{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T13:42:17Z","timestamp":1768743737951,"version":"3.49.0"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2018,8,29]],"date-time":"2018-08-29T00:00:00Z","timestamp":1535500800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100001320","name":"Wolfson Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001320","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Dig Dis Sci"],"published-print":{"date-parts":[[2018,11]]},"DOI":"10.1007\/s10620-018-5233-y","type":"journal-article","created":{"date-parts":[[2018,8,29]],"date-time":"2018-08-29T21:17:15Z","timestamp":1535577435000},"page":"2840-2852","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5831-3892","authenticated-orcid":false,"given":"Philip J.","family":"Broadhurst","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R.","family":"Hart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,8,29]]},"reference":[{"key":"5233_CR1","unstructured":"International Agency for Research on Cancer. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. 2013. http:\/\/globocan.iarc.fr . Accessed 08 Sept 2017."},{"key":"5233_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ejca.2015.12.026","volume":"57","author":"T Conroy","year":"2016","unstructured":"Conroy T, Bachet JB, Ayav A, et al. Current standards and new innovative approaches for treatment of pancreatic cancer. Eur J Cancer. 2016;57:10\u201322.","journal-title":"Eur J Cancer"},{"key":"5233_CR3","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","volume":"364","author":"T Conroy","year":"2011","unstructured":"Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817\u20131825.","journal-title":"N Engl J Med"},{"key":"5233_CR4","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/S1470-2045(15)00027-3","volume":"16","author":"S Kordes","year":"2015","unstructured":"Kordes S, Pollak MN, Zwinderman AH, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16:839\u2013847.","journal-title":"Lancet Oncol"},{"key":"5233_CR5","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1007\/s10620-011-1709-8","volume":"56","author":"S Singh","year":"2011","unstructured":"Singh S, Tang SJ, Sreenarasimhaiah J, Lara LF, Siddiqui A. The clinical utility and limitations of serum carbohydrate antigen (CA19-9) as a diagnostic tool for pancreatic cancer and cholangiocarcinoma. Dig Dis Sci. 2011;56:2491\u20132496. https:\/\/doi.org\/10.1007\/s10620-011-1709-8","journal-title":"Dig Dis Sci"},{"key":"5233_CR6","first-page":"5501","volume":"47","author":"MA Tempero","year":"1987","unstructured":"Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res. 1987;47:5501\u20135503.","journal-title":"Cancer Res"},{"key":"5233_CR7","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1158\/1078-0432.CCR-15-1722","volume":"22","author":"M Reni","year":"2016","unstructured":"Reni M, Dugnani E, Cereda S, et al. (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial. Clin Cancer Res. 2016;22:1076\u20131085.","journal-title":"Clin Cancer Res"},{"key":"5233_CR8","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","volume":"60","author":"CJ Bailey","year":"2017","unstructured":"Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60:1566\u20131576.","journal-title":"Diabetologia"},{"key":"5233_CR9","unstructured":"WHO. Model list of essential medicines, 19th list, 2017. http:\/\/www.who.int\/medicines\/publications\/essentialmedicines\/en\/ . Accessed 26 Feb 2018."},{"key":"5233_CR10","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1056\/NEJM199602293340906","volume":"334","author":"CJ Bailey","year":"1996","unstructured":"Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574\u2013579.","journal-title":"N Engl J Med"},{"key":"5233_CR11","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1016\/j.bcp.2005.09.011","volume":"70","author":"J Muller","year":"2005","unstructured":"Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70:1851\u20131860.","journal-title":"Biochem Pharmacol"},{"key":"5233_CR12","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1124\/dmd.107.015495","volume":"35","author":"M Zhou","year":"2007","unstructured":"Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos Biol Fate Chem. 2007;35:1956\u20131962.","journal-title":"Drug Metab Dispos Biol Fate Chem"},{"key":"5233_CR13","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/978-3-642-14541-4_3","volume-title":"Drug Transporters, City","author":"AT Nies","year":"2011","unstructured":"Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. In: Fromm MF, Kim RB, eds. Drug Transporters, City. Berlin: Springer; 2011:105\u2013167."},{"key":"5233_CR14","doi-asserted-by":"publisher","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","volume":"50","author":"GG Graham","year":"2011","unstructured":"Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81\u201398.","journal-title":"Clin Pharmacokinet"},{"key":"5233_CR15","doi-asserted-by":"publisher","first-page":"415","DOI":"10.2217\/14622416.9.4.415","volume":"9","author":"H Takane","year":"2008","unstructured":"Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9:415\u2013422.","journal-title":"Pharmacogenomics"},{"key":"5233_CR16","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1124\/dmd.113.055616","volume":"42","author":"A Kim","year":"2014","unstructured":"Kim A, Chung I, Yoon SH, et al. Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos Biol Fate Chem. 2014;42:1174\u20131179.","journal-title":"Drug Metab Dispos Biol Fate Chem"},{"key":"5233_CR17","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1111\/j.1365-2125.1987.tb03090.x","volume":"23","author":"A Somogyi","year":"1987","unstructured":"Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23:545\u2013551.","journal-title":"Br J Clin Pharmacol"},{"key":"5233_CR18","doi-asserted-by":"publisher","first-page":"C35","DOI":"10.2337\/diacare.21.3.C35","volume":"21","author":"RC Turner","year":"1998","unstructured":"Turner RC. The U.K. prospective diabetes study: a review. Diabetes Care. 1998;21:C35\u2013C38.","journal-title":"Diabetes Care"},{"key":"5233_CR19","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1056\/NEJMoa066224","volume":"355","author":"SE Kahn","year":"2006","unstructured":"Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427\u20132443.","journal-title":"N Engl J Med"},{"key":"5233_CR20","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1111\/j.1464-5491.2007.02078.x","volume":"24","author":"MN Cook","year":"2007","unstructured":"Cook MN, Girman CJ, Stein PP, Alexander CM. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care. Diabet Med J Br Diabet Assoc. 2007;24:350\u2013358.","journal-title":"Diabet Med J Br Diabet Assoc"},{"key":"5233_CR21","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/ng.735","volume":"43","author":"K Zhou","year":"2011","unstructured":"Zhou K, Bellenguez C, Spencer CC, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117\u2013120.","journal-title":"Nat Genet"},{"key":"5233_CR22","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1136\/bmj.315.7107.524","volume":"315","author":"AD Morris","year":"1997","unstructured":"Morris AD, Boyle DI, MacAlpine R, et al. The diabetes audit and research in Tayside Scotland (darts) study: electronic record linkage to create a diabetes register. BMJ. 1997;315:524\u2013528.","journal-title":"BMJ"},{"key":"5233_CR23","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.2217\/pgs.12.115","volume":"13","author":"I Tkac","year":"2012","unstructured":"Tkac I. Replication of the association of gene variant near ATM and response to metformin. Pharmacogenomics. 2012;13:1331\u20131332.","journal-title":"Pharmacogenomics"},{"key":"5233_CR24","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1007\/s00125-012-2537-x","volume":"55","author":"N Leeuwen van","year":"2012","unstructured":"van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012;55:1971\u20131977.","journal-title":"Diabetologia"},{"key":"5233_CR25","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/ng.2236","volume":"44","author":"SW Yee","year":"2012","unstructured":"Yee SW, Chen L, Giacomini KM. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:359\u2013360.","journal-title":"Nat Genet"},{"key":"5233_CR26","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/ng.2235","volume":"44","author":"A Woods","year":"2012","unstructured":"Woods A, Leiper JM, Carling D. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:360\u2013361.","journal-title":"Nat Genet."},{"key":"5233_CR27","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/ng.735","volume":"43","author":"K Zhou","year":"2011","unstructured":"Zhou K, Bellenguez C, Spencer CCA, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117\u2013120.","journal-title":"Nat Genet"},{"key":"5233_CR28","first-page":"4059","volume":"81","author":"K Cusi","year":"1996","unstructured":"Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab.. 1996;81:4059\u20134067.","journal-title":"J Clin Endocrinol Metab."},{"key":"5233_CR29","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.cmet.2010.04.001","volume":"11","author":"SA Hawley","year":"2010","unstructured":"Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11:554\u2013565.","journal-title":"Cell Metab"},{"key":"5233_CR30","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1042\/bj3480607","volume":"348","author":"MR Owen","year":"2000","unstructured":"Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607\u2013614.","journal-title":"Biochem J"},{"key":"5233_CR31","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1741-7007-11-36","volume":"11","author":"DG Hardie","year":"2013","unstructured":"Hardie DG, Alessi DR. LKB1 and AMPK and the cancer-metabolism link\u2014ten years after. BMC Biol. 2013;11:36.","journal-title":"BMC Biol"},{"key":"5233_CR32","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/nrm2249","volume":"8","author":"DG Hardie","year":"2007","unstructured":"Hardie DG. AMP-activated\/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774\u2013785.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"5233_CR33","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nrm3311","volume":"13","author":"DG Hardie","year":"2012","unstructured":"Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251\u2013262.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"5233_CR34","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","volume":"115","author":"K Inoki","year":"2003","unstructured":"Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577\u2013590.","journal-title":"Cell"},{"key":"5233_CR35","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","volume":"124","author":"S Wullschleger","year":"2006","unstructured":"Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471\u2013484.","journal-title":"Cell"},{"key":"5233_CR36","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nrc3215","volume":"12","author":"M Pollak","year":"2012","unstructured":"Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159\u2013169.","journal-title":"Nat Rev Cancer"},{"key":"5233_CR37","doi-asserted-by":"publisher","first-page":"23892","DOI":"10.1074\/jbc.273.37.23892","volume":"273","author":"ML Goalstone","year":"1998","unstructured":"Goalstone ML, Leitner JW, Wall K, et al. Effect of insulin on farnesyltransferase: specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor. J Biol Chem. 1998;273:23892\u201323896.","journal-title":"J Biol Chem"},{"key":"5233_CR38","doi-asserted-by":"publisher","first-page":"7192","DOI":"10.3748\/wjg.14.7192","volume":"14","author":"L-W Wang","year":"2008","unstructured":"Wang L-W, Li Z-S, Zou D-W, Jin Z-D, Gao J, Xu G-M. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 2008;14:7192\u20137198.","journal-title":"World J Gastroenterol"},{"key":"5233_CR39","doi-asserted-by":"publisher","first-page":"83","DOI":"10.2174\/1566524016666151222145551","volume":"16","author":"G Zhou","year":"2016","unstructured":"Zhou G, Yu J, Wang A, et al. Metformin restrains pancreatic duodenal homeobox-1 (PDX-1) function by inhibiting ERK signaling in pancreatic ductal adenocarcinoma. Curr Mol Med. 2016;16:83\u201390.","journal-title":"Curr Mol Med"},{"key":"5233_CR40","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.3892\/mmr.2016.5592","volume":"14","author":"Y Shi","year":"2016","unstructured":"Shi Y, He Z, Jia Z, Xu C. Inhibitory effect of metformin combined with gemcitabine on pancreatic cancer cells in vitro and in vivo. Mol Med Rep. 2016;14:2921\u20132928.","journal-title":"Mol Med Rep"},{"key":"5233_CR41","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nrc2620","volume":"9","author":"K Polyak","year":"2009","unstructured":"Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265.","journal-title":"Nat Rev Cancer"},{"key":"5233_CR42","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.4161\/cc.6.19.4914","volume":"6","author":"LL Campbell","year":"2007","unstructured":"Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007;6:2332\u20132338.","journal-title":"Cell Cycle"},{"key":"5233_CR43","doi-asserted-by":"publisher","first-page":"7507","DOI":"10.1158\/0008-5472.CAN-09-2994","volume":"69","author":"HA Hirsch","year":"2009","unstructured":"Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507.","journal-title":"Cancer Res"},{"key":"5233_CR44","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1158\/0008-5472.CAN-10-3471","volume":"71","author":"D Iliopoulos","year":"2011","unstructured":"Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71:3196.","journal-title":"Cancer Res"},{"key":"5233_CR45","doi-asserted-by":"publisher","first-page":"367","DOI":"10.4161\/cc.11.2.18813","volume":"11","author":"X-S Deng","year":"2012","unstructured":"Deng X-S, Wang S, Deng A, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:367\u2013376.","journal-title":"Cell Cycle"},{"key":"5233_CR46","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.4161\/cc.8.13.8814","volume":"8","author":"B Liu","year":"2009","unstructured":"Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009;8:2031\u20132040.","journal-title":"Cell Cycle"},{"key":"5233_CR47","doi-asserted-by":"publisher","first-page":"909","DOI":"10.4161\/cc.8.6.7933","volume":"8","author":"IN Alimova","year":"2009","unstructured":"Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8:909\u2013915.","journal-title":"Cell Cycle"},{"key":"5233_CR48","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1750-2187-3-18","volume":"3","author":"Y Zhuang","year":"2009","unstructured":"Zhuang Y, Miskimins K, Zhuang Y, Miskimins WK. Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal. 2009;3:18.","journal-title":"J Mol Signal"},{"key":"5233_CR49","doi-asserted-by":"publisher","first-page":"3576","DOI":"10.1038\/sj.onc.1211024","volume":"27","author":"IB Sahra","year":"2008","unstructured":"Sahra IB, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576.","journal-title":"Oncogene"},{"key":"5233_CR50","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ygyno.2009.09.024","volume":"116","author":"LA Cantrell","year":"2010","unstructured":"Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation\u2014implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92\u201398.","journal-title":"Gynecol Oncol"},{"key":"5233_CR51","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1007\/s00018-007-7080-4","volume":"64","author":"A Isakovic","year":"2007","unstructured":"Isakovic A, Harhaji L, Stevanovic D, et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci CMLS. 2007;64:1290\u20131302.","journal-title":"Cell Mol Life Sci CMLS"},{"key":"5233_CR52","doi-asserted-by":"publisher","first-page":"88","DOI":"10.4161\/cc.8.1.7499","volume":"8","author":"A Vazquez-Martin","year":"2009","unstructured":"Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle. 2009;8:88\u201396.","journal-title":"Cell Cycle"},{"key":"5233_CR53","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/377441a0","volume":"377","author":"EJ Brown","year":"1995","unstructured":"Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995;377:441\u2013446.","journal-title":"Nature"},{"key":"5233_CR54","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.exger.2005.07.007","volume":"40","author":"VN Anisimov","year":"2005","unstructured":"Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2\/neu transgenic mice. Exp Gerontol. 2005;40:685\u2013693.","journal-title":"Exp Gerontol"},{"key":"5233_CR55","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1042\/BJ20080557","volume":"412","author":"X Huang","year":"2008","unstructured":"Huang X, Wullschleger S, Shpiro N, et al. Important role of the LKB1\u2013AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412:211\u2013221.","journal-title":"Biochem J"},{"key":"5233_CR56","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1111\/j.1349-7006.2008.00933.x","volume":"99","author":"A Tomimoto","year":"2008","unstructured":"Tomimoto A, Endo H, Sugiyama M, et al. Metformin suppresses intestinal polyp growth in ApcMin\/+mice. Cancer Sci. 2008;99:2136\u20132141.","journal-title":"Cancer Sci"},{"key":"5233_CR57","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1158\/1940-6207.CAPR-10-0055","volume":"3","author":"RM Memmott","year":"2010","unstructured":"Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res. 2010;3:1066\u20131076.","journal-title":"Cancer Prev Res"},{"key":"5233_CR58","doi-asserted-by":"publisher","first-page":"S25","DOI":"10.1007\/s001250051393","volume":"40","author":"D Ish-Shalom","year":"1997","unstructured":"Ish-Shalom D, Christoffersen CT, Vorwerk P, et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia. 1997;40:S25\u2013S31.","journal-title":"Diabetologia"},{"key":"5233_CR59","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1007\/s11605-016-3173-4","volume":"20","author":"M Cerullo","year":"2016","unstructured":"Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin use is associated with improved survival in patients undergoing resection for pancreatic cancer. J Gastrointest Surg. 2016;20:1572\u20131580.","journal-title":"J Gastrointest Surg"},{"key":"5233_CR60","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1200\/JCO.2015.63.3511","volume":"34","author":"R Chaiteerakij","year":"2016","unstructured":"Chaiteerakij R, Petersen GM, Bamlet WR, et al. Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J Clin Oncol. 2016;34:1898\u20131904.","journal-title":"J Clin Oncol"},{"key":"5233_CR61","doi-asserted-by":"publisher","first-page":"299","DOI":"10.2337\/dc11-1313","volume":"35","author":"CJ Currie","year":"2012","unstructured":"Currie CJ, Poole CD, Jenkins-Jones S, Gale EAM, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35:299\u2013304.","journal-title":"Diabetes Care"},{"key":"5233_CR62","doi-asserted-by":"publisher","first-page":"e6229","DOI":"10.1097\/MD.0000000000006229","volume":"96","author":"MA Frouws","year":"2017","unstructured":"Frouws MA, Mulder BGS, Bastiaannet E, et al. No association between metformin use and survival in patients with pancreatic cancer: an observational cohort study. Medicine. 2017;96:e6229.","journal-title":"Medicine"},{"key":"5233_CR63","doi-asserted-by":"publisher","first-page":"2905","DOI":"10.1158\/1078-0432.CCR-11-2994","volume":"15","author":"N Sadeghi","year":"2012","unstructured":"Sadeghi N, Abbruzzese JL, Yeung S-CJ, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;15:2905\u20132912.","journal-title":"Clin Cancer Res"},{"key":"5233_CR64","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1038\/ajg.2011.483","volume":"107","author":"M Bodmer","year":"2012","unstructured":"Bodmer M, Becker C, Meier C, Jick SS, Meier C. Use of antidiabetic agents and the risk of pancreatic cancer: a case\u2013control analysis. Am J Gastroenterol. 2012;107:620\u2013626.","journal-title":"Am J Gastroenterol"},{"key":"5233_CR65","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/S1470-2045(15)00565-3","volume":"17","author":"T Higurashi","year":"2016","unstructured":"Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475\u2013483.","journal-title":"Lancet Oncol"},{"key":"5233_CR66","doi-asserted-by":"crossref","first-page":"84224","DOI":"10.18632\/oncotarget.20478","volume":"8","author":"Y Zhao","year":"2017","unstructured":"Zhao Y, Gong C, Wang Z, et al. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget. 2017;8:84224\u201384236.","journal-title":"Oncotarget"},{"key":"5233_CR67","doi-asserted-by":"publisher","first-page":"5928","DOI":"10.1136\/bmj.d5928","volume":"343","author":"JPT Higgins","year":"2011","unstructured":"Higgins JPT, Altman DG, G\u00f8tzsche PC, et al. The Cochrane collaboration\u2019s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:5928.","journal-title":"BMJ"},{"key":"5233_CR68","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1097\/MPA.0000000000000470","volume":"45","author":"MM Kozak","year":"2016","unstructured":"Kozak MM, Anderson EM, von Eyben R, et al. Statin and metformin use prolongs survival in patients with resectable pancreatic cancer. Pancreas. 2016;45:64\u201370.","journal-title":"Pancreas"},{"key":"5233_CR69","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.dld.2015.12.006","volume":"48","author":"SH Lee","year":"2016","unstructured":"Lee SH, Yoon SH, Lee HS, et al. Can metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2. Digest Liver Dis. 2016;48:435\u2013440.","journal-title":"Digest Liver Dis"},{"key":"5233_CR70","doi-asserted-by":"publisher","first-page":"171","DOI":"10.4143\/crt.2014.292","volume":"48","author":"Y Choi","year":"2015","unstructured":"Choi Y, Kim T-Y, Oh D-Y, et al. The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat. 2015;48:171\u2013179.","journal-title":"Cancer Res Treat"},{"key":"5233_CR71","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1097\/MPA.0b013e3182965a3c","volume":"42","author":"A Hwang","year":"2013","unstructured":"Hwang A, Haynes K, Hwang W-T, Yang Y-X. Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas. 2013;42:1054\u20131059.","journal-title":"Pancreas"},{"key":"5233_CR72","doi-asserted-by":"publisher","first-page":"A439","DOI":"10.1016\/j.jval.2015.09.1072","volume":"18","author":"A Jo","year":"2015","unstructured":"Jo A, Kim Y, Kang S, Kim M, Ko M. PCN57 - The effect of metformin use and mortality among those with pancreatic cancer and type 2 diabetes mellitus: findings from a nationwide population retrospective cohort study. Value Health. 2015;18:A439.","journal-title":"Value Health"},{"key":"5233_CR73","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1038\/ajg.2016.288","volume":"111","author":"S Amin","year":"2016","unstructured":"Amin S, Mhango G, Lin J, et al. Metformin improves survival in patients with pancreatic ductal adenocarcinoma and pre-existing diabetes: a propensity score analysis. Am J Gastroenterol. 2016;111:1350\u20131357.","journal-title":"Am J Gastroenterol"},{"key":"5233_CR74","doi-asserted-by":"publisher","first-page":"e0151632","DOI":"10.1371\/journal.pone.0151632","volume":"11","author":"CM Ambe","year":"2016","unstructured":"Ambe CM, Mahipal A, Fulp J, Chen L, Malafa MP. Effect of metformin use on survival in resectable pancreatic cancer: a single-institution experience and review of the literature. PLOS ONE. 2016;11:e0151632.","journal-title":"PLOS ONE"}],"container-title":["Digestive Diseases and Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10620-018-5233-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5233-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5233-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,8]],"date-time":"2020-11-08T12:39:19Z","timestamp":1604839159000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10620-018-5233-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,29]]},"references-count":74,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2018,11]]}},"alternative-id":["5233"],"URL":"https:\/\/doi.org\/10.1007\/s10620-018-5233-y","relation":{},"ISSN":["0163-2116","1573-2568"],"issn-type":[{"value":"0163-2116","type":"print"},{"value":"1573-2568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,29]]},"assertion":[{"value":"4 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"No conflict of interests to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}