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Pancreatic Neoplasms: HELP
Articles by Claudio Doglioni
Based on 48 articles published since 2010
(Why 48 articles?)
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Between 2010 and 2020, C. Doglioni wrote the following 48 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial New era for pancreatic endoscopic ultrasound: From imaging to molecular pathology of pancreatic cancer. 2019

Archibugi, Livia / Testoni, Sabrina Gloria Giulia / Redegalli, Miriam / Petrone, Maria Chiara / Reni, Michele / Falconi, Massimo / Doglioni, Claudio / Capurso, Gabriele / Arcidiacono, Paolo Giorgio. ·Pancreato-Biliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. · Pathology Department, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. · Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. · Pancreatic Surgery Department, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. · Pancreato-Biliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy. capurso.gabriele@hsr.it. ·World J Gastrointest Oncol · Pubmed #31798775.

ABSTRACT: With recent advances in molecular pathology and the development of new chemotherapy regimens, the knowledge of the molecular alterations of pancreatic ductal adenocarcinoma (PDAC) is becoming appealing for stratifying patients for prognosis and response to a defined treatment. Archival formalin-fixed, paraffin-embedded samples are a useful source of genomic deoxyribonucleic acid; nevertheless, most studies employed formalin-fixed, paraffin-embedded samples deriving from surgical specimens, which are therefore representative of <20% of PDAC patients. Indeed, the development of a reliable methodology for endoscopic ultrasound-guided tissue acquisition, stabilization, and analysis is crucial for the development of molecular markers for clinical use in order to achieve "personalized medicine". With the development of new needles, this technique is able to retrieve a high quantity and quality of PDAC tissue that can be used not only for diagnosis but also for mutational and transcriptome evaluations and for the development of primary cell or tissue cultures. In the present editorial, we discuss the current knowledge regarding the use of endoscopic ultrasound as a tool to obtain samples for molecular analyses, its possible pitfalls, and its use for the development of disease models such as xenografts or organoids.

2 Review Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas. 2019

Zaccari, Piera / Cardinale, Vincenzo / Severi, Carola / Pedica, Federica / Carpino, Guido / Gaudio, Eugenio / Doglioni, Claudio / Petrone, Maria Chiara / Alvaro, Domenico / Arcidiacono, Paolo Giorgio / Capurso, Gabriele. ·Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy. · Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00161 Rome, Italy. · Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy. · Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome 00161, Italy. · Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Division of Human Anatomy, Sapienza University of Rome, Rome 00161, Italy. · PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy. · Department of Translational and Precision Medicine, Sapienza University of Rome, Rome 00161, Italy. · PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy, arcidiacono.paologiorgio@hsr.it. ·World J Gastroenterol · Pubmed #31496617.

ABSTRACT: the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.

3 Review Nerves and Pancreatic Cancer: New Insights into a Dangerous Relationship. 2019

Gasparini, Giulia / Pellegatta, Marta / Crippa, Stefano / Lena, Marco Schiavo / Belfiori, Giulio / Doglioni, Claudio / Taveggia, Carla / Falconi, Massimo. ·Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. gasparini.giulia@hsr.it. · Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. gasparini.giulia@hsr.it. · Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. pellegatta.marta@hsr.it. · Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. crippa1.stefano@hsr.it. · Vita Salute San Raffaele University, 20132 Milan, Italy. crippa1.stefano@hsr.it. · Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. schiavolena.marco@hsr.it. · Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. belfiori.giulio@hsr.it. · Vita Salute San Raffaele University, 20132 Milan, Italy. doglioni.claudio@hsr.it. · Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. doglioni.claudio@hsr.it. · Axo-Glial Interaction Unit, INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. taveggia.carla@hsr.it. · Pancreas Translational & Clinical Research Center, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. falconi.massimo@hsr.it. · Vita Salute San Raffaele University, 20132 Milan, Italy. falconi.massimo@hsr.it. ·Cancers (Basel) · Pubmed #31248001.

ABSTRACT: Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer-particularly in pancreatic ductal adenocarcinoma (PDAC)-PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously ("present" or "absent"). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.

4 Review Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology. 2016

Crippa, Stefano / Partelli, Stefano / Belfiori, Giulio / Palucci, Marco / Muffatti, Francesca / Adamenko, Olga / Cardinali, Luca / Doglioni, Claudio / Zamboni, Giuseppe / Falconi, Massimo. ·Stefano Crippa, Stefano Partelli, Marco Palucci, Francesca Muffatti, Olga Adamenko, Massimo Falconi, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, 20132 Milan, Italy. ·World J Gastroenterol · Pubmed #28018101.

ABSTRACT: Neuroendocrine carcinomas (NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin-based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors.

5 Review PDX-1 (pancreatic/duodenal homeobox-1 protein 1). 2014

Pedica, F / Beccari, S / Pedron, S / Montagna, L / Piccoli, P / Doglioni, C / Chilosi, M. · ·Pathologica · Pubmed #25845046.

ABSTRACT: The homeodomain-containing transcription factor pancreatic duodenal homeobox 1 (PDX-1) plays a key role in pancreatic development and β-cell function. It is a major regulator of transcription in pancreatic cells, and transactivates the insulin gene by binding to a specific DNA motif in its promoter region. Glucose also regulates insulin gene transcription through PDX-1. It has been shown that PDX-1 is required for maintaining pancreatic islet functions by activating gene expression and has a dual role in pancreatic development. It initially contributes to pancreatic formation during embryogenesis and subsequently regulates the pancreatic islet cell physiology in mature islet cells. Because of this key role in the embryologic development of the pancreas, PDX-1 expression has been investigated in pancreatic cancer cell lines and human tumors. Moreover, a few reports have described expression of PDX-1 in other human neoplasms and have investigated its potential role in differential diagnosis, but data on normal human tissues are lacking. Understanding the molecular mechanisms of pancreas formation, and especially the function of PDX-1, may contribute to the improved treatment and prevention of debilitating diseases such as diabetes, insulinomas and pancreatic carcinomas. Nevertheless, further studies are needed concerning its possible application in routine practice.

6 Clinical Trial Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. 2018

Reni, Michele / Zanon, Silvia / Peretti, Umberto / Chiaravalli, Marta / Barone, Diletta / Pircher, Chiara / Balzano, Gianpaolo / Macchini, Marina / Romi, Silvia / Gritti, Elena / Mazza, Elena / Nicoletti, Roberto / Doglioni, Claudio / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Radiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. ·Lancet Gastroenterol Hepatol · Pubmed #30220407.

ABSTRACT: BACKGROUND: Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS: This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m FINDINGS: Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION: Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING: Celgene.

7 Clinical Trial A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma. 2018

Reni, Michele / Zanon, Silvia / Balzano, Gianpaolo / Passoni, Paolo / Pircher, Chiara / Chiaravalli, Marta / Fugazza, Clara / Ceraulo, Domenica / Nicoletti, Roberto / Arcidiacono, Paolo Giorgio / Macchini, Marina / Peretti, Umberto / Castoldi, Renato / Doglioni, Claudio / Falconi, Massimo / Partelli, Stefano / Gianni, Luca. ·Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiotherapy, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pathology Unit, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. ·Eur J Cancer · Pubmed #30149366.

ABSTRACT: BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.

8 Clinical Trial Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. 2018

Reni, Michele / Balzano, Gianpaolo / Zanon, Silvia / Zerbi, Alessandro / Rimassa, Lorenza / Castoldi, Renato / Pinelli, Domenico / Mosconi, Stefania / Doglioni, Claudio / Chiaravalli, Marta / Pircher, Chiara / Arcidiacono, Paolo Giorgio / Torri, Valter / Maggiora, Paola / Ceraulo, Domenica / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy. · Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy. · Department of Surgery, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Onco-Hematology Department, Oncology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pathology Unit, Vita-Salute San Raffaele University, Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS San Raffaele Scientific Institute, Milan, Italy. · IRCCS Mario Negri Institute for Pharmacological Research, Milan, Italy. · Department of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pancreatic Surgery, Vita-Salute San Raffaele University, Milan, Italy. ·Lancet Gastroenterol Hepatol · Pubmed #29625841.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. METHODS: We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m FINDINGS: Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. INTERPRETATION: Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. FUNDING: PERLAVITA ONLUS and MyEverest ONLUS.

9 Clinical Trial Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma. 2016

Reni, Michele / Balzano, Gianpaolo / Zanon, Silvia / Passoni, Paolo / Nicoletti, Roberto / Arcidiacono, Paolo Giorgio / Pepe, Gino / Doglioni, Claudio / Fugazza, Clara / Ceraulo, Domenica / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Surgery, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Radiotherapy, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Radiology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Gastroenterology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Nuclear Medicine Unit, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Pathology Unit, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. ·Br J Cancer · Pubmed #27404453.

ABSTRACT: BACKGROUND: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). METHODS: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. RESULTS: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by ⩾49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. CONCLUSIONS: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration.

10 Clinical Trial Phase II trial of salvage therapy with trabectedin in metastatic pancreatic adenocarcinoma. 2016

Belli, Carmen / Piemonti, Lorenzo / D'Incalci, Maurizio / Zucchetti, Massimo / Porcu, Luca / Cappio, Stefano / Doglioni, Claudio / Allavena, Paola / Ceraulo, Domenica / Maggiora, Paola / Dugnani, Erica / Cangi, Maria Giulia / Garassini, Greta / Reni, Michele. ·Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. · Diabetes Research Institute, San Raffaele Scientific Institute, 20132, Milan, Italy. · Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156, Milan, Italy. · Department of Radiology, San Raffaele Scientific Institute, 20132, Milan, Italy. · Pathology Unit, San Raffaele Scientific Institute, 20132, Milan, Italy. · Department Immunology and Inflammation, IRCCS Clinical and Research Institute Humanitas, 20089, Rozzano, Milan, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. reni.michele@hsr.it. ·Cancer Chemother Pharmacol · Pubmed #26666646.

ABSTRACT: PURPOSE: No standard salvage chemotherapy has been identified for metastatic pancreatic adenocarcinoma (mPA), and there is an urgent need for active agents against this disease. This phase II trial explored the activity of trabectedin in mPA progressing after gemcitabine-based first-line chemotherapy. METHODS: Patients with gemcitabine-resistant disease received trabectedin 1.3 mg/m(2) as a 3-h intravenous continuous infusion every 3 weeks until disease progression or unacceptable toxicity or for a maximum of 6 months. The primary endpoint was progression-free survival rate at 6 months (PFS-6). Since trabectedin modulates the production of selected inflammatory mediators, this study also aimed to identify inflammatory biomarkers predictive for response to trabectedin. RESULTS: Between February 2011 and February 2012, 25 patients received trabectedin. PFS-6 was 4%, median PFS 1.9 months (range 0.8-7.4), and median overall survival 5.2 months (range 1.1-24.3). Grade >2 toxicity consisted of neutropenia in 44% of patients, febrile neutropenia and thrombocytopenia both in 12%, anemia in 8%, fatigue in 12%, and AST and ALT increase in 8 and 4%, respectively. Trabectedin was shown to modulate the production of inflammatory mediators, and at disease progression, levels of a subgroup of cytokines/chemokines were modified. Furthermore, tissue analysis identified 30 genes associated with better prognosis. CONCLUSIONS: Although it has shown some ability to modulate inflammatory process, single-agent trabectedin had no activity as salvage therapy for mPA.

11 Clinical Trial (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial. 2016

Reni, Michele / Dugnani, Erica / Cereda, Stefano / Belli, Carmen / Balzano, Gianpaolo / Nicoletti, Roberto / Liberati, Daniela / Pasquale, Valentina / Scavini, Marina / Maggiora, Paola / Sordi, Valeria / Lampasona, Vito / Ceraulo, Domenica / Di Terlizzi, Gaetano / Doglioni, Claudio / Falconi, Massimo / Piemonti, Lorenzo. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it. · Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. · Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it. ·Clin Cancer Res · Pubmed #26459175.

ABSTRACT: PURPOSE: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. EXPERIMENTAL DESIGN: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. RESULTS: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. CONCLUSIONS: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.

12 Clinical Trial Feasibility and yield of a novel 22-gauge histology EUS needle in patients with pancreatic masses: a multicenter prospective cohort study. 2013

Larghi, Alberto / Iglesias-Garcia, Julio / Poley, Jan-Werner / Monges, Geneviève / Petrone, Maria Chiara / Rindi, Guido / Abdulkader, Ihab / Arcidiacono, Paolo Giorgio / Costamagna, Guido / Biermann, Katharina / Bories, Erwan / Doglioni, Claudio / Dominguez-Muñoz, J Enrique / Hassan, Cesare / Bruno, Marco / Giovannini, Marc. ·Digestive Endoscopy Unit, Catholic University, Largo A. Gemelli 8, 00168, Rome, Italy, albertolarghi@yahoo.it. ·Surg Endosc · Pubmed #23644834.

ABSTRACT: BACKGROUND: The option of obtaining tissue samples for histological examination during endoscopic ultrasound (EUS) has theoretical and practical advantages over cytology alone. The aim of this study was to evaluate the feasibility, yield, and diagnostic accuracy of a new EUS 22-G fine-needle biopsy (FNB) device in patients with solid pancreatic masses in a multicenter, prospective study. METHODS: All consecutive patients who underwent EUS-guided fine-needle biopsy (EUS-FNB) using a newly developed 22-G FNB needle between September 2010 and October 2010 were enrolled in the study. The EUS-FNB technique was standardized among the participating endoscopists. Only a single needle pass was performed. RESULTS: A total of 61 patients (35 males, mean age 64.2 ± 12.4 years) with solid pancreatic masses with a mean size of 32.4 ± 8.5 mm (range 13-90 mm) participated. EUS-FNB was performed through the duodenum in 35 cases (57.4 %) and was technically feasible in all but one of the 61 (98.4 %) patients without complications. Tissue samples for histological examination were obtained from 55 patients (90.2 %) and were deemed adequate in 54 of the cases (88.5 %). The diagnoses established by EUS-FNB were adenocarcinoma (39 patients), neuroendocrine tumors (5), chronic focal pancreatitis (5), sarcoma (2), lymphoma (1), acinar cellular tumor (1), and pancreatic metastasis from renal cell carcinoma (1). In an intention-to-treat (ITT) analysis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the histologic diagnosis of a pancreatic mass were 87.5, 100, 100, 41.7, and 88.5 %, respectively. CONCLUSIONS: EUS-FNB was technically feasible in 98 % of patients with a solid pancreatic mass. A suitable sample for histological evaluation was obtained in 88.5 % of the cases after only one single needle pass. The apparently low negative predictive value is likely to be improved by increasing the number of needle passes.

13 Clinical Trial Does cytotechnician training influence the accuracy of EUS-guided fine-needle aspiration of pancreatic masses? 2012

Petrone, Maria Chiara / Arcidiacono, Paolo Giorgio / Carrara, Silvia / Mezzi, Gianni / Doglioni, Claudio / Testoni, Pier Alberto. ·Division of Gastroenterology and Gastrointestinal Endoscopy, Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Milan, Italy. petrone.mariachiara@hsr.it ·Dig Liver Dis · Pubmed #22226546.

ABSTRACT: BACKGROUND/AIM: The presence of on-site cytopathologists improves the diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic masses; however, on-site cytopathologists are not available to all endoscopic units. We hypothesized that experienced cytotechnicians can accurately assess whether an on-site pancreatic mass fine needle aspiration specimen is adequate. The aim of this study was to evaluate the effect of formal cytotechnician training on the diagnostic accuracy of EUS-FNA of pancreatic masses. METHODS: Single-centre, prospective study. The cytotechnician made an on-site assessment of specimen adequacy with immediate evaluation of smears over a 12-month period (pre-training period) then over another 12-month period (post-training period), with a year's intermediate training when the cytopathologist and the cytotechnician worked together in the room. The gold standard used to establish the final diagnosis was based on a non-equivocal fine needle aspiration biopsy reviewed by the same expert cytopathologist. The main outcome measurements were the cytotechnician diagnostic accuracy before and after the training period. RESULTS: A total of 107 patients were enrolled in the pre-training period. Cytotechnician in-room adequacy was 68.2% (73/107). The diagnostic accuracy was 74.8%. The adequacy for the blind-review pathologist was 93.4% (100/107), significantly higher (p=0.008) than the cytotechnician's results. During the post-training period, 95 EUS-FNA were performed and reviewed. Cytotechnician in-room adequacy was 87.4% (83/95). The diagnostic accuracy was 90.5%. The adequacy for the blinded pathologist was 95.8% (91/95), not significantly different from the cytotechnician (p=0.23). CONCLUSIONS: An adequate training period with an expert pathologist significantly improves the cytotechnician skill in terms of judging adequacy and diagnostic accuracy.

14 Clinical Trial A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). 2012

Reni, Michele / Cereda, Stefano / Rognone, Alessia / Belli, Carmen / Ghidini, Michele / Longoni, Simonetta / Fugazza, Clara / Rezzonico, Sara / Passoni, Paolo / Slim, Najla / Balzano, Giampaolo / Nicoletti, Roberto / Cappio, Stefano / Doglioni, Claudio / Villa, Eugenio. ·Department of Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. reni.michele@hsr.it ·Cancer Chemother Pharmacol · Pubmed #21626049.

ABSTRACT: PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

15 Article Positive neck margin at frozen section analysis is a significant predictor of tumour recurrence and poor survival after pancreatodudenectomy for pancreatic cancer. 2020

Crippa, Stefano / Guarneri, Giovanni / Belfiori, Giulio / Partelli, Stefano / Pagnanelli, Michele / Gasparini, Giulia / Balzano, Gianpaolo / Lena, Marco Schiavo / Rubini, Corrado / Doglioni, Claudio / Zamboni, Giuseppe / Falconi, Massimo. ·Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, Università Vita Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, Università Vita Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, Università Politecnica Delle Marche, Ospedali Riuniti, Ancona, Italy. · Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar, Italy. · Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, Università Vita Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: falconi.massimo@hsr.it. ·Eur J Surg Oncol · Pubmed #32098733.

ABSTRACT: BACKGROUND: The possible benefit of frozen section (FS) analysis during (PD) for pancreatic ductal adenocarcinoma (PDAC) and of additional resection up to total pancreatectomy (TP) is debated. Aim of this work is to evaluate the prognostic role of positive FS analysis after PD for PDAC. METHODS: Multicentric retrospective analysis on prospective databases of three institutions. Based on FS analysis patients were classified as FS negative/FS positive. All positive FS patients underwent extended PD (EPD) or TP. Postoperative outcomes, disease-free (DFS) and disease-specific survival (DSS) were evaluated. RESULTS: Of 371 patients, 58 (16%) had positive FS. This resulted in 313 (84%) SPD (standard pancreatoduodenectomy), 22 (6%) EPD and 36 (10%) TP. Postoperative mortality was higher in patients undergoing TP (11% compared to 4.5% in EPD and 1% in SPD; p = 0.01). 26% of patients underwent neoadjuvant therapy, and it did not decrease the rate of positive FS. Systemic/local relapse rates were 59% and 41% in negative FS group, and 78% and 22% in positive FS group (p = 0.031). Median DFS and DSS were 20 and 37 months in negative FS group, and 12 and 23 months in positive FS patients (p = 0.001). Independent predictors of recurrence were G3, N1/N2 status and positive FS. R1 resection, G3, N1/N2 status, perineural invasion and positive FS were independent predictors of DSS. CONCLUSIONS: Positive FS analysis is a poor prognostic factor after PD for PDAC. It is significantly associated with a high rate of R1 resection at final histology, PDAC recurrence and poor survival.

16 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.

17 Article The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer. 2019

Brunetto, Emanuela / De Monte, Lucia / Balzano, Gianpaolo / Camisa, Barbara / Laino, Vincenzo / Riba, Michela / Heltai, Silvia / Bianchi, Marco / Bordignon, Claudio / Falconi, Massimo / Bondanza, Attilio / Doglioni, Claudio / Protti, Maria Pia. ·Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. · Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit and Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Innovative Immunotherapies Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · MolMed SpA, Milan, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. protti.mariapia@hsr.it. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. protti.mariapia@hsr.it. ·J Immunother Cancer · Pubmed #30760333.

ABSTRACT: BACKGROUND: The thymic stromal lymphopoietin (TSLP), a key cytokine for development of Th2 immunity, is produced by cancer associated fibroblasts (CAFs) in pancreatic cancer where predominant tumor infiltrating Th2 over Th1 cells correlates with reduced patients' survival. Which cells and molecules are mostly relevant in driving TSLP secretion by CAFs in pancreatic cancer is not defined. METHODS: We performed in vitro, in vivo and ex-vivo analyses. For in vitro studies we used pancreatic cancer cell lines, primary CAFs cultures, and THP1 cells. TSLP secretion by CAFs was used as a read-out system to identify in vitro relevant tumor-derived inflammatory cytokines and molecules. For in vivo studies human pancreatic cancer cells and CAFs were orthotopically injected in immunodeficient mice. For ex-vivo studies immunohistochemistry was performed to detect ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) expression in surgical samples. Bioinformatics was applied to interrogate published data sets. RESULTS: We show in vitro that IL-1α and IL-1β released by pancreatic cancer cells and tumor cell-conditioned macrophages are crucial for TSLP secretion by CAFs. Treatment of immunodeficient mice orthotopically injected with human IL-1 positive pancreatic cancer cells plus CAFs using the IL-1R antagonist anakinra significantly reduced TSLP expression in the tumor. Importantly, we found that pancreatic cancer cells release alarmins, among which ASC, able to induce IL-1β secretion in macrophages. The relevance of ASC was confirmed ex-vivo by its expression in both tumor cells and tumor associated macrophages in pancreatic cancer surgical samples and survival data analyses showing statistically significant inverse correlation between ASC expression and survival in pancreatic cancer patients. CONCLUSIONS: Our findings indicate that tumor released IL-1α and IL-1β and ASC are key regulators of TSLP secretion by CAFs and their targeting should ultimately dampen Th2 inflammation and improve overall survival in pancreatic cancer.

18 Article The size of well differentiated pancreatic neuroendocrine tumors correlates with Ki67 proliferative index and is not associated with age. 2019

Partelli, Stefano / Muffatti, Francesca / Rancoita, Paola Maria Vittoria / Andreasi, Valentina / Balzano, Gianpaolo / Crippa, Stefano / Doglioni, Claudio / Rubini, Corrado / Zamboni, Giuseppe / Falconi, Massimo. ·Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · University Centre for Statistics in the Biomedical Sciences, "Vita-Salute" University, Milan, Italy. · Department of Pathology, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Department of Pathology, Polytechnic University of Marche Region, Ancona, Italy. · Department of Pathology, "Sacro Cuore-Don Calabria" Hospital, Negrar, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. ·Dig Liver Dis · Pubmed #30723019.

ABSTRACT: BACKGROUND: Concerns exist about a conservative management of well-differentiated nonfunctioning small pancreatic neuroendocrine tumors (NF-PanNET) in young patients and when preoperative Ki67 proliferative index is ≥3%. AIM: To evaluate an association between age, tumor size and grading in patients with sporadic NF-PanNET who underwent curative resection. METHODS: Patients who underwent surgery for sporadic NF-PanNET (excluding G3) were retrospectively analyzed. Linear regression analysis was performed to evaluate a possible correlation between continuous variables, whereas multiple logistic regression analysis was performed for determining predictors of NF-PanNET-G2. RESULTS: Overall, 235 patients with NF-PanNET-G1/G2 were included. The median largest radiological diameter was 25 mm. Age correlated neither with tumor size (P = 0.675) nor with Ki67 index (P = 0.376). On multivariate linear regression analysis, factors independently associated with Ki67 index were NF-PanNET size (P = 0.031), perineural invasion (P = 0.004), microvascular invasion (P = 0.001) and necrosis (P = 0.009). The most accurate NF-PanNET size for predicting NF-PanNET-G2 was 25 mm. On multivariate analysis, a NF-PanNET size >25 mm was independently associated with the risk of having a PanNET-G2 (P = 0.025). CONCLUSION: No correlations exist between age and NF-PanNET size or proliferative index. Therefore, an a priori aggressive attitude is not justified in young patients with small NF-PanNET, as a long-life expectancy is probably unlikely to increase the risk of malignant transformation.

19 Article A multicenter randomized trial comparing a 25-gauge EUS fine-needle aspiration device with a 20-gauge EUS fine-needle biopsy device. 2019

van Riet, Priscilla A / Larghi, Alberto / Attili, Fabia / Rindi, Guido / Nguyen, Nam Quoc / Ruszkiewicz, Andrew / Kitano, Masayuki / Chikugo, Takaaki / Aslanian, Harry / Farrell, James / Robert, Marie / Adeniran, Adebowale / Van Der Merwe, Schalk / Roskams, Tania / Chang, Kenneth / Lin, Fritz / Lee, John G / Arcidiacono, Paolo Giorgio / Petrone, Mariachiara / Doglioni, Claudio / Iglesias-Garcia, Julio / Abdulkader, Ihab / Giovannini, Marc / Bories, Erwan / Poizat, Flora / Santo, Erwin / Scapa, Erez / Marmor, Silvia / Bucobo, Juan Carlos / Buscaglia, Jonathan M / Heimann, Alan / Wu, Maoxin / Baldaque-Silva, Francisco / Moro, Carlos Fernández / Erler, Nicole S / Biermann, Katharina / Poley, Jan-Werner / Cahen, Djuna L / Bruno, Marco J. ·Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. · Department of Endoscopy, Catholic University Rome, Rome, Italy. · Department of Pathology, Catholic University Rome, Rome, Italy. · Department of Endoscopy, Royal Adelaide Hospital, Adelaide, Australia. · Department of Pathology, Royal Adelaide Hospital, Adelaide, Australia. · Department of Endoscopy, Kinki University, Osaka-Sayama, Japan. · Department of Pathology, Kinki University, Osaka-Sayama, Japan. · Department of Endoscopy, Yale University School of Medicine, New Haven, Connecticut, USA. · Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA. · Department of Endoscopy, University Hospital Leuven, Leuven, Belgium. · Department of Pathology, University Hospital Leuven, Leuven, Belgium. · Department of Endoscopy, University of California, Irvine, California, USA. · Department of Pathology, University of California, Irvine, California, USA. · Department of Endoscopy, Vita Salute San Raffaele University, Milan, Italy. · Department of Pathology, Vita Salute San Raffaele University, Milan, Italy. · Department of Endoscopy, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain. · Department of Pathology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain. · Department of Endoscopy, Institut Paoli-Calmettes, Marseilles, France. · Department of Pathology, Institut Paoli-Calmettes, Marseilles, France. · Department of Endoscopy, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Department of Endoscopy, Stony Brook University Hospital, Stony Brook, New York, USA. · Department of Pathology, Stony Brook University Hospital, Stony Brook, New York, USA. · Department of Upper GI Diseases, Unit of Gastrointestinal Endoscopy, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. · Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden. · Department of Biostatistics, Erasmus MC University Medical Center Rotterdam, the Netherlands. · Department of Pathology, Erasmus MC University Medical Center Rotterdam, the Netherlands. ·Gastrointest Endosc · Pubmed #30367877.

ABSTRACT: BACKGROUND AND AIMS: Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle. METHODS: Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders. RESULTS: A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P < .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836). CONCLUSION: The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.).

20 Article Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study. 2018

Rindi, Guido / Klersy, Catherine / Albarello, Luca / Baudin, Eric / Bianchi, Antonio / Buchler, Markus W / Caplin, Martyn / Couvelard, Anne / Cros, Jérôme / de Herder, Wouter W / Delle Fave, Gianfranco / Doglioni, Claudio / Federspiel, Birgitte / Fischer, Lars / Fusai, Giuseppe / Gavazzi, Francesca / Hansen, Carsten P / Inzani, Frediano / Jann, Henning / Komminoth, Paul / Knigge, Ulrich P / Landoni, Luca / La Rosa, Stefano / Lawlor, Rita T / Luong, Tu V / Marinoni, Ilaria / Panzuto, F / Pape, Ulrich-Frank / Partelli, Stefano / Perren, Aurel / Rinzivillo, Maria / Rubini, Corrado / Ruszniewski, Philippe / Scarpa, Aldo / Schmitt, Anja / Schinzari, Giovanni / Scoazec, Jean-Yves / Sessa, Fausto / Solcia, Enrico / Spaggiari, Paola / Toumpanakis, Christos / Vanoli, Alessandro / Wiedenmann, Bertram / Zamboni, Giuseppe / Zandee, Wouter T / Zerbi, Alessandro / Falconi, Massimo. ·Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italyguido.rindi@unicatt.it. · Service of Biometry and Clinical Epidemiology, Research Department, and IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Oncology, Cancer Campus, Villejuif, France. · Department of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Surgery, University Hospital Heidelberg, Neu Heidelberg, Germany. · Neuroendocrine Tumour Unit, Centre for Gastroenterology, London, United Kingdom. · Department of Pathology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Section Endocrinology, Department of Internal Medicine, Erasmus University Medical Center and and Erasmus MC Cancer Institute Rotterdam, Rotterdam ENETS Center of Excellence, Rotterdam, The Netherlands. · Digestive and Liver Disease Unit, Sant'Andrea University Hospital, Roma ENETS Center of Excellence, Rome, Italy. · Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Department of Surgery, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Pancreatic Surgery, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité, Campus Virchow Klinikum and Charite Mitte, University Medicine Berlin, Berlin ENETS Center of Excellence, Berlin, Germany. · Institute of Pathology, Stadtspital Triemli, Zurich, Switzerland. · Department of Surgery and Oncology, General and Pancreatic Surgery, The Pancreas Institute, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, Ospedale di Circolo, Università dell'Insubria, Varese, Italy. · Section of Pathology and ARC-Net Research Centre, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Institute of Pathology, University of Bern, Bern, Switzerland. · Pancreatic Surgery Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, Marche Polytechnic University, Ancona, Italy. · Department of Gastroenterology and Pancreatology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Department of Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Medical Biology and Pathology, Cancer Campus, Villejuif, France. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Pathology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy. ·Neuroendocrinology · Pubmed #30300897.

ABSTRACT: BACKGROUND: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). OBJECTIVES: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. METHOD: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. RESULTS: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. CONCLUSIONS: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

21 Article Gene expression analysis of embryonic pancreas development master regulators and terminal cell fate markers in resected pancreatic cancer: A correlation with clinical outcome. 2018

Dugnani, Erica / Sordi, Valeria / Pellegrini, Silvia / Chimienti, Raniero / Marzinotto, Ilaria / Pasquale, Valentina / Liberati, Daniela / Balzano, Gianpaolo / Doglioni, Claudio / Reni, Michele / Gandolfi, Alessandra / Falconi, Massimo / Lampasona, Vito / Piemonti, Lorenzo. ·Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Division of Genetics and Cell Biology, Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. · Department of Pathology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. · Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: piemonti.lorenzo@hsr.it. ·Pancreatology · Pubmed #30293872.

ABSTRACT: BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse. METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDAC patients. RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in human PDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence. CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.

22 Article Four-class tumor staging for early diagnosis and monitoring of murine pancreatic cancer using magnetic resonance and ultrasound. 2018

Dugnani, Erica / Pasquale, Valentina / Marra, Paolo / Liberati, Daniela / Canu, Tamara / Perani, Laura / De Sanctis, Francesco / Ugel, Stefano / Invernizzi, Francesca / Citro, Antonio / Venturini, Massimo / Doglioni, Claudio / Esposito, Antonio / Piemonti, Lorenzo. ·Division of Immunology, Transplantation and Infectious diseases, Diabetes Research Institute, Milan, Italy. · Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy. · Division of Genetics and Cell Biology, Genomic Unit for the diagnosis of human pathologies, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy. · University Hospital and Department of Medicine, Immunology Section, Verona, Italy. · Department of Pathology, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy. · Vita-Salute San Raffaele University, Milan, Italy. ·Carcinogenesis · Pubmed #30052815.

ABSTRACT: Background: The widely used genetically engineered mouse LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, termed KPC, spontaneously develops pancreatic cancer mirroring all phases of the carcinogenesis but in asynchronous manner. Preclinical studies need defined criteria for the enrollment of the KPC sharing the same stage of carcinogenesis. Aim: To define a tumor-staging criteria using magnetic resonance (MR) and ultrasound (US) and then to correlate the imaging stage with overall survival of KPC mice. Methods: Forty KPC (2- to 5-month-old mice) were imaged by axial fat-saturated T2-weighted sequences at MR and by brightness mode US to establish criteria for tumor staging. Immunohistopathology was used to validate imaging. A second cohort of 25 KPC was used to correlate imaging stage with survival by Kaplan-Meier analysis. Results: We defined a four-class tumor staging system ranking from stages 1 to 4. Stage 1 was described as radiologically healthy pancreas; precursor lesions were detectable in histology only. Cystic papillary neoplasms, besides other premalignant alterations, marked stage 2 in the absence of cancer nodules. Stages 3 and 4 identified mice affected by overt pancreatic cancer with size <5 or ≥5 mm, respectively. Regarding the prognosis, this staging system correlated with disease-related mortality whatever may be the KPC age when they staged. Conclusion: This imaging-based four-class tumor staging is an effective and safe method to stage pancreatic cancer development in KPC. As a result, regardless of their age, KPC mice can be synchronized based on prognosis or on a specific phase of tumorigenesis, such as the early but already radiologically detectable one (stage 2).

23 Article Long-term follow-up of low-risk branch-duct IPMNs of the pancreas: is main pancreatic duct dilatation the most worrisome feature? 2018

Petrone, Maria Chiara / Magnoni, Pietro / Pergolini, Ilaria / Capurso, Gabriele / Traini, Mariaemilia / Doglioni, Claudio / Mariani, Alberto / Crippa, Stefano / Arcidiacono, Paolo Giorgio. ·Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. petrone.mariachiara@hsr.it. · Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Surgery, Università Politecnica delle Marche, Ancona, Italy. · Digestive and Liver Disease Unit, S. Andrea University Hospital, Rome, Italy. · Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreas Translational & Clinical Research Center, Division of Pancreatic Surgery, Università Vita-Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy. ·Clin Transl Gastroenterol · Pubmed #29895904.

ABSTRACT: OBJECTIVES: The management of branch-duct IPMN remains controversial due to the relatively low rate of malignant degeneration and the uncertain predictive role of high-risk stigmata (HRS) and worrisome features (WFs) identified by the 2012 International Consensus Guidelines. Our aim was to evaluate the evolution of originally low-risk (Fukuoka-negative) BD-IPMNs during a long follow-up period in order to determine whether the appearance of any clinical or morphological variables may be independently associated with the development of malignancy over time. METHODS: A prospectively collected database of all patients with BD-IPMN referring to our Institute between 2002 and 2016 was retrospectively analyzed. Univariate and multivariate analysis of association between changes during follow-up, including appearance of HRS/WFs, and development of malignancy (high-grade dysplasia/invasive carcinoma) was performed. RESULTS: A total of 167 patients were selected for analysis, and seven developed malignant disease (4.2%). During a median follow-up time of 55 months, HRS appeared in only three cases but predicted malignancy with 100% specificity. Worrisome features, on the other hand, appeared in 44 patients (26.3%). Appearance of mural nodules and MPD dilatation >5 mm showed a significant association with malignancy in multivariate analysis (p = 0.004 and p = 0.001, respectively). MPD dilatation in particular proved to be the strongest independent risk factor for development of malignancy (OR = 24.5). CONCLUSIONS: The risk of pancreatic malignancy in this population is low but definite. The presence of major WFs, and especially MPD dilatation, should prompt a tighter follow-up with EUS and a valid cytological analysis whenever feasible.

24 Article Recurrence of Pancreatic Neuroendocrine Tumors and Survival Predicted by Ki67. 2018

Genç, C G / Falconi, M / Partelli, S / Muffatti, F / van Eeden, S / Doglioni, C / Klümpen, H J / van Eijck, C H J / Nieveen van Dijkum, E J M. ·Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. · Pancreatic Surgery Unit, Pancreas Translational and Research Institute, Scientific Institute, San Raffaele Hospital, University Vita e Salute, Milan, Italy. · Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. · Department of Pathology, Scientific Institute, San Raffaele Hospital, University Vita e Salute, Milan, Italy. · Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands. · Cancer Center Amsterdam, Amsterdam, The Netherlands. · Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. e.j.nieveenvandijkum@amc.uva.nl. ·Ann Surg Oncol · Pubmed #29789972.

ABSTRACT: BACKGROUND: Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs) and adjuvant treatment currently is not indicated. This study investigated the role of Ki67 with regard to recurrence and survival after curative resection of panNET. METHODS: Patients with resected non-functioning panNET diagnosed between 1992 and 2016 from three institutions were retrospectively analyzed. Patients who had G1 or G2 tumor without distant metastases or hereditary syndromes were included in the study. The patients were re-categorized into Ki67 0-5 and Ki67 6-20%. Cox regression analysis with log-rank testing for recurrence and survival was performed. RESULTS: The study enrolled 241 patients (86%) with Ki67 0-5% and 39 patients (14%) with Ki67 6-20%. Recurrence was seen in 34 patients (14%) with Ki67 0-5% after a median period of 34 months and in 16 patients (41%) with Ki67 6-20% after a median period of 16 months (p < 0.001). The 5-year recurrence-free and 10-year disease-specific survival periods were respectively 90 and 91% for Ki67 0-5% and respectively 55 and 26% for Ki67 6-20% (p < 0.001). The overall survival period after recurrence was 44.9 months, which was comparable between the two groups (p = 0.283). In addition to a Ki67 rate higher than 5%, tumor larger than 4 cm and lymph node metastases were independently associated with recurrence. CONCLUSIONS: Patients at high risk for recurrence after curative resection of G1 or G2 panNET can be identified by a Ki67 rate higher than 5%. These patients should be more closely monitored postoperatively to detect recurrence early and might benefit from adjuvant treatment. A clear postoperative follow-up regimen is proposed.

25 Article The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms. 2018

Partelli, Stefano / Javed, Ammar A / Andreasi, Valentina / He, Jin / Muffatti, Francesca / Weiss, Matthew J / Sessa, Fausto / La Rosa, Stefano / Doglioni, Claudio / Zamboni, Giuseppe / Wolfgang, Christopher L / Falconi, Massimo. ·Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland. · Department of Pathology, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Department of Pathology, Ospedale "Sacro Cuore-Don Calabria", Negrar, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. ·Eur J Surg Oncol · Pubmed #29610023.

ABSTRACT: BACKGROUND: The most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. METHODS: A retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. RESULTS: 157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. CONCLUSIONS: The number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs.

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