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Pancreatic Neoplasms: HELP
Articles by Matthew H. Kulke
Based on 36 articles published since 2009
(Why 36 articles?)
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Between 2009 and 2019, M. H. Kulke wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. 2010

Kulke, Matthew H / Anthony, Lowell B / Bushnell, David L / de Herder, Wouter W / Goldsmith, Stanley J / Klimstra, David S / Marx, Stephen J / Pasieka, Janice L / Pommier, Rodney F / Yao, James C / Jensen, Robert T / Anonymous5451513. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115, USA. Matthew_kulke@dfci.harvard.edu ·Pancreas · Pubmed #20664472.

ABSTRACT: Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major subtypes of gastrointestinal NETs. Historically, there has been little consensus on the classification and management of patients with these tumor subtypes. We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies.

2 Review Medical Management of Pancreatic Neuroendocrine Tumors: Current and Future Therapy. 2016

Chan, Jennifer A / Kulke, Matthew H. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 1220, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: jang@partners.org. · Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 1220, 450 Brookline Avenue, Boston, MA 02215, USA. ·Surg Oncol Clin N Am · Pubmed #27013373.

ABSTRACT: When diagnosed at an early stage, resection of pancreatic neuroendocrine tumors (NETs) is often curative. Unfortunately, curative surgery is rarely an option for patients with metastatic disease. Multiple options are available for the management of patients with advanced pancreatic NETs, including surgery, liver-directed therapy, and systemic therapies. Because of the heterogeneity of disease biology and presentation, a multidisciplinary approach to management is critical. Treatment with somatostatin analogs, sunitinib, everolimus, and alkylating agents provide effective systemic therapeutic options for patients. Future studies to evaluate the optimal timing, sequence, and combination of therapies, as well as to identify predictors of response, are warranted.

3 Review Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects. 2015

Koumarianou, Anna / Kaltsas, Gregory / Kulke, Matthew H / Oberg, Kjell / Strosberg, Jonathan R / Spada, Francesca / Galdy, Salvatore / Barberis, Massimo / Fumagalli, Caterina / Berruti, Alfredo / Fazio, Nicola. ·Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, Athens, Greece. ·Neuroendocrinology · Pubmed #25924937.

ABSTRACT: Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.

4 Review A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors. 2015

Halperin, Daniel M / Kulke, Matthew H / Yao, James C. ·Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030; email: dmhalperin@mdanderson.org , jyao@mdanderson.org. ·Annu Rev Med · Pubmed #25341008.

ABSTRACT: Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.

5 Review Systemic therapy for advanced pancreatic neuroendocrine tumors. 2013

Kulke, Matthew H. ·Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. Matthew_Kulke@dfci.harvard.edu ·Semin Oncol · Pubmed #23391115.

ABSTRACT: Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.

6 Review Management of pancreatic neuroendocrine tumors. 2012

Halperin, Daniel M / Kulke, Matthew H. ·Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. ·Gastroenterol Clin North Am · Pubmed #22341253.

ABSTRACT: -- No abstract --

7 Review Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. 2011

Kulke, Matthew H / Bendell, Johanna / Kvols, Larry / Picus, Joel / Pommier, Rodney / Yao, James. ·Dana-Farber Cancer Institute, Boston MA, USA. matthew_kulke@dfci.harvard.edu ·J Hematol Oncol · Pubmed #21672194.

ABSTRACT: Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise, with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET.

8 Review Progress in the treatment of neuroendocrine tumors. 2009

Chan, Jennifer A / Kulke, Matthew H. ·Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. jang@partners.org ·Curr Oncol Rep · Pubmed #19336011.

ABSTRACT: Traditional treatments for patients with advanced neuroendocrine tumors include surgical debulking, hepatic embolization, somatostatin analogues, and interferon-alpha. Patients with pancreatic neuroendocrine tumors also may benefit from treatment with the alkylating agents streptozocin or temozolomide. In recent years, several promising new approaches have been investigated in patients with advanced neuroendocrine tumors. One such approach has been the use of radiopeptide therapy targeting somatostatin receptors. Additionally, agents targeting the vascular endothelial growth factor pathway and mammalian target of rapamycin have shown preliminary evidence of activity and are currently being evaluated in large randomized studies.

9 Clinical Trial A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. 2017

Kulke, M H / Ruszniewski, P / Van Cutsem, E / Lombard-Bohas, C / Valle, J W / De Herder, W W / Pavel, M / Degtyarev, E / Brase, J C / Bubuteishvili-Pacaud, L / Voi, M / Salazar, R / Borbath, I / Fazio, N / Smith, D / Capdevila, J / Riechelmann, R P / Yao, J C. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. · Department of Gastroenterology and Pancreatology University of Paris VII and Beaujon Hospital, Paris, France. · Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France. · Department of Medical Oncology, University of Manchester/The Christie Hospital, Manchester, UK. · Department of Endocrine Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Hepatology and Gastroenterology, Charité University of Medicine, Berlin, Germany. · Department of Oncology, Novartis AG, Basel, Switzerland. · Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, USA. · Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, Hospital of Barcelona, Barcelona, Spain. · Department of Gastroenterology Saint-Luc University Hospital, Brussels, Belgium. · Department of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · Department of Oncology, St. Andrew Hospital, Bordeaux, France. · Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. · Department of Oncology, Cancer Institute of the State of São Paulo, São Paulo, Brazil. · Department of Gastrointestinal and Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28327907.

ABSTRACT: Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

10 Clinical Trial A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. 2016

Fazio, Nicola / Buzzoni, Roberto / Baudin, Eric / Antonuzzo, Lorenzo / Hubner, Richard A / Lahner, Harald / DE Herder, Wouter W / Raderer, Markus / Teulé, Alexandre / Capdevila, Jaume / Libutti, Steven K / Kulke, Matthew H / Shah, Manisha / Dey, Debarshi / Turri, Sabine / Aimone, Paola / Massacesi, Cristian / Verslype, Chris. ·European Institute of Oncology, Milan, Italy nicola.fazio@ieo.it. · IRCCS National Tumor Institute, Milan, Italy. · Institut Gustave Roussy, Villejuif, France. · Careggi University Hospital, Florence, Italy. · The Christie NHS Foundation Trust, Manchester, U.K. · University of Duisburg-Essen, Essen, Germany. · Erasmus MC, Rotterdam, the Netherlands. · University Hospital of Vienna, Vienna, Austria. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. · Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY, U.S.A. · Dana-Farber Cancer Institute, Boston, MA, U.S.A. · The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, U.S.A. · Novartis Healthcare Private Limited, Hyderabad, India. · Novartis Pharma AG, Basel, Switzerland. · Novartis Oncology, Paris, France. · University Hospitals Leuven, Leuven, Belgium. ·Anticancer Res · Pubmed #26851029.

ABSTRACT: BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

11 Clinical Trial Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. 2015

Phan, Alexandria T / Halperin, Daniel M / Chan, Jennifer A / Fogelman, David R / Hess, Kenneth R / Malinowski, Paige / Regan, Eileen / Ng, Chaan S / Yao, James C / Kulke, Matthew H. ·Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jyao@mdanderson.org. ·Lancet Oncol · Pubmed #25956795.

ABSTRACT: BACKGROUND: Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. METHODS: We did a parallel cohort study of patients with metastatic or locally advanced grade 1-2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. FINDINGS: Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21·9%, 95% CI 11·0-38·8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). INTERPRETATION: Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. FUNDING: US National Cancer Institute of the National Institutes of Health.

12 Clinical Trial A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. 2013

Chan, Jennifer A / Blaszkowsky, Lawrence / Stuart, Keith / Zhu, Andrew X / Allen, Jill / Wadlow, Raymond / Ryan, David P / Meyerhardt, Jeffrey / Gonzalez, Marielle / Regan, Eileen / Zheng, Hui / Kulke, Matthew H. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. ·Cancer · Pubmed #23733618.

ABSTRACT: BACKGROUND: Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). A phase 1/2 study was performed to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients who have advanced pancreatic NET. METHODS: Patients were treated with temozolomide at a dose of 150 mg/m(2) per day on days 1 through 7 and days 15 through 21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival. RESULTS: A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached. CONCLUSIONS: Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted.

13 Clinical Trial A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. 2013

Strosberg, J R / Chan, J A / Ryan, D P / Meyerhardt, J A / Fuchs, C S / Abrams, T / Regan, E / Brady, R / Weber, J / Campos, T / Kvols, L K / Kulke, M H. ·Department of GI Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA. jonathan.strosberg@moffitt.org ·Endocr Relat Cancer · Pubmed #23572164.

ABSTRACT: The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.

14 Clinical Trial Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. 2011

Yao, James C / Pavel, Marianne / Phan, Alexandria T / Kulke, Matthew H / Hoosen, Sakina / St Peter, Jessica / Cherfi, Azzeddine / Öberg, Kjell E. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, Texas 77030, USA. jyao@mdanderson.org ·J Clin Endocrinol Metab · Pubmed #21994954.

ABSTRACT: CONTEXT: Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors. OBJECTIVE: The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus. PATIENTS AND METHODS: Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels. RESULTS: In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study. CONCLUSIONS: Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

15 Clinical Trial Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. 2010

Yao, James C / Lombard-Bohas, Catherine / Baudin, Eric / Kvols, Larry K / Rougier, Philippe / Ruszniewski, Philippe / Hoosen, Sakina / St Peter, Jessica / Haas, Tomas / Lebwohl, David / Van Cutsem, Eric / Kulke, Matthew H / Hobday, Timothy J / O'Dorisio, Thomas M / Shah, Manisha H / Cadiot, Guillaume / Luppi, Gabriele / Posey, James A / Wiedenmann, Bertram. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA. jyao@mdanderson.org ·J Clin Oncol · Pubmed #19933912.

ABSTRACT: PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

16 Clinical Trial Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904. 2009

Kulke, Matthew H / Tempero, Margaret A / Niedzwiecki, Donna / Hollis, Donna R / Kindler, Hedy L / Cusnir, Michael / Enzinger, Peter C / Gorsch, Stefan M / Goldberg, Richard M / Mayer, Robert J. ·Dana-Farber Cancer Institute, Boston, MA, USA. matthew_kulke@dfci.harvard.edu ·J Clin Oncol · Pubmed #19858396.

ABSTRACT: PURPOSE: The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study. PATIENTS AND METHODS: Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 50 mg/m(2) on days 1 and 15 (arm A); gemcitabine 1,500 mg/m(2) at a rate of 10 mg/m(2)/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m(2) with docetaxel 40 mg/m(2) on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m(2) with irinotecan 100 mg/m(2) on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival. Results Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens. CONCLUSION: Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.

17 Article Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. 2019

Cejas, Paloma / Drier, Yotam / Dreijerink, Koen M A / Brosens, Lodewijk A A / Deshpande, Vikram / Epstein, Charles B / Conemans, Elfi B / Morsink, Folkert H M / Graham, Mindy K / Valk, Gerlof D / Vriens, Menno R / Castillo, Carlos Fernandez-Del / Ferrone, Cristina R / Adar, Tomer / Bowden, Michaela / Whitton, Holly J / Da Silva, Annacarolina / Font-Tello, Alba / Long, Henry W / Gaskell, Elizabeth / Shoresh, Noam / Heaphy, Christopher M / Sicinska, Ewa / Kulke, Matthew H / Chung, Daniel C / Bernstein, Bradley E / Shivdasani, Ramesh A. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. · Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. yotam.drier@mail.huji.ac.il. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. yotam.drier@mail.huji.ac.il. · Lautenberg Center for Immunology and Cancer Research, Hebrew University, Faculty of Medicine, Jerusalem, Israel. yotam.drier@mail.huji.ac.il. · Department of Endocrine Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Internal Medicine, Amsterdam UMC, Amsterdam, the Netherlands. · Department of Pathology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. ·Nat Med · Pubmed #31263286.

ABSTRACT: Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'

18 Article Characterization of the Neuroendocrine Tumor Immune Microenvironment. 2018

da Silva, Annacarolina / Bowden, Michaela / Zhang, Sui / Masugi, Yohei / Thorner, Aaron R / Herbert, Zachary T / Zhou, Chensheng Willa / Brais, Lauren / Chan, Jennifer A / Hodi, F Stephen / Rodig, Scott / Ogino, Shuji / Kulke, Matthew H. ·Center for Cancer Genome Discovery. · Molecular Biology Core Facilities, and. · Department of Pathology, Brigham and Women's Hospital. ·Pancreas · Pubmed #30153220.

ABSTRACT: OBJECTIVES: The immune environment and the potential for neuroendocrine tumors (NETs) to respond to immune checkpoint inhibitors remain largely unexplored. We assessed immune checkpoint marker expression, lymphocytic infiltrate, and associated mutational profiles in a cohort of small intestine and pancreatic NETs. METHODS: We assessed expression of PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2) in archival tissue from 64 small intestine (SINETs) and 31 pancreatic NETs (pNET). We additionally assessed T-cell infiltrates, categorizing T-cell subsets based on expression of the T-cell markers CD3, CD8, CD45RO (PTPRC), or FOXP3. Finally, we explored associations between immune checkpoint marker expression, lymphocytic infiltrate, and tumor mutational profiles. RESULTS: Expression of PD-1 or PD-L1 in small intestine or pancreatic NET was rare, whereas expression of PD-L2 was common in both NET subtypes. T-cell infiltrates were more abundant in pNET than in SINET. We found no clear associations between immune checkpoint marker expression, immune infiltrates, and specific mutational profile within each tumor type. CONCLUSIONS: Our findings provide an initial assessment of the immune environment of well-differentiated NETs. Further studies to define the immunologic differences between pNET and SINET, as well as the role of PD-L2 in these tumors, are warranted.

19 Article Guidance on 2018

Abbott, Amanda / Sakellis, Christopher G / Andersen, Eric / Kuzuhara, Yuji / Gilbert, Lauren / Boyle, Kelly / Kulke, Matthew H / Chan, Jennifer A / Jacene, Heather A / Van den Abbeele, Annick D. ·Department of Imaging and Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts amanda_abbott@dfci.harvard.edu. · Department of Imaging and Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Department of Environmental Health and Safety, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Adult Ambulatory Services, Nursing, and Imaging Services, Dana-Farber Cancer Institute, Boston, Massachusetts; and. · Program in Neuroendocrine and Carcinoid Tumors, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. ·J Nucl Med Technol · Pubmed #30076245.

ABSTRACT:

20 Article Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours. 2018

Raymond, Eric / Kulke, Matthew H / Qin, Shukui / Yu, Xianjun / Schenker, Michael / Cubillo, Antonio / Lou, Wenhui / Tomasek, Jiri / Thiis-Evensen, Espen / Xu, Jian-Ming / Croitoru, Adina E / Khasraw, Mustafa / Sedlackova, Eva / Borbath, Ivan / Ruff, Paul / Oberstein, Paul E / Ito, Tetsuhide / Jia, Liqun / Hammel, Pascal / Shen, Lin / Shrikhande, Shailesh V / Shen, Yali / Sufliarsky, Jozef / Khan, Gazala N / Morizane, Chigusa / Galdy, Salvatore / Khosravan, Reza / Fernandez, Kathrine C / Rosbrook, Brad / Fazio, Nicola. ·Department of Medical Oncology, Paris Saint-Joseph Hospital Group, Paris, France. · Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China. · Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. · Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania. · Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain. · Zhongshan Hospital, Fudan University, Shanghai, China. · Faculty of Medicine, Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic. · Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · No. 307 Hospital, Academy of Military Medical Sciences, Beijing, China. · Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania. · Andrew Love Cancer Center, Geelong Hospital, Victoria, Victoria, Australia. · Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Prague, Czech Republic. · Hepato-Gastroenterology Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. · Division of Hematology/Oncology, Columbia University Medical Center, New York, New York, USA. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · China-Japan Friendship Hospital, Beijing, China. · Service d'Oncologie Digestive, Hôpital Beaujon, Clichy, France. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University Cancer Hospital and Institute, Beijing, China. · GI and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · West China Hospital of Sichuan University, Chengdu, China. · 2nd Department of Oncology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. · Henry Ford Health System, Detroit, Michigan, USA. · National Cancer Center, Tokyo, Japan. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italy. · Pfizer Oncology, Pfizer Inc., San Diego, California, USA. · Pfizer Oncology, Pfizer Inc., Cambridge, Massachusetts, USA. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italynicola.fazio@ieo.it. ·Neuroendocrinology · Pubmed #29991024.

ABSTRACT: BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

21 Article Altered exocrine function can drive adipose wasting in early pancreatic cancer. 2018

Danai, Laura V / Babic, Ana / Rosenthal, Michael H / Dennstedt, Emily A / Muir, Alexander / Lien, Evan C / Mayers, Jared R / Tai, Karen / Lau, Allison N / Jones-Sali, Paul / Prado, Carla M / Petersen, Gloria M / Takahashi, Naoki / Sugimoto, Motokazu / Yeh, Jen Jen / Lopez, Nicole / Bardeesy, Nabeel / Fernandez-Del Castillo, Carlos / Liss, Andrew S / Koong, Albert C / Bui, Justin / Yuan, Chen / Welch, Marisa W / Brais, Lauren K / Kulke, Matthew H / Dennis, Courtney / Clish, Clary B / Wolpin, Brian M / Vander Heiden, Matthew G. ·Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada. · Mayo Clinic, Rochester, MN, USA. · Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · University of California San Diego School of Medicine, La Jolla, CA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. · MD Anderson, Department of Radiation Oncology, Houston, TX, USA. · Stanford Cancer Institute, Stanford, CA, USA. · David Geffen School of Medicine at University of California, Los Angeles, CA, USA. · Section of Hematology/Oncology, Boston University and Boston Medical Center, Boston, MA, USA. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. bwolpin@partners.org. · Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mvh@mit.edu. · Dana-Farber Cancer Institute, Boston, MA, USA. mvh@mit.edu. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. mvh@mit.edu. ·Nature · Pubmed #29925948.

ABSTRACT: Malignancy is accompanied by changes in the metabolism of both cells and the organism

22 Article Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. 2018

Aguirre, Andrew J / Nowak, Jonathan A / Camarda, Nicholas D / Moffitt, Richard A / Ghazani, Arezou A / Hazar-Rethinam, Mehlika / Raghavan, Srivatsan / Kim, Jaegil / Brais, Lauren K / Ragon, Dorisanne / Welch, Marisa W / Reilly, Emma / McCabe, Devin / Marini, Lori / Anderka, Kristin / Helvie, Karla / Oliver, Nelly / Babic, Ana / Da Silva, Annacarolina / Nadres, Brandon / Van Seventer, Emily E / Shahzade, Heather A / St Pierre, Joseph P / Burke, Kelly P / Clancy, Thomas / Cleary, James M / Doyle, Leona A / Jajoo, Kunal / McCleary, Nadine J / Meyerhardt, Jeffrey A / Murphy, Janet E / Ng, Kimmie / Patel, Anuj K / Perez, Kimberly / Rosenthal, Michael H / Rubinson, Douglas A / Ryou, Marvin / Shapiro, Geoffrey I / Sicinska, Ewa / Silverman, Stuart G / Nagy, Rebecca J / Lanman, Richard B / Knoerzer, Deborah / Welsch, Dean J / Yurgelun, Matthew B / Fuchs, Charles S / Garraway, Levi A / Getz, Gad / Hornick, Jason L / Johnson, Bruce E / Kulke, Matthew H / Mayer, Robert J / Miller, Jeffrey W / Shyn, Paul B / Tuveson, David A / Wagle, Nikhil / Yeh, Jen Jen / Hahn, William C / Corcoran, Ryan B / Carter, Scott L / Wolpin, Brian M. ·Dana-Farber Cancer Institute, Boston, Massachusetts. andrew_aguirre@dfci.harvard.edu carter.scott@jimmy.harvard.edu brian_wolpin@dfci.harvard.edu. · Broad Institute of Harvard and MIT, Cambridge, Massachusetts. · Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Biomedical Informatics, Department of Pathology, Stony Brook University, Stony Brook, New York. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medical Affairs, Guardant Health, Inc., Redwood City, California. · BioMed Valley Discoveries, Kansas City, Missouri. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. ·Cancer Discov · Pubmed #29903880.

ABSTRACT: Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame

23 Article Plasma inflammatory cytokines and survival of pancreatic cancer patients. 2018

Babic, A / Schnure, N / Neupane, N P / Zaman, M M / Rifai, N / Welch, M W / Brais, L K / Rubinson, D A / Morales-Oyarvide, V / Yuan, C / Zhang, S / Poole, E M / Wolpin, B M / Kulke, M H / Barbie, D A / Wong, K / Fuchs, C S / Ng, K. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. · Perelman School of Medicine, University of Pennsylvania Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA. · Thomas Jefferson University, 1020 Walnut Street, Philadelphia, PA, 19107, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA. · Yale Cancer Center, Yale School of Medicine, Smilow Cancer Hospital, 333 Cedar Street, New Haven, CT, 06510, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. Kimmie_Ng@dfci.harvard.edu. ·Clin Transl Gastroenterol · Pubmed #29691365.

ABSTRACT: OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend <0.0001 for all four comparisons). Furthermore, patients with higher circulating concentrations of all four cytokines had a median survival of 3.7 months; whereas, those with lower levels had a median survival of 19.2 months (HR = 4.55, 95% CI: 2.87-7.20, P-trend <0.0001). CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted.

24 Article Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. 2018

Klein, Alison P / Wolpin, Brian M / Risch, Harvey A / Stolzenberg-Solomon, Rachael Z / Mocci, Evelina / Zhang, Mingfeng / Canzian, Federico / Childs, Erica J / Hoskins, Jason W / Jermusyk, Ashley / Zhong, Jun / Chen, Fei / Albanes, Demetrius / Andreotti, Gabriella / Arslan, Alan A / Babic, Ana / Bamlet, William R / Beane-Freeman, Laura / Berndt, Sonja I / Blackford, Amanda / Borges, Michael / Borgida, Ayelet / Bracci, Paige M / Brais, Lauren / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, Bas / Buring, Julie / Campa, Daniele / Capurso, Gabriele / Cavestro, Giulia Martina / Chaffee, Kari G / Chung, Charles C / Cleary, Sean / Cotterchio, Michelle / Dijk, Frederike / Duell, Eric J / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gallinger, Steven / M Gaziano, J Michael / Gazouli, Maria / Giles, Graham G / Giovannucci, Edward / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Hegyi, Peter / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Jacobs, Eric J / Jamroziak, Krzysztof / Janout, Vladimir / Kaaks, Rudolf / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Kooperberg, Charles / Kulke, Matthew H / Kupcinskas, Juozas / Kurtz, Robert J / Laheru, Daniel / Landi, Stefano / Lawlor, Rita T / Lee, I-Min / LeMarchand, Loic / Lu, Lingeng / Malats, Núria / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Mohelníková-Duchoňová, Beatrice / Neale, Rachel E / Neoptolemos, John P / Oberg, Ann L / Olson, Sara H / Orlow, Irene / Pasquali, Claudio / Patel, Alpa V / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Scelo, Ghislaine / Sesso, Howard D / Severi, Gianluca / Shu, Xiao-Ou / Silverman, Debra / Smith, Jill P / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Tavano, Francesca / Thornquist, Mark D / Tobias, Geoffrey S / Van Den Eeden, Stephen K / Vashist, Yogesh / Visvanathan, Kala / Vodicka, Pavel / Wactawski-Wende, Jean / Wang, Zhaoming / Wentzensen, Nicolas / White, Emily / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Zheng, Wei / Kraft, Peter / Li, Donghui / Chanock, Stephen / Obazee, Ofure / Petersen, Gloria M / Amundadottir, Laufey T. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA. · Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA. · International Agency for Research on Cancer (IARC), 69372, Lyon, France. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. · Department of Biology, University of Pisa, 56126, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. · Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada. · Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT, 06510, USA. · Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy. · Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Boston VA Healthcare System, Boston, MA, 02132, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA. · First Department of Medicine, University of Szeged, 6725, Szeged, Hungary. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic. · Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain. · CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain. · Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain. · Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain. · CIBERONC, 28029, Madrid, Spain. · Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy. · Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · Department of General Surgery, University of Heidelburg, Heidelberg, Germany. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. · Department of Medicine, Georgetown University, Washington, 20057, USA. · Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. · Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov. ·Nat Commun · Pubmed #29422604.

ABSTRACT: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10

25 Article Development of a Framework Based on Reflective MCDA to Support Patient-Clinician Shared Decision-Making: The Case of the Management of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET) in the United States. 2018

Wagner, Monika / Samaha, Dima / Khoury, Hanane / O'Neil, William M / Lavoie, Louis / Bennetts, Liga / Badgley, Danielle / Gabriel, Sylvie / Berthon, Anthony / Dolan, James / Kulke, Matthew H / Goetghebeur, Mireille. ·Analytica Laser, Montreal, Canada. m.wagner@analytica-laser.com. · Analytica Laser, Montreal, Canada. · Ipsen Pharma, Paris, France. · University of Rochester, New York, USA. · Dana Farber Cancer Institute, Boston, USA. ·Adv Ther · Pubmed #29270780.

ABSTRACT: INTRODUCTION: Well- or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are often slow-growing, and some patients with unresectable, asymptomatic, non-functioning tumors may face the choice between watchful waiting (WW), or somatostatin analogues (SSA) to delay progression. We developed a comprehensive multi-criteria decision analysis (MCDA) framework to help patients and physicians clarify their values and preferences, consider each decision criterion, and support communication and shared decision-making. METHODS: The framework was adapted from a generic MCDA framework (EVIDEM) with patient and clinician input. During a workshop, patients and clinicians expressed their individual values and preferences (criteria weights) and, on the basis of two scenarios (treatment vs WW; SSA-1 [lanreotide] vs SSA-2 [octreotide]) with evidence from a literature review, expressed how consideration of each criterion would impact their decision in favor of either option (score), and shared their knowledge and insights verbally and in writing. RESULTS: The framework included benefit-risk criteria and modulating factors, such as disease severity, quality of evidence, costs, and constraints. Overall and progression-free survival being most important, criteria weights ranged widely, highlighting variations in individual values and the need to share them. Scoring and considering each criterion prompted a rich exchange of perspectives and uncovered individual assumptions and interpretations. At the group level, type of benefit, disease severity, effectiveness, and quality of evidence favored treatment; cost aspects favored WW (scenario 1). For scenario 2, most criteria did not favor either option. CONCLUSIONS: Patients and clinicians consider many aspects in decision-making. The MCDA framework provided a common interpretive frame to structure this complexity, support individual reflection, and share perspectives. FUNDING: Ipsen Pharma.

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