore, the use of the newest laser microdissection techniques is critical for the analysis of PDAC biological characteristics. This article highlights the most recent and clinically relevant aspects of genetic, epigenetic and proteomic analyses of PDAC from the perspective of the application of laser microdissection.

3 Article Tumor Regression Grading Assessment in Locally Advanced Pancreatic Cancer After Neoadjuvant FOLFIRINOX: Interobserver Agreement and Prognostic Implications. 2020

Cacciato Insilla, Andrea / Vivaldi, Caterina / Giordano, Mirella / Vasile, Enrico / Cappelli, Carla / Kauffmann, Emanuele / Napoli, Niccolò / Falcone, Alfredo / Boggi, Ugo / Campani, Daniela. ·Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy. · Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy. · Division of Medical Oncology, Pisa University Hospital, Pisa, Italy. · Diagnostic and Interventional Radiology, Pisa University Hospital, Pisa, Italy. · Department of Transplant and General Surgery, University of Pisa, Pisa, Italy. ·Front Oncol · Pubmed #32117724.

ABSTRACT: Neoadjuvant therapy represents an increasingly used strategy in pancreatic cancer, and this means that more pancreatic resections need to be evaluated for therapy effect. Several grading systems have been proposed for the histological assessment of tumor regression in pre-treated patients with pancreatic cancer, but issues like practical application, level of agreement and prognostic significance are still debated. To date, a standardized and widely accepted score has not been established yet. In this study, two pathologists with expertise in pancreatic cancer used 4 of the most frequently reported systems (College of American Pathologists, Evans, MD Anderson, and Hartman) to evaluate tumor regression in 29 locally advanced pancreatic cancers previously treated with modified FOLFIRINOX regimen, to establish the level of agreement between pathologists and to determine their potential prognostic value. Cases were additionally evaluated with a fifth grading system inspired to the Dworak score, normally used for colo-rectal cancer, to identify an alternative, relevant option. Results obtained for current grading systems showed different levels of agreement, and they often proved to be very subjective and inaccurate. In addition, no significant correlation was observed with survival. Interestingly, Dworak score showed a higher degree of concordance and a significant correlation with overall survival in individual assessments. These data reflect the need to re-evaluate grading systems for pancreatic cancer to establish a more reproducible and clinically relevant score.

4 Article Early Tumor Shrinkage and Depth of Response Evaluation in Metastatic Pancreatic Cancer Treated with First Line Chemotherapy: An Observational Retrospective Cohort Study. 2019

Vivaldi, Caterina / Fornaro, Lorenzo / Cappelli, Carla / Pecora, Irene / Catanese, Silvia / Salani, Francesca / Cacciato Insilla, Andrea / Kauffmann, Emanuele / Donati, Francescamaria / Pasquini, Giulia / Massa, Valentina / Napoli, Niccolò / Lencioni, Monica / Boraschi, Piero / Campani, Daniela / Boggi, Ugo / Caramella, Davide / Falcone, Alfredo / Vasile, Enrico. ·Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Via Savi 6, 56126 Pisa, Italy. caterinavivaldi@gmail.com. · Division of Medical Oncology, Pisa University Hospital, Via Roma 67, 56126 Pisa, Italy. caterinavivaldi@gmail.com. · Division of Medical Oncology, Pisa University Hospital, Via Roma 67, 56126 Pisa, Italy. · Department of Diagnostic Imaging, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy. · Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Surgical Pathology, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy. · Department of Transplant and General Surgery, Pisa University Hospital, Via Paradisa 2, 56124 Pisa, Italy. · Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. · Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Via Savi 6, 56126 Pisa, Italy. ·Cancers (Basel) · Pubmed #31277449.

ABSTRACT: Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions' longest diameters (SLD) after 6-8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group;

5 Article A propensity score-matched analysis of robotic versus open pancreatoduodenectomy for pancreatic cancer based on margin status. 2019

Kauffmann, Emanuele F / Napoli, Niccolò / Menonna, Francesca / Iacopi, Sara / Lombardo, Carlo / Bernardini, Juri / Amorese, Gabriella / Cacciato Insilla, Andrea / Funel, Niccola / Campani, Daniela / Cappelli, Carla / Caramella, Davide / Boggi, Ugo. ·Division of General and Transplant Surgery, University of Pisa, Pisa, Italy. · Division of Anesthesia and Intensive Care, University of Pisa, Pisa, Italy. · Division of Pathology, University of Pisa, Pisa, Italy. · Division of Radiology, University of Pisa, Pisa, Italy. · Division of General and Transplant Surgery, University of Pisa, Pisa, Italy. u.boggi@med.unipi.it. · Azienda Ospedaliera Universitaria Pisana, Università di Pisa, Via Paradisa 2, 56124, Pisa, Italy. u.boggi@med.unipi.it. ·Surg Endosc · Pubmed #29943061.

ABSTRACT: BACKGROUND: No study has shown the oncologic non-inferiority of robotic pancreatoduodenectomy (RPD) versus open pancreatoduodenectomy (OPD) for pancreatic cancer (PC). METHODS: This is a single institution propensity score matched study comparing RPD and ODP for resectable PC, based on factors predictive of R1 resection (≤ 1 mm). Only patients operated on after completion of the learning curve in both procedures and for whom circumferential margins were assessed according to the Leeds pathology protocol were included. The primary study endpoint was the rate of R1 resection. Secondary study endpoints were as follows: number of examined lymph nodes (N), rate of perioperative transfusions, percentage of patients receiving adjuvant therapies, occurrence of local recurrence, overall survival, disease-free survival, and sample size calculation for randomized controlled trials (RCT). RESULTS: Factors associated with R1 resection were tumor diameter, number of positive N, N ratio, logarithm odds of positive N, and duodenal infiltration. The matching process identified 20 RPDs and 24 OPDs. All RPDs were completed robotically. R1 resection was identified in 11 RPDs (55.0%) and in 10 OPDs (41.7%) (p = 0.38). There was no difference in the rate of R1 at each margin as well as in the proportion of patients with multiple R1 margins. RPD and OPD were also equivalent with respect to all secondary study endpoints, with a trend towards lower rate of blood transfusions in RPD. Based on the figures presented herein, a non-inferiority RCT comparing RPD and OPD having the rate of R1 resection as the primary study endpoint requires 3355 pairs. CONCLUSIONS: RPD and OPD achieved the same rate of R1 resections in resectable PC. RPD was also non-inferior to OPD with respect to all secondary study endpoints. Because of the high number of patients required to run a RCT, further assessment of RPD for PC would require the implementation of an international registry.

6 Article Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET. 2015

Lombardi, M / De Lio, N / Funel, N / Sardella, C / Russo, D / Urbani, C / Rossi, G / Campani, D / Martino, E / Marcocci, C / Boggi, U / Bogazzi, F. ·Department of Clinical and Experimental Medicine, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124, Pisa, Italy. marty81@tiscali.it. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Surgical, Medical and Molecular Pathology of Critical Area, University of Pisa, Pisa, Italy. · Department of Clinical and Experimental Medicine, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124, Pisa, Italy. · Unit of Epidemiology and Biostatistics, Institute of Clinical Physiology, National Research Council, Pisa, Italy. ·J Endocrinol Invest · Pubmed #25501604.

ABSTRACT: BACKGROUND: Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF-pNET to surgery already exists; but a conservative approach for small (≤2 cm) NF neoplasms has been proposed. AIM: To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. SUBJECTS AND METHODS: Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan-Meier method and the Cox regression model. RESULTS: The 8-year cause-specific survival of NF-pNET was 79.3%. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74%), compared to large NF-pNET (27%). Distant metastases were present in 29.7% (n = 11) and 17.4% (n = 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39% of the 23 NF-pNET, turned out to have a malignant potential. CONCLUSIONS: Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable.

7 Article Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours. 2015

Cappelli, Carla / Boggi, Ugo / Mazzeo, Salvatore / Cervelli, Rosa / Campani, Daniela / Funel, Niccola / Contillo, Benedetta Pontillo / Bartolozzi, Carlo. ·Diagnostic and Interventional Radiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy, carlacappelli1@gmail.com. ·Eur Radiol · Pubmed #25447971.

ABSTRACT: OBJECTIVES: Preoperative suspicion of malignancy in pancreatic neuroendocrine tumours (pNETs) is mostly based on tumour size. We retrospectively reviewed the contrast enhancement pattern (CEP) of a series of pNETs on multiphasic multidetector computed tomography (MDCT), to identify further imaging features predictive of lesion aggressiveness. METHODS: Sixty pNETs, diagnosed in 52 patients, were classified based on CEP as: type A showing early contrast enhancement and rapid wash-out; type B presenting even (B1) or only (B2) late enhancement. All tumours were resected allowing pathologic correlations. RESULTS: Nineteen pNETs showed type A CEP (5-20 mm), 29 type B1 CEP (5-80 mm) and 12 type B2 (15-100 mm). All tumours were classified as well differentiated tumours, 19 were benign (WDt-b), 15 with uncertain behaviour (WDt-u) and 26 carcinomas (WDC). None of A lesions were malignant (12 WDt-b; 7 WDt-u), all B2 lesions were WDC, 7 B1 lesions were WDt-b, 8 WDt-u and 14 WDC; 4/34 (12 %) lesions ≤2cm were WDC. CEP showed correlation with all histological prognostic indicators. CONCLUSIONS: Correlating with the lesion grading and other histological prognostic predictors, CEP may preoperatively suggest the behaviour of pNETs, assisting decisions about treatment. Moreover CEP allows recognition of malignant small tumours, incorrectly classified on the basis of their dimension.

8 Article Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models. 2014

Ricci, Claudio / Mota, Carlos / Moscato, Stefania / D'Alessandro, Delfo / Ugel, Stefano / Sartoris, Silvia / Bronte, Vincenzo / Boggi, Ugo / Campani, Daniela / Funel, Niccola / Moroni, Lorenzo / Danti, Serena. ·a Department of Pathology and Diagnostics ; University of Verona ; Verona , Italy. ·Biomatter · Pubmed #25482337.

ABSTRACT: We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.

9 Article A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients. 2014

Maftouh, Mina / Avan, Amir / Funel, Niccola / Paolicchi, Elisa / Vasile, Enrico / Pacetti, Paola / Vaccaro, Vanja / Faviana, Pinuccia / Campani, Daniela / Caponi, Sara / Mambrini, Andrea / Boggi, Ugo / Cantore, Maurizio / Milella, Michele / Peters, Godefridus J / Reni, Michele / Giovannetti, Elisa. ·Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, CCA room 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. ·Pharmacogenomics · Pubmed #24798718.

ABSTRACT: AIM: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. MATERIALS & METHODS: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). RESULTS: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. CONCLUSION: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC.

10 Article Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. 2013

Avan, Amir / Caretti, Viola / Funel, Niccola / Galvani, Elena / Maftouh, Mina / Honeywell, Richard J / Lagerweij, Tonny / Van Tellingen, Olaf / Campani, Daniela / Fuchs, Dieter / Verheul, Henk M / Schuurhuis, Gerrit-Jan / Boggi, Ugo / Peters, Godefridus J / Würdinger, Thomas / Giovannetti, Elisa. ·Authors' Affiliations: Departments of Medical Oncology, Hematology, Neurosurgery and Pediatric Oncology/Hematology, Neuro-oncology Research Group, VU University Medical Center; Diagnostic Oncology Division, Netherlands Cancer Institute; VisualSonics, Amsterdam, the Netherlands; Departments of Neurology and Pediatrics, Stanford University School of Medicine, Stanford, California; Division of Surgical Pathology, Division of General and Transplant Surgery, University of Pisa, Pisa, Italy; and Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, Massachusetts. ·Cancer Res · Pubmed #24085787.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here, we developed four orthotopic mouse models using primary human PDAC cells genetically engineered to express firefly- and Gaussia luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models, we conducted detailed histopathologic and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs, and lymph nodes. Genetic characteristics were compared with the originator tumor and primary tumor cells using array-based comparative genomic hybridization, using frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models; we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival, and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathologic, and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.

11 Article Adjuvant chemotherapy seems beneficial for invasive intraductal papillary mucinous neoplasms. 2013

Caponi, S / Vasile, E / Funel, N / De Lio, N / Campani, D / Ginocchi, L / Lucchesi, M / Caparello, C / Lencioni, M / Cappelli, C / Costa, F / Pollina, L / Ricci, S / Mosca, F / Falcone, A / Boggi, U. ·Department of Oncology, Transplants, and New Technologies, U.O. Oncologia 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Polo Oncologico Area Vasta Nord-Ovest, Istituto Toscano Tumori, Via Roma 67, 56126 Pisa, Italy. ·Eur J Surg Oncol · Pubmed #23290583.

ABSTRACT: AIMS: The incidence of intraductal papillary mucinous neoplasm (IPMN) is rising and these neoplasms now represent up to 25% of resected pancreatic neoplasms. The optimal postoperative management of resected invasive IPMN is still debated in the absence of large prospective clinical trials and of validated prognostic factors in this setting. The objective of our study was to identify potential prognostic factors and to investigate the role of adjuvant therapies for patients radically resected for invasive IPMN. METHODS: We retrospectively reviewed clinical and pathological data regarding a large series of patients with invasive IPMN who underwent surgical resection in the last six years at University Hospital of Pisa. RESULTS: Sixty-four patients were considered for the analysis, thirty-three of whom received adjuvant chemotherapy with gemcitabine. In our series node involvement and high tumoral grade emerged as the major pathologic prognostic factors. Patients treated with adjuvant chemotherapy with gemcitabine experienced a longer disease-free survival than those who received surgery alone. CONCLUSIONS: Gemcitabine-based chemotherapy seems beneficial as adjuvant treatment for patients with resected invasive IPMN.

12 Article Ectopic expression of FSH receptor isoforms in neoplastic but not in endothelial cells from pancreatic neuroendocrine tumors. 2013

Sardella, C / Russo, D / Raggi, F / Lombardi, M / Urbani, C / Brogioni, S / Boggi, U / Funel, N / Chifenti, B / Campani, D / Fanelli, G / Marchetti, P / Basolo, F / Locci, M T / Martino, E / Bogazzi, F. ·Department of Endocrinology, University of Pisa, Pisa, Italy. ·J Endocrinol Invest · Pubmed #22732316.

ABSTRACT: FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH-dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p-NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p- NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co-localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated.

13 Article High-throughput microRNA (miRNAs) arrays unravel the prognostic role of MiR-211 in pancreatic cancer. 2012

Giovannetti, Elisa / van der Velde, Arjan / Funel, Niccola / Vasile, Enrico / Perrone, Vittorio / Leon, Leticia G / De Lio, Nelide / Avan, Amir / Caponi, Sara / Pollina, Luca E / Gallá, Valentina / Sudo, Hiroko / Falcone, Alfredo / Campani, Daniela / Boggi, Ugo / Peters, Godefridus J. ·Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. elisa.giovannetti@gmail.com ·PLoS One · Pubmed #23155457.

ABSTRACT: BACKGROUND: Only a subset of radically resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of prognostic factors is warranted. Recently miRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients. METHODOLOGY/PRINCIPAL FINDINGS: High-resolution miRNA profiles were obtained with the Toray's 3D-Gene™-miRNA-chip, detecting more than 1200 human miRNAs. RNA was successfully isolated from paraffin-embedded primary tumors of 19 out of 26 stage-pT3N1 homogeneously treated patients (adjuvant gemcitabine 1000 mg/m(2)/day, days-1/8/15, every 28 days), carefully selected according to their outcome (OS<12 (N = 13) vs. OS>30 months (N = 6), i.e. short/long-OS). Highly stringent statistics included t-test, distance matrix with Spearman-ranked correlation, and iterative approaches. Unsupervised hierarchical analysis revealed that PDACs clustered according to their short/long-OS classification, while the feature selection algorithm RELIEF identified the top 4 discriminating miRNAs between the two groups. These miRNAs target more than 1500 transcripts, including 169 targeted by two or more. MiR-211 emerged as the best discriminating miRNA, with significantly higher expression in long- vs. short-OS patients. The expression of this miRNA was subsequently assessed by quantitative-PCR in an independent cohort of laser-microdissected PDACs from 60 resected patients treated with the same gemcitabine regimen. Patients with low miR-211 expression according to median value had a significantly shorter median OS (14.8, 95%CI = 13.1-16.5, vs. 25.7 months, 95%CI = 16.2-35.1, log-rank-P = 0.004). Multivariate analysis demonstrated that low miR-211 expression was an independent factor of poor prognosis (hazard ratio 2.3, P = 0.03) after adjusting for all the factors influencing outcome. CONCLUSIONS/SIGNIFICANCE: Through comprehensive microarray analysis and PCR validation we identified miR-211 as a prognostic factor in resected PDAC. These results prompt further prospective studies and research on the biological role of miR-211 in PDAC.

14 Article Loss of heterozygosity status of D9S105 marker is associated with downregulation of Krüppel-like factor 4 expression in pancreatic ductal adenocarcinoma and pancreatic intraepithelial lesions. 2011

Funel, Niccola / Morelli, Mariangela / Giovannetti, Elisa / Del Chiaro, Marco / Pollina, Luca Emanuele / Mosca, Franco / Boggi, Ugo / Cavazzana, Andrea / Campani, Daniela. ·Division of General and Transplantation Surgery, University of Pisa, Pisa, Italy. ·Pancreatology · Pubmed #21412023.

ABSTRACT: The transcription factor Krüppel-like factor 4 (KLF4) may act both as an oncogene and a tumor suppressor in a tissue-dependent manner, and further studies on its role in pancreatic ductal adenocarcinoma (PDAC) progression and clinical outcome are warranted. Therefore, we investigated the loss of heterozygosity (LOH) in the 9q22.3-32 region and loss of KFL4 gene expression in epithelial cells from 35 PDAC, 6 pancreatic intraductal neoplasias (PanINs) and 6 normal ducts, isolated by laser microdissection, as well as their correlation with overall survival (OS) in patients treated with gemcitabine in the adjuvant setting. LOH was evaluated with 4 microsatellite markers and in situ hybridization, while KLF4 expression was studied by reverse transcription-PCR and immunohistochemistry. LOH in at least 1 locus was observed in 25 of 35 PDAC cases and in 5 of 6 PanINs, respectively. In particular, the loss of the D9S105 marker was present in 46.9% of PDAC and 83.3% of PanINs, becoming the most deleted marker, while no LOH in D9S105 was observed in normal Wirsung pancreatic duct. Lack of KLF4 mRNA expression was significantly associated with: (1) genomic deletion flanking KLF4 in PDAC and in PanINs (with LOH of D9S105), (2) low-grade PDAC-associated PanIN, (3) lack of KLF4 protein expression, and (4) shorter OS. These results strongly suggest a relationship between D9S105 deletion and downregulation of KLF4 gene expression as an early event in PDAC progression, as well as a possible role of KLF4 as a prognostic biomarker in gemcitabine-treated patients. and IAP.

15 Article KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma. 2011

Zammarchi, Francesca / Morelli, Mariangela / Menicagli, Michele / Di Cristofano, Claudio / Zavaglia, Katia / Paolucci, Alessandra / Campani, Daniela / Aretini, Paolo / Boggi, Ugo / Mosca, Franco / Cavazzana, Andrea / Cartegni, Luca / Bevilacqua, Generoso / Mazzanti, Chiara Maria. ·Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Am J Pathol · Pubmed #21224073.

ABSTRACT: Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 laser-microdissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis.

16 Article Ukrain affects pancreas cancer cell phenotype in vitro by targeting MMP-9 and intra-/extracellular SPARC expression. 2010

Funel, Niccola / Costa, Francesco / Pettinari, Letizia / Taddeo, Adriano / Sala, Alessandra / Chiriva-Internati, Maurizio / Cobos, Everardo / Colombo, Graziano / Milzani, Aldo / Campani, Daniela / Dalle-Donne, Isabella / Gagliano, Nicoletta. ·Department of Surgery, University of Pisa, Pisa, Italy. ·Pancreatology · Pubmed #20975318.

ABSTRACT: BACKGROUND/AIMS: We investigated whether the anticancer drug Ukrain (UK) is able to modulate the expression of some of the key markers of tumor progression in pancreatic cell carcinoma, in order to assess its potential therapeutic effect. METHODS: Three cell lines (HPAF-II, PL45, HPAC) were treated with UK (5, 10 and 20 μM) for 48 h, or left untreated. Secreted protein acidic and rich in cysteine (SPARC) mRNA levels were assessed by real-time PCR. Matrix metalloproteinases (MMP)-2 and -9 activity was analyzed by SDS zymography; SPARC protein levels in cell lysates and supernatants were determined by Western blot. Cell cycle was determined by flow cytometric analysis, and invasion by matrigel invasion assay. RESULTS: UK down-regulated MMP-2 and MMP-9, suggesting that UK may decrease pancreatic cancer cell invasion, as confirmed by the matrigel invasion assay. SPARC protein down-regulation in supernatants points to an inhibition by UK of extracellular matrix remodeling in the tumor microenvironment. At the same time, SPARC mRNA and cellular protein level up-regulation suggests that UK can affect cell proliferation by cell cycle inhibition, showing a cell cycle G2/M arrest in UK-treated cells. CONCLUSION: Our results suggest that UK modulates two major aspects involved in tumorigenesis of pancreatic cancer cells, such as extracellular matrix remodeling and cell proliferation.

17 Article Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas. 2010

Corbo, Vincenzo / Ritelli, Rossana / Barbi, Stefano / Funel, Niccola / Campani, Daniela / Bardelli, Alberto / Scarpa, Aldo. ·ARC-NET Research Center, University of Verona, Policlinico GB Rossi, Verona, Italy. ·PLoS One · Pubmed #20838624.

ABSTRACT: BACKGROUND: Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are aggressive neoplasms for which no effective therapeutic strategy is currently available. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a DNA-sequence analysis of a selected set of 35 kinase genes in a panel of 52 pancreatic exocrine neoplasms, including 36 pancreatic ductal adenocarcinoma, and 16 ampulla of Vater cancer. Among other changes we found somatic mutations in ATM, EGFR, EPHA3, EPHB2, and KIT, none of which was previously described in cancers. CONCLUSIONS/SIGNIFICANCE: Although the alterations identified require further experimental evaluation, the localization within defined protein domains indicates functional relevance for most of them. Some of the mutated genes, including the tyrosine kinases EPHA3 and EPHB2, are clearly amenable to pharmacological intervention and could represent novel therapeutic targets for these incurable cancers.

18 Article MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. 2010

Giovannetti, Elisa / Funel, Niccola / Peters, Godefridus J / Del Chiaro, Marco / Erozenci, Leyla A / Vasile, Enrico / Leon, Leticia G / Pollina, Luca E / Groen, Annemieke / Falcone, Alfredo / Danesi, Romano / Campani, Daniela / Verheul, Henk M / Boggi, Ugo. ·VU University Medical Center, Amsterdam, the Netherlands. ·Cancer Res · Pubmed #20460539.

ABSTRACT: MicroRNA-21 (miR-21) was reported to be overexpressed and contributes to invasion and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether miR-21 expression was associated with the overall survival (OS) of PDAC patients treated with gemcitabine and to provide mechanistic insights for new therapeutic targets. miR-21 expression was evaluated in cells (including 7 PDAC cell lines, 7 primary cultures, fibroblasts, and a normal pancreatic ductal cell line) and tissues (neoplastic specimens from 81 PDAC patients and normal ductal samples) isolated by laser microdissection. The role of miR-21 on the pharmacologic effects of gemcitabine was studied with a specific miR-21 precursor (pre-miR-21). Patients with high miR-21 expression had a significantly shorter OS both in the metastatic and in the adjuvant setting. Multivariate analysis confirmed the prognostic significance of miR-21. miR-21 expression in primary cultures correlated with expression in their respective tissues and with gemcitabine resistance. Pre-miR-21 transfection significantly decreased antiproliferative effects and apoptosis induction by gemcitabine, whereas matrix metalloproteinase (MMP)-2/MMP-9 and vascular endothelial growth factor expression were upregulated. Addition of inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin resulted in decrease of phospho-Akt and prevented pre-miR-21-induced resistance to the proapoptotic effects of gemcitabine. miR-21 expression correlated with outcome in PDAC patients treated with gemcitabine. Modulation of apoptosis, Akt phosphorylation, and expression of genes involved in invasive behavior may contribute to the role of miR-21 in gemcitabine chemoresistance and to the rational development of new targeted combinations.

19 Minor The odd case of a small and mucinous-like acinar cell cystoadenocarcinoma of the pancreas. 2012

Perrone, Vittorio G / Mariniello, Donatella M / De Lio, Nelide / Caniglia, Fabio / Cappelli, Carla / Campani, Daniela / Funel, Niccola / Amorese, Gabriella / Boggi, Ugo. · ·Pancreatology · Pubmed #23127530.

ABSTRACT: -- No abstract --

20 Minor Correlation of basal EGFR expression with pancreatic cancer grading but not with clinical outcome after gemcitabine-based treatment. 2011

Funel, N / Vasile, E / Del Chiaro, M / Boggi, U / Falcone, A / Campani, D / Scarpa, A / Giovannetti, E. · ·Ann Oncol · Pubmed #21196439.

ABSTRACT: -- No abstract --