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Pancreatic Neoplasms: HELP
Articles by Francesco Di Costanzo
Based on 9 articles published since 2009
(Why 9 articles?)
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Between 2009 and 2019, F. Di Costanzo wrote the following 9 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors. 2017

Antonuzzo, L / Del Re, M / Barucca, V / Spada, F / Meoni, G / Restante, G / Danesi, R / Di Costanzo, F / Fazio, N. ·S.C. Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Medical Genetics, University of Siena, Siena, Italy. Electronic address: lorenzo.antonuzzo@gmail.com. · Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. · Division of Medical Oncology, Misericordia General Hospital, Grosseto, Italy. · Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · S.C. Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. ·Cancer Treat Rev · Pubmed #28535439.

ABSTRACT: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms representing less than 2% of all pancreatic malignancies. The PI3K-AKT-mTOR pathway is often deregulated in pNETs and seems to play a key role in tumorigenesis. Everolimus, an inhibitor of the mTOR pathway, has demonstrated efficacy in the treatment of pNETs. Nevertheless de novo or acquired drug resistance is responsible for disease progression and represents a major obstacle to overcome by clinicians. Blocking the PI3K/AKT/mTOR pathway may cover the supposed main mechanisms of resistance to everolimus. Therefore, BEZ-235, a potent oral dual PI3K/mTOR inhibitor was investigated in clinical trials. Globally more than 250 patients with different types of solid tumors were treated. Two studies were conducted in pNETs with BEZ-235 as single agent. The former was a phase 2 trial conducted in pNETs resistant to everolimus while the latter a randomized trial comparing everolimus and BEZ-235. Unfortunately, both the studies disappointed the expectations and were prematurely halted mainly due to severe toxicity. On this basis we reviewed m-TOR inhibitors in pNETs, focusing on their mechanisms of resistance and toxicity.

2 Clinical Trial Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study. 2014

Cascinu, Stefano / Berardi, Rossana / Sobrero, Alberto / Bidoli, Paolo / Labianca, Roberto / Siena, Salvatore / Ferrari, Daris / Barni, Sandro / Aitini, Enrico / Zagonel, Vittorina / Caprioni, Francesco / Villa, Federica / Mosconi, Stefania / Faloppi, Luca / Tonini, Giuseppe / Boni, Corrado / Conte, Pierfranco / Di Costanzo, Francesco / Cinquini, Michela / Anonymous2180774. ·Medical Oncology Unit, Università Politecnica delle Marche, Ospedali Riuniti di Ancona, Ancona, Italy. Electronic address: cascinu@yahoo.com. · Medical Oncology Unit, Università Politecnica delle Marche, Ospedali Riuniti di Ancona, Ancona, Italy. · Medical Oncology Unit, Ospedale S. Martino, Genova, Italy. · Medical Oncology Unit, Ospedale S. Gerardo, Monza, Italy. · Medical Oncology Unit, Ospedali Riuniti, Bergamo, Italy. · Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy. · Medical Oncology Unit, Ospedale S. Paolo, Milano, Italy. · Medical Oncology Unit, Treviglio Hospital, Treviglio, Italy. · Medical Oncology Unit, C. Poma Hospital, Mantova, Italy. · Medical Oncology Unit, Istituto Oncologico Veneto, Padova, Italy. · Medical Oncology Unit, University Campus Bio-Medico, Rome, Italy. · Medical Oncology Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy. · Medical Oncology Unit, Policlinico Universitario, Modena, Italy. · Medical Oncology Unit Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. · New Drug Development Strategies Laboratory, Mario Negri Institute, Milano, Italy. ·Dig Liver Dis · Pubmed #24189171.

ABSTRACT: BACKGROUND: The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer. METHODS: Locally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400mg bid (arm A) or without sorafenib (arm B). RESULTS: One hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7-6.5) and 4.5 months (95% CI: 2.5-5.2), respectively (HR=0.92; 95% CI: 0.62-1.35). Median overall survival was 7.5 (95% CI: 5.6-9.7) and 8.3 months (95% CI: 6.2-8.7), respectively (HR=0.95; 95% CI: 0.62-1.48). Response rates were 3.4% in arm A and 3.6% in arm B. CONCLUSIONS: Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.

3 Clinical Trial Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. 2010

Colucci, Giuseppe / Labianca, Roberto / Di Costanzo, Francesco / Gebbia, Vittorio / Cartenì, Giacomo / Massidda, Bruno / Dapretto, Elisa / Manzione, Luigi / Piazza, Elena / Sannicolò, Mirella / Ciaparrone, Marco / Cavanna, Luigi / Giuliani, Francesco / Maiello, Evaristo / Testa, Antonio / Pederzoli, Paolo / Falconi, Massimo / Gallo, Ciro / Di Maio, Massimo / Perrone, Francesco / Anonymous600652 / Anonymous610652 / Anonymous620652. ·Medical and Experimental Oncology Unit, Oncology Institute Giovanni Paolo II, Bari, Italy. ·J Clin Oncol · Pubmed #20194854.

ABSTRACT: PURPOSE: Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696). PATIENTS AND METHODS: Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) > or = 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m(2) weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m(2) added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral alpha .05, 355 events were needed and 400 patients planned. RESULTS: Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS > or = 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity. CONCLUSION: The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.

4 Article The Italian Rare Pancreatic Exocrine Cancer Initiative. 2019

Brunetti, Oronzo / Luchini, Claudio / Argentiero, Antonella / Tommasi, Stefania / Mangia, Anita / Aprile, Giuseppe / Marchetti, Paolo / Vasile, Enrico / Casadei Gardini, Andrea / Scartozzi, Mario / Barni, Sandro / Delfanti, Sara / De Vita, Fernando / Di Costanzo, Francesco / Milella, Michele / Cella, Chiara Alessandra / Berardi, Rossana / Cataldo, Ivana / Santini, Daniele / Doglioni, Claudio / Maiello, Evaristo / Lawlor, Rita T / Mazzaferro, Vincenzo / Lonardi, Sara / Giuliante, Felice / Brandi, Giovanni / Scarpa, Aldo / Cascinu, Stefano / Silvestris, Nicola. ·1 Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. · 2 Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · 3 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. · 4 Functional Biomorphology Laboratory, IRCCS-Istituto Tumori, Bari, Italy. · 5 Medical Oncology Unit, Hospital of Vicenza, Vicenza, Italy. · 6 Medical Oncology Unit, Sant'Andrea Hospital, University of Rome La Sapienza, Rome, Italy. · 7 Medical Oncology Unit, University Hospital of Pisa, Pisa, Italy. · 8 Medical Oncology Unit, Scientific Institute of Romagna for the Study and Treatment of Cancer (IRST), Meldola, Italy. · 9 Medical Oncology Unit, University of Cagliari, Cagliari, Italy. · 10 Medical Oncology Unit, ASST Bergamo Ovest, Treviglio, Italy. · 11 Medical Oncology Unit, IRCCS Foundation Polyclinic San Matteo, Pavia, Italy. · 12 Medical Oncology Unit, II University of Naples, Naples, Italy. · 13 Medical Oncology Unit, Careggi University Hospital, Florence, Italy. · 14 Medical Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy. · 15 Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), Milan, Italy. · 16 Medical Oncology Unit, Polytechnic University of the Marche, "Ospedali Riuniti Ancona," Ancona, Italy. · 17 Department of Pathology and Diagnostics, University of Verona Hospital Trust, Policlinico GB Rossi, Verona, Italy. · 18 Medical Oncology Unit, University Campus Biomedico, Rome, Italy. · 19 Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · 20 Medical Oncology Unit, IRCCS "Casa Sollievo della Sofferenza" Foundation, San Giovanni Rotondo, Italy. · 21 Arc-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · 22 Hepato-Biliary-Pancreatic Surgery, University of Milan, Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy. · 23 Medical Oncology Unit, IRCCS Veneto Institute of Oncology (IOV), Padua, Italy. · 24 Hepatobiliary Surgery Unit, IRCCS A. Gemelli Polyclinic Foundation, Catholic University of the Sacred Heart, Rome, Italy. · 25 Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. · 26 Medical Oncology Unit, Modena Cancer Center, University Hospital of Modena, Modena, Italy. · 27 Scientific Direction, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. ·Tumori · Pubmed #30967031.

ABSTRACT: 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.

5 Article Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis. 2018

Brunetti, Oronzo / Aprile, Giuseppe / Marchetti, Paolo / Vasile, Enrico / Casadei Gardini, Andrea / Scartozzi, Mario / Barni, Sandro / Delfanti, Sara / De Vita, Fernando / Di Costanzo, Francesco / Milella, Michele / Cella, Chiara Alessandra / Berardi, Rossana / Cataldo, Ivana / Scarpa, Aldo / Basile, Debora / Mazzuca, Federica / Graziano, Giusi / Argentiero, Antonella / Santini, Daniele / Reni, Michele / Cascinu, Stefano / Silvestris, Nicola. ·Medical Oncology Unit, Sant'Andrea Hospital, University of Rome La Sapienza, Rome. · Medical Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa. · Department of MedicalOncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola. · Medical Oncology Unit, University of Cagliari, Cagliari. · Medical Oncology Unit, ASST Bergamo Ovest, Treviglio. · Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia. · Medical Oncology Unit, II University of Naples, Naples. · Medical OncologyUnit, Azienda Ospedaliero-Universitaria Careggi, Florence. · Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome. · Division of Gastrointestinal and Neuroendocrine Tumors, IEO, Milan. · Medical Oncology Unit, Università Politecnica Marche - Ospedali Riuniti Ancona, Ancona. · Department of Pathology and Diagnostics, University of Verona, ARCNET, Verona. · Department of Medical Oncology, University and General Hospital, Udine. · Scientific Direction, Cancer Institute "Giovanni Paolo II," Bari. · Medical Oncology Unit, University Campus Biomedico, Rome. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan. · Modena Cancer Center, University of Modena and Reggio Emilia, Azienda Ospedaliera-Universitaria di Modena, Modena, Italy. ·Pancreas · Pubmed #29771769.

ABSTRACT: 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.

6 Article Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. 2018

Pusceddu, Sara / Vernieri, Claudio / Di Maio, Massimo / Marconcini, Riccardo / Spada, Francesca / Massironi, Sara / Ibrahim, Toni / Brizzi, Maria Pia / Campana, Davide / Faggiano, Antongiulio / Giuffrida, Dario / Rinzivillo, Maria / Cingarlini, Sara / Aroldi, Francesca / Antonuzzo, Lorenzo / Berardi, Rossana / Catena, Laura / De Divitiis, Chiara / Ermacora, Paola / Perfetti, Vittorio / Fontana, Annalisa / Razzore, Paola / Carnaghi, Carlo / Davì, Maria Vittoria / Cauchi, Carolina / Duro, Marilina / Ricci, Sergio / Fazio, Nicola / Cavalcoli, Federica / Bongiovanni, Alberto / La Salvia, Anna / Brighi, Nicole / Colao, Annamaria / Puliafito, Ivana / Panzuto, Francesco / Ortolani, Silvia / Zaniboni, Alberto / Di Costanzo, Francesco / Torniai, Mariangela / Bajetta, Emilio / Tafuto, Salvatore / Garattini, Silvio Ken / Femia, Daniela / Prinzi, Natalie / Concas, Laura / Lo Russo, Giuseppe / Milione, Massimo / Giacomelli, Luca / Buzzoni, Roberto / Delle Fave, Gianfranco / Mazzaferro, Vincenzo / de Braud, Filippo. ·Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. Electronic address: sara.pusceddu@istitutotumori.mi.it. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. · Dipartimento di Oncologia, Università degli Studi di Torino, A. O. Ordine Mauriziano, Turin, Italy. · Dipartimento di Oncologia, Santa Chiara Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. · IEO - Istituto Europeo di Oncologia, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. · Centro di Osteoncologia e Tumori Rari, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy. · Policlinico Sant'Orsola Malpighi, Bologna, Italy. · Unità di chirurgia tiroidea e paratiroidea, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy. · IOM- Istituto Oncologico del Mediterraneo, Catania, Italy. · Azienda Ospedaliera Universitaria Sant'Andrea, ENETS Center of Excellence, Rome, Italy. · Azienda Ospedaliera Universitaria, Verona, Italy. · Fondazione Poliambulanza, Brescia, Italy. · A. O. U. Careggi, Firenze, Italy. · Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. · Policlinico di Monza, Monza, Italy. · IRCCS Fondazione Pascale, ENETS Center of Excellence, Naples, Italy. · Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy. · Fondazione IRCCS Policlinico San Matteo, SC oncologia, Pavia, Italy. · Policlinico di Modena, Italy. · Unit of Endocrinology, Ospedale Mauriziano, Torino, Italy. · Istituto Clinico Humanitas, Rozzano, ENETS Center of Excellence, Italy. · Ospedale Policlinico Borgo Roma, Verona, Italy. · Ospedale S Croce e Carle, Cuneo, Italy. · Ospedale Valduce Como, Italy. · Endocrinology Section, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Medical-Surgical Science and Traslational Medicine Departement, Sapienza University, Rome, Italy. · Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Universita' degli Studi di Milano, Milan, Italy. ·Gastroenterology · Pubmed #29655834.

ABSTRACT: BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

7 Article Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors. 2017

Berardi, Rossana / Torniai, Mariangela / Pusceddu, Sara / Spada, Francesca / Ibrahim, Toni / Brizzi, Maria Pia / Antonuzzo, Lorenzo / Ferolla, Piero / Panzuto, Francesco / Silvestris, Nicola / Partelli, Stefano / Ferretti, Benedetta / Freddari, Federica / Gucciardino, Calogero / Testa, Enrica / Concas, Laura / Murgioni, Sabina / Bongiovanni, Alberto / Zichi, Clizia / Riva, Nada / Rinzivillo, Maria / Brunetti, Oronzo / Giustini, Lucio / Di Costanzo, Francesco / Delle Fave, Gianfranco / Fazio, Nicola / De Braud, Filippo / Falconi, Massimo / Cascinu, Stefano. ·Clinica di Oncologia Medica, Università Politecnica delle Marche, AOU Ospedali Riuniti di, Ancona, Italy. · Medicina Oncologica 1, ENETS Center of excellence, Fondazione IRCCS Istituto Tumori, Milano, Italy. · Unità di Oncologia Medica Gastrointestinale e Tumori Neuroendocrini (Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors), IEO Istituto Europeo di Oncologia, Milano, Italy. · Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Oncologia Medica, A.O.U. San Luigi, Orbassano (TO), Italy. · SC di Oncologia Medica, Azienda Opedaliero-Universitaria Careggi, Firenze, Italy. · Doctorate Course in Genetics, Oncology and Clinical Medicine, University of Siena, Siena, Italy. · Multidisciplinary NET Group, Umbria Regional Cancer Network, Perugia, Italy. · Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy. · Medical Oncology Unit, National Cancer Institute Giovanni Paolo II, Bari, Italy. · Chirurgia del Pancreas, Università Politecnica delle Marche, AOU Ospedali Riuniti di, Ancona, Italy. · Chirurgia del Pancreas, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milano, Italy. · Oncologia Medica, Ospedale di San Severino, San Severino Marche (MC), Italy. · Oncologia Medica, Ospedale di Senigallia, Senigallia, Italy. · Oncologia Medica, Ospedale di Fermo, Fermo, Italy. · Oncologia Medica, Ospedale di Urbino, Urbino, Italy. · Oncologia Medica, Università di Modena e Reggio Emilia, Modena, Italy. ·Cancer Med · Pubmed #28547856.

ABSTRACT: The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0-76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

8 Article Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors. 2016

Spada, Francesca / Antonuzzo, Lorenzo / Marconcini, Riccardo / Radice, Davide / Antonuzzo, Andrea / Ricci, Sergio / Di Costanzo, Francesco / Fontana, Annalisa / Gelsomino, Fabio / Luppi, Gabriele / Nobili, Elisabetta / Galdy, Salvatore / Cella, Chiara Alessandra / Sonzogni, Angelica / Pisa, Eleonora / Barberis, Massimo / Fazio, Nicola. ·Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy. ·Neuroendocrinology · Pubmed #26789262.

ABSTRACT: PURPOSE: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. METHODS: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. RESULTS: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. CONCLUSION: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

9 Article hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma. 2015

Lastraioli, E / Perrone, G / Sette, A / Fiore, A / Crociani, O / Manoli, S / D'Amico, M / Masselli, M / Iorio, J / Callea, M / Borzomati, D / Nappo, G / Bartolozzi, F / Santini, D / Bencini, L / Farsi, M / Boni, L / Di Costanzo, F / Schwab, A / Onetti Muda, A / Coppola, R / Arcangeli, A. ·Department of Experimental and Clinical Medicine, University of Florence, Viale GB Morgagni 50, Florence 50134, Italy. · Department of Pathology, Pathology Unit, Campus Bio-Medico University, via del Portillo 200, Rome 00128, Italy. · 1] Department of Experimental and Clinical Medicine, University of Florence, Viale GB Morgagni 50, Florence 50134, Italy [2] DI.V.A.L Toscana Srl, Via Madonna del Piano 6, Sesto Fiorentino 50019, Italy. · Department of General Surgery, Campus Bio-Medico University, via del Portillo 200, Rome 00128, Italy. · Casa di Cura Villa Margherita, Viale di Villa Massimo 48, Rome 00161, Italy. · Department of Medical Oncology, Campus Bio-Medico University, via del Portillo 200, Rome 00128, Italy. · Department of General Surgery and Surgical Oncology, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, Florence 50134, Italy. · Clinical Trials Coordinating Center, Azienda Ospedaliero-Universitaria Careggi/Istituto Toscano Tumori, Largo Brambilla 3, Florence 50134, Italy. · Department of Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, Florence 50134, Italy. · Physiologisches Institut II, University of Münster, Robert-Koch-Str. 27b, Münster D-48149, Germany. ·Br J Cancer · Pubmed #25719829.

ABSTRACT: BACKGROUND: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. METHODS: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. RESULTS: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. CONCLUSIONS: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.