Ferlay, J. et al. GLOBOCAN 2012: cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer [online] http://globocan.iarc.fr, (2013).
Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).
He, J. et al. 2564 resected periampullary adenocarcinomas at a single institution: trends over three decades. HPB (Oxford) 16, 83–90 (2014).
Rosato, V. et al. Population attributable risk for pancreatic cancer in Northern Italy. Pancreas 44, 216–220 (2015).
Boffetta, P., Boccia, S. & La Vecchia, C. (eds) A Quick Guide to Cancer Epidemiology (Springer, 2014).
International Agency for Research on Cancer (IARC). Cancer incidence in five continents. Vol. X. IARC [online] http://ci5.iarc.fr, (2013).
Malvezzi, M. et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann. Oncol. 26, 779–786 (2015). This work demonstrates that pancreatic cancer is a major neoplasm without favourable incidence and mortality trends over the past decades, and its prognosis remains dismal.
Cancer Research UK. Pancreatic cancer statistics. Cancer Research UK [online] www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer, (2015).
Anderson, K., Mack, T. & Silverman, D. in Cancer of the Pancreas (eds Schottenfeld, D. & Fraumeni, J.) 721–762 (Oxford Univ. Press, 2006).
Bosetti, C. et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case–Control Consortium (Panc4). Ann. Oncol. 23, 1880–1888 (2012).
Parkin, D. M. 2. Tobacco-attributable cancer burden in the UK in 2010. Br. J. Cancer 105, S6–S13 (2011).
Whiteman, D. C. et al. Cancers in Australia in 2010 attributable to modifiable factors: introduction and overview. Aust. N. Z. J. Public Health 39, 403–407 (2015).
Boffetta, P., Hecht, S., Gray, N., Gupta, P. & Straif, K. Smokeless tobacco and cancer. Lancet Oncol. 9, 667–675 (2008).
Behrens, G. et al. Physical activity and risk of pancreatic cancer: a systematic review and meta-analysis. Eur. J. Epidemiol. 30, 279–298 (2015).
Genkinger, J. M. et al. Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Ann. Oncol. 26, 2257–2266 (2015).
Larsson, S. C. & Wolk, A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br. J. Cancer 106, 603–607 (2012).
Rohrmann, S. et al. Meat and fish consumption and risk of pancreatic cancer: results from the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer 132, 617–624 (2013).
Bosetti, C. et al. Nutrient-based dietary patterns and pancreatic cancer risk. Ann. Epidemiol. 23, 124–128 (2013).
MacMahon, B., Yen, S., Trichopoulos, D., Warren, K. & Nardi, G. Coffee and cancer of the pancreas. N. Engl. J. Med. 304, 630–633 (1981).
Tramacere, I. et al. Alcohol drinking and pancreatic cancer risk: a meta-analysis of the dose–risk relation. Int. J. Cancer 126, 1474–1486 (2010).
Lucenteforte, E. et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case–Control Consortium (PanC4). Ann. Oncol. 23, 374–382 (2012).
Bosetti, C. et al. Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium. Ann. Oncol. 25, 2065–2072 (2014).
Chari, S. T. et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134, 95–101 (2008).
Bosetti, C. et al. Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium (PanC4). Ann. Oncol. 24, 2903–2910 (2013).
Turati, F. et al. Family history of cancer and the risk of cancer: a network of case–control studies. Ann. Oncol. 24, 2651–2656 (2013).
Rizzato, C. et al. ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium. Oncol. Rep. 29, 1637–1644 (2013).
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & Depinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).
Tanaka, M. Thirty years of experience with intraductal papillary mucinous neoplasm of the pancreas: from discovery to international consensus. Digestion 90, 265–272 (2014).
Preis, M. & Korc, M. Signaling pathways in pancreatic cancer. Crit. Rev. Eukaryot. Gene Expr. 21, 115–129 (2011).
Pasca di Magliano, M. et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE 2, e1155 (2007).
Tanizaki, J., Okamoto, I., Sakai, K. & Nakagawa, K. Differential roles of trans -phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification. Br. J. Cancer 105, 807–813 (2011).
Gore, A. J., Deitz, S. L., Palam, L. R., Craven, K. E. & Korc, M. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. J. Clin. Invest. 124, 338–352 (2014).
Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
Wang, L. et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res. 22, 208–219 (2012).
Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).
Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015). A landmark analysis of the mutational landscape of pancreatic cancer, defining four subtypes depending on patterns of structural variation: stable, locally rearranged, scattered and unstable.
Witkiewicz, A. K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016). This comprehensive study defines four subtypes of pancreatic cancer based on expression profile: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine.
Chang, D. K., Grimmond, S. M. & Biankin, A. V. Pancreatic cancer genomics. Curr. Opin. Genet. Dev. 24, 74–81 (2014).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Blackford, A. et al. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 69, 3681–3688 (2009).
Nones, K. et al. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int. J. Cancer 135, 1110–1118 (2014).
Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).
Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).
Daemen, A. et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc. Natl Acad. Sci. USA 112, E4410–E4417 (2015).
Gore, J. & Korc, M. Pancreatic cancer stroma: friend or foe? Cancer Cell 25, 711–712 (2014).
Biankin, A. V. & Maitra, A. Subtyping pancreatic cancer. Cancer Cell 28, 411–413 (2015).
Kottakis, F. & Bardeesy, N. Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome. Nat. Genet. 47, 1102–1103 (2015).
Seymour, A. B. et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54, 2761–2764 (1994).
Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).
Amedei, A., Niccolai, E. & Prisco, D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum. Vaccin. Immunother. 10, 3354–3368 (2014).
Inman, K. S., Francis, A. A. & Murray, N. R. Complex role for the immune system in initiation and progression of pancreatic cancer. World J. Gastroenterol. 20, 11160–11181 (2014).
Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).
Erkan, M. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161 (2008).
Bever, K. M. et al. The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy. HPB (Oxford) 17, 292–298 (2014).
Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).
Wang, L. M. et al. The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget 7, 4183–4194 (2016).
Apte, M. V., Wilson, J. S., Lugea, A. & Pandol, S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210–1219 (2013).
Hamada, S. et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 421, 349–354 (2012). This paper reports that enhancement of cancer cell stemness by pancreatic stellate cells influences the chemoresistance and recurrence of pancreatic cancer.
Xu, Z. et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am. J. Pathol. 177, 2585–2596 (2010). This is the first study to demonstrate that pancreatic stellate cells can migrate from the primary tumour site to distant sites where they probably facilitate seeding and survival of metastatic cancer cells.
Patel, M. B. et al. The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell–endothelial cell interactions: antiangiogenic implications in pancreatic cancer. Carcinogenesis 35, 1891–1900 (2014).
Ene-Obong, A. et al. Activated pancreatic stellate cells sequester CD8+ T-cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 45, 1121–1132 (2013).
Tang, D. et al. High expression of galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int. J. Cancer 130, 2337–2348 (2012).
Mace, T. A., Bloomston, M. & Lesinski, G. B. Pancreatic cancer-associated stellate cells: a viable target for reducing immunosuppression in the tumor microenvironment. Oncoimmunology 2, e24891 (2013).
Ma, Y., Hwang, R. F., Logsdon, C. D. & Ullrich, S. E. Dynamic mast cell–stromal cell interactions promote growth of pancreatic cancer. Cancer Res. 73, 3927–3937 (2013).
Shi, C. et al. Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage–stellate cell interaction. Lab. Invest. 94, 409–421 (2014).
Li, X. et al. Sonic Hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20, 4326–4338 (2014).
Kikuta, K. et al. Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic β-cells. Biochem. Biophys. Res. Commun. 433, 292–297 (2013).
Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
Erkan, M. et al. Cancer–stellate cell interactions perpetuate the hypoxia–fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 11, 497–508 (2009).
Kong, B. et al. Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. Oncotarget 6, 32154–32160 (2015).
Schonenberger, M. J. & Kovacs, W. J. Hypoxia signaling pathways: modulators of oxygen-related organelles. Front. Cell Dev. Biol. 3, 42 (2015).
Ye, L. Y. et al. Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: a meta-analysis. Pancreatology 14, 391–397 (2014).
Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).
Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).
Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
Cohen, R. et al. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget 6, 16832–16847 (2015).
Caldas, C. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 8, 27–32 (1994).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003). This paper describes the original GEMM model that demonstrated pancreatic cancer initiation and progression in a model system. Many subsequent models have been based on this GEMM model.
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).
Huang, L. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015).
Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015). This is the first description of human and mouse pancreatic ductal organoids, stimulating new research areas and exploratory clinical applications for pancreatic cancer.
Huch, M. et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32, 2708–2721 (2013).
Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
Hruban, R. H. et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 66, 95–106 (2006).
Izeradjene, K. et al. KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11, 229–243 (2007).
Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).
Mann, K. M. et al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 5934–5941 (2012).
Perez-Mancera, P. A. et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 486, 266–270 (2012).
Rad, R. et al. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nat. Genet. 47, 47–56 (2015).
Navas, C. et al. EGF receptor signaling is essential for K-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).
DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).
Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).
Collins, M. A. et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012).
Saborowski, M. et al. A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev. 28, 85–97 (2014).
Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).
Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).
von Figura, G. et al. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell Biol. 16, 255–267 (2014).
Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).
Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).
Bailey, J. M. et al. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene http://dx.doi.org/10.1038/onc.2015.441 (2015).
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
Bayne, L. J. et al. Tumor-derived granulocyte–macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).
Gilabert, M. et al. Pancreatic cancer-induced cachexia is Jak2-dependent in mice. J. Cell. Physiol. 229, 1437–1443 (2014).
Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).
Dawson, D. W. et al. High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev. Res. (Phila.) 6, 1064–1073 (2013).
Zambirinis, C. P. et al. TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J. Exp. Med. 212, 2077–2094 (2015).
Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).
Kim, E. J. et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin. Cancer Res. 20, 5937–5945 (2014).
Catenacci, D. V. et al. Randomized Phase Ib/II study of gemcitabine plus placebo or vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).
Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).
Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015).
Keenan, B. P. et al. A Listeriavaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146, 1784–1794 (2014).
Alagesan, B. et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin. Cancer Res. 21, 396–404 (2015).
Cook, N. et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J. Exp. Med. 209, 437–444 (2012).
Bausch, D. et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clin. Cancer Res. 17, 302–309 (2011).
Neesse, A. et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 62, 1034–1043 (2013).
Faca, V. M. et al. A mouse to human search for plasma proteome changes associated with pancreatic tumor development. PLoS Med. 5, e123 (2008).
Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015).
Chiou, S. H. et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing. Genes Dev. 29, 1576–1585 (2015).
Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
Lennon, A. M. et al. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res. 74, 3381–3389 (2014).
Poruk, K. E. et al. The clinical utility of CA 19–19 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr. Mol. Med. 13, 340–351 (2013).
Sausen, M. et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat. Commun. 6, 7686 (2015).
Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl Med. 6, 224ra24 (2014). This paper demonstrates that mutant DNA shed from early-stage (surgically resectable) pancreatic cancers can be detected in the plasma, suggesting that circulating tumour DNA might be a useful approach for the early detection of pancreatic cancer.
Mayers, J. R. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193–1198 (2014).
Mirus, J. E. et al. Cross-species antibody microarray interrogation identifies a 3-protein panel of plasma biomarkers for early diagnosis of pancreas cancer. Clin. Cancer Res. 21, 1764–1771 (2015).
Javeed, N. et al. Pancreatic cancer-derived exosomes cause paraneoplastic β-cell dysfunction. Clin. Cancer Res. 21, 1722–1733 (2015). Together with reference 133, this paper shows that advances in analytical technologies and detection capabilities will yield sensitive and specific non-invasive diagnostic tests for early-stage pancreatic cancer, thereby increasing pancreatic cancer resection rates.
Cote, G. A. et al. A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am. J. Gastroenterol. 109, 1942–1952 (2014).
Johnston, F. M. et al. Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin. Cancer Res. 15, 6511–6518 (2009).
Zhang, S. et al. Mesothelin virus-like particle immunization controls pancreatic cancer growth through CD8+ T cell induction and reduction in the frequency of CD4+ Foxp3+ ICOS- regulatory T cells. PLoS ONE 8, e68303 (2013).
Wolfgang, C. L. et al. Recent progress in pancreatic cancer. CA Cancer J. Clin. 63, 318–348 (2013).
Lee, E. S. & Lee, J. M. Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J. Gastroenterol. 20, 7864–7877 (2014).
Motosugi, U. et al. Detection of pancreatic carcinoma and liver metastases with gadoxetic acid-enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT. Radiology 260, 446–453 (2011).
Tsurusaki, M., Sofue, K. & Murakami, T. Current evidence for the diagnostic value of gadoxetic acid-enhanced magnetic resonance imaging for liver metastasis. Hepatol. Res. http://dx.doi.org/10.1111/hepr.12646 (2016).
Harinck, F. et al. A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals. Gut http://dx.doi.org/10.1136/gutjnl-2014-308008 (2015).
Shin, E. J. et al. Linear-array EUS improves detection of pancreatic lesions in high-risk individuals: a randomized tandem study. Gastrointest. Endosc. 82, 812–818 (2015).
Parikh, U., Marcus, C., Sarangi, R., Taghipour, M. & Subramaniam, R. M. FDG PET/CT in pancreatic and hepatobiliary carcinomas: value to patient management and patient outcomes. PET Clin. 10, 327–343 (2015).
Sah, R. P., Nagpal, S. J., Mukhopadhyay, D. & Chari, S. T. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat. Rev. Gastroenterol. Hepatol. 10, 423–433 (2013).
Hruban, R. H., Pitman, M. B. & Klimstra, D. S. Tumors of the Pancreas. Atlas of Tumor Pathology (American Registry of Pathology and Armed Forces Institute of Pathology, 2007).
Wilentz, R. E. et al. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am. J. Pathol. 156, 37–43 (2000). This work demonstrates that immunolabelling for SMAD4 is an accurate surrogate for detecting DNA mutations in SMAD4. This paper helped to bring molecular analyses to the daily practice of pathology.
Basturk, O. et al. A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).
Voong, K. R. et al. Resected pancreatic adenosquamous carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy and radiation in 38 patients. Hum. Pathol. 41, 113–122 (2010).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Crippa, S. et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann. Surg. 247, 571–579 (2008).
Waters, J. A. et al. Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage. J. Am. Coll. Surg. 213, 275–283 (2011).
Mayo, S. C. et al. Management of patients with pancreatic adenocarcinoma: national trends in patient selection, operative management, and use of adjuvant therapy. J. Am. Coll. Surg. 214, 33–45 (2012).
Chari, S. T. et al. Early detection of sporadic pancreatic cancer: summative review. Pancreas 44, 693–712 (2015).
Klein, A. P. et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS ONE 8, e72311 (2013).
Risch, H. A., Yu, H., Lu, L. & Kidd, M. S. Detectable symptomatology preceding the diagnosis of pancreatic cancer and absolute risk of pancreatic cancer diagnosis. Am. J. Epidemiol. 182, 26–34 (2015).
Klein, A. P. et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 64, 2634–2638 (2004). This registry-based study quantifies pancreatic cancer risk in families and demonstrates that an increased risk begins as early as 45 years of age.
Al-Sukhni, W. et al. Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. J. Gastrointest. Surg. 16, 771–783 (2012).
Canto, M. I. et al. International Cancer of the Pancreas Screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 62, 339–347 (2013). This paper reports on a panel consensus from a consortium meeting regarding screening high-risk families.
Tanaka, M. et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12, 183–197 (2012).
Pandharipande, P. V. et al. Targeted screening of individuals at high risk for pancreatic cancer: results of a simulation model. Radiology 275, 177–187 (2015).
Burris, H. A. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).
Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).
Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011). This study establishes the superiority of 5-fluorouracil, oxaliplatin and irinotecan over gemcitabine based on improved progression-free and overall survival.
Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013). This study establishes the superiority of gemcitabine and albumin-bound paclitaxel over gemcitabine based on improved progression-free and overall survival.
Tempero, M. et al. Randomized Phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J. Clin. Oncol. 21, 3402–3408 (2003).
Golan, T. et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br. J. Cancer 111, 1132–1138 (2014).
Cunningham, D. et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 27, 5513–5518 (2009).
Fine, R. L. et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother. Pharmacol. 61, 167–175 (2008).
Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, Phase 3 trial. Lancet 387, 545–557 (2016).
Hammel, P. et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international Phase III LAP 07 study. J. Clin. Oncol. Abstr. 31, LBA4003 (2013).
Bramhall, S. R. et al. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br. J. Surg. 82, 111–115 (1995).
van Heek, N. T. et al. Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands. Ann. Surg. 242, 781–788; discussion 788–790 (2005).
Carpelan-Holmstrom, M. et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut 54, 385–387 (2005).
Gudjonsson, B. Carcinoma of the pancreas: critical analysis of costs, results of resections, and the need for standardized reporting. J. Am. Coll. Surg. 181, 483–503 (1995).
Bilimoria, K. Y. et al. National failure to operate on early stage pancreatic cancer. Ann. Surg. 246, 173–180 (2007). This article highlights that many patients with early-stage pancreatic cancer are not offered surgery as the optimal treatment option.
Amini, N., Spolverato, G., Kim, Y. & Pawlik, T. M. Trends in hospital volume and failure to rescue for pancreatic surgery. J. Gastrointest. Surg. 19, 1581–1592 (2015).
de Wilde, R. F. et al. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br. J. Surg. 99, 404–410 (2012).
Hartwig, W. et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann. Surg. 254, 311–319 (2011).
Neoptolemos, J. P. et al. Adjuvant chemotherapy with fluorouracil plus folinic acid versus gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304, 1073–1081 (2010).
Neoptolemos, J. P. et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200–1210 (2004). This is one of the largest trials of adjuvant therapy for pancreatic cancer, firmly establishing the role of adjuvant chemotherapy for pancreatic cancer.
Oettle, H. et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310, 1473–1481 (2013).
Cameron, J. L., Riall, T. S., Coleman, J. & Belcher, K. A. One thousand consecutive pancreaticoduodenectomies. Ann. Surg. 244, 10–15 (2006).
Diener, M. K. et al. Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma. Cochrane Database Syst. Rev. 11, CD006053 (2014).
Hartwig, W. et al. Total pancreatectomy for primary pancreatic neoplasms: renaissance of an unpopular operation. Ann. Surg. 261, 537–546 (2015).
Mehrabi, A. et al. A systematic review and meta-analysis of laparoscopic versus open distal pancreatectomy for benign and malignant lesions of the pancreas: it's time to randomize. Surgery 157, 45–55 (2015).
Correa-Gallego, C. et al. Minimally-invasive versus open pancreaticoduodenectomy: systematic review and meta-analysis. J. Am. Coll. Surg. 218, 129–139 (2014).
Abdelgadir Adam, M. et al. Minimally invasive versus open pancreaticoduodenectomy for cancer: practice patterns and short-term outcomes among 7061 patients. Ann. Surg. 262, 372–377 (2015).
Cirocchi, R. et al. A systematic review on robotic pancreaticoduodenectomy. Surg. Oncol. 22, 238–246 (2013).
Zureikat, A. H. et al. 250 robotic pancreatic resections: safety and feasibility. Ann. Surg. 258, 554–559; discussion 559–562 (2013).
Bockhorn, M. et al. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 155, 977–988 (2014). This is an international consensus paper defining resectability criteria for pancreatic cancer. This paper influenced subsequent patient therapy and trial design.
Tempero, M. A. et al. Pancreatic adenocarcinoma, version 2. 2014: featured updates to the NCCN guidelines. J. Natl Compr. Canc. Netw. 12, 1083–1093 (2014).
Yu, X. Z. et al. Benefit from synchronous portal-superior mesenteric vein resection during pancreaticoduodenectomy for cancer: a meta-analysis. Eur. J. Surg. Oncol. 40, 371–378 (2014).
Zhou, Y., Zhang, Z., Liu, Y., Li, B. & Xu, D. Pancreatectomy combined with superior mesenteric vein–portal vein resection for pancreatic cancer: a meta-analysis. World J. Surg. 36, 884–891 (2012).
Giovinazzo, F., Turri, G., Katz, M. H., Heaton, N. & Ahmed, I. Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma. Br. J. Surg. 103, 179–191 (2016).
Mollberg, N. et al. Arterial resection during pancreatectomy for pancreatic cancer: a systematic review and meta-analysis. Ann. Surg. 254, 882–893 (2011).
Beane, J. D. et al. Distal pancreatectomy with celiac axis resection: what are the added risks? HPB (Oxford) 17, 777–784 (2015).
Smoot, R. L. & Donohue, J. H. Modified Appleby procedure for resection of tumors of the pancreatic body and tail with celiac axis involvement. J. Gastrointest. Surg. 16, 2167–2169 (2012).
Hirano, S. et al. Distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic body cancer: long-term results. Ann. Surg. 246, 46–51 (2007).
Hartwig, W. et al. Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome. Ann. Surg. 250, 81–87 (2009).
Tol, J. A. et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 156, 591–600 (2014).
Dasari, B. V. et al. Extended versus standard lymphadenectomy for pancreatic head cancer:meta-analysis of randomized controlled trials. J. Gastrointest. Surg. 19, 1725–1732 (2015).
Michalski, C. W. et al. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br. J. Surg. 94, 265–273 (2007).
Gleisner, A. L. et al. Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 110, 2484–2492 (2007).
Michalski, C. W. et al. Resection of primary pancreatic cancer and liver metastasis: a systematic review. Dig. Surg. 25, 473–480 (2008).
Arnaoutakis, G. J. et al. Pulmonary resection for isolated pancreatic adenocarcinoma metastasis: an analysis of outcomes and survival. J. Gastrointest. Surg. 15, 1611–1617 (2011).
Gillen, S., Schuster, T., Friess, H. & Kleeff, J. Palliative resections versus palliative bypass procedures in pancreatic cancer — a systematic review. Am. J. Surg. 203, 496–502 (2012).
Chandrasegaram, M. D. et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br. J. Surg. 102, 1459–1472 (2015).
Esposito, I. et al. Most pancreatic cancer resections are R1 resections. Ann. Surg. Oncol. 15, 1651–1660 (2008). This is one of the first and largest studies demonstrating high R1 rates in pancreatic cancer following standardized pathological processing and reporting. This and similar work resulted in changes of several national and international guidelines.
Schlitter, A. M. & Esposito, I. Definition of microscopic tumor clearance (r0) in pancreatic cancer resections. Cancers (Basel) 2, 2001–2010 (2010).
Campbell, F. et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology 55, 277–283 (2009).
Traverso, L. W. Pancreatic cancer: surgery alone is not sufficient. Surg. Endosc. 20, S446–S449 (2006).
Regine, W. F. et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U. S. Intergroup/RTOG 9704 Phase III trial. Ann. Surg. Oncol. 18, 1319–1326 (2011).
Gillen, S., Schuster, T., Meyer Zum Buschenfelde, C., Friess, H. & Kleeff, J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 7, e1000267 (2010).
Heinrich, S. et al. Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter Phase III study (NEOPAC study). BMC Cancer 11, 346 (2011).
Tachezy, M. et al. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery versus primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA — a randomized multicenter Phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer 14, 411 (2014).
Ferrone, C. R. et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann. Surg. 261, 12–17 (2015).
Nitsche, U. et al. Resectability after first-line FOLFIRINOX in initially unresectable locally advanced pancreatic cancer: a single-center experience. Ann. Surg. Oncol. 22 (Suppl. 3), 1212–1220 (2015).
Katz, M. H. G. et al. Preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by chemoradiation (CRT) for borderline resectable (BLR) pancreatic cancer (PDAC): initial results from Alliance Trial A021101. J. Clin. Oncol. Abstr. 33 (Suppl.), 4008 (2015).
Cancer Research UK. ESPAC-5F: European study group for pancreatic cancer — trial 5F. Cancer Research UK [online] www.isrctn.com/ISRCTN89500674, (2014).
Pawlik, T. M. et al. Evaluating the impact of a single-day multidisciplinary clinic on the management of pancreatic cancer. Ann. Surg. Oncol. 15, 2081–2088 (2008).
Rainbird, K., Perkins, J., Sanson-Fisher, R., Rolfe, I. & Anseline, P. The needs of patients with advanced, incurable cancer. Br. J. Cancer 101, 759–764 (2009).
Aaronson, N. K. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85, 365–376 (1993).
Cella, D. F. et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J. Clin. Oncol. 11, 570–579 (1993).
Fitzsimmons, D. et al. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur. J. Cancer 35, 939–941 (1999).
Cella, D. et al. Validity of the FACT Hepatobiliary (FACT-Hep) questionnaire for assessing disease-related symptoms and health-related quality of life in patients with metastatic pancreatic cancer. Qual. Life Res. 22, 1105–1112 (2013).
Serrano, P. E. et al. Quality of life in a prospective, multicenter Phase 2 trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 90, 270–277 (2014).
Short, M. et al. Impact of gemcitabine chemotherapy and 3-dimensional conformal radiation therapy/5-fluorouracil on quality of life of patients managed for pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 85, 157–162 (2013).
Huang, J. J. et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann. Surg. 231, 890–898 (2000).
Reni, M. et al. Quality of life assessment in advanced pancreatic adenocarcinoma: results from a Phase III randomized trial. Pancreatology 6, 454–463 (2006).
Hurt, C. N. et al. Health-related quality of life in SCALOP, a randomized Phase 2 trial comparing chemoradiation therapy regimens in locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 93, 810–818 (2015).
Gaertner, J. et al. The role of end-of-life issues in the design and reporting of cancer clinical trials: a structured literature review. PLoS ONE 10, e0136640 (2015).
Biankin, A. V., Piantadosi, S. & Hollingsworth, S. J. Patient-centric trials for therapeutic development in precision oncology. Nature 526, 361–370 (2015).
Chang, D. K., Grimmond, S. M., Evans, T. R. J. & Biankin, A. V. Mining the genomes of exceptional responders. Nat. Rev. Cancer 14, 291–292 (2014).
Steenhuysen, J. Personal genome test will sell at new low price of $250. Scientific American [online] http://www.scientificamerican.com/article/craig-venter-s-company-in-deal-for-whole-exome-tests-at-new-low-cost/, (2015).
European Alliance for Personalised Medicine. Pancreatic cancer white paper 2015. Deadly ‘silent’ cancer needs a voice in EU research and investment. European Alliance for Personalised Medicine [online] http://www.euapm.eu/pdf/EAPM_Eapancreatic_cancer_white_paper_2015.pdf, (2015).
Hingorani, S. R. et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized Phase II study. J. Clin. Oncol. Abstr. 33 (Suppl.), 4006 (2015).
Hurwitz, H. I. et al. Randomized, double-blind, Phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J. Clin. Oncol. 33, 4039–4047 (2015).
Masso-Valles, D. et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 75, 1675–1681 (2015).
Kleeff, J. et al. Pancreatic cancer microenvironment. Int. J. Cancer 121, 699–705 (2007).
Soares, K. C. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 38, 1–11 (2015).
Dindo, D., Demartines, N. & Clavien, P. A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann. Surg. 240, 205–213 (2004).
Bassi, C. et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 138, 8–13 (2005).
Wente, M. N. et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 142, 761–768 (2007).
Wente, M. N. et al. Postpancreatectomy hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery 142, 20–25 (2007).
US National Cancer Institute. Common terminology criteria for adverse events (CTCAE), version 4.03. NCI [online] http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, (2010).
World Health Organization. WHO's cancer pain ladder for adults. WHO [online] http://www.who.int/cancer/palliative/painladder/en/, (2016).
Wyse, J. M., Carone, M., Paquin, S. C., Usatii, M. & Sahai, A. V. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J. Clin. Oncol. 29, 3541–3546 (2011).
Jones, W. B., Jordan, P. & Pudi, M. Pain management of pancreatic head adenocarcinomas that are unresectable: celiac plexus neurolysis and splanchnicectomy. J. Gastrointest. Oncol. 6, 445–451 (2015).
Kitano, M. et al. Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial. Am. J. Gastroenterol. 108, 1713–1722 (2013).
Walter, D. et al. Cost efficacy of metal stents for palliation of extrahepatic bile duct obstruction in a randomized controlled trial. Gastroenterology 149, 130–138 (2015).
Jeurnink, S. M. et al. Predictors of survival in patients with malignant gastric outlet obstruction: a patient-oriented decision approach for palliative treatment. Dig. Liver Dis. 43, 548–552 (2011).
Larssen, L., Hauge, T. & Medhus, A. W. Stent treatment of malignant gastric outlet obstruction: the effect on rate of gastric emptying, symptoms, and survival. Surg. Endosc. 26, 2955–2960 (2012).
National Comprehensive Cancer Network. Distress management clinical practice guidelines in oncology, version 3.2015. NCCN [online] http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#supportive, (2015).
Torgerson, S. & Wiebe, L. A. Supportive care of the patient with advanced pancreatic cancer. Oncology (Williston Park) 27, 183–190 (2013).
Del Fabbro, E. Current and future care of patients with the cancer anorexia–cachexia syndrome. Am. Soc. Clin. Oncol. Educ. Book 35, e229–e237 (2015).
Le, D. T. et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33, 1325–1333 (2015).
Xiao, Y. & Freeman, G. J. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 5, 16–18 (2015).
Khaled, Y. S., Wright, K., Melcher, A. & Jayne, D. Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines. Lancet 385, S56 (2015).
Bublil, E. M. & Yarden, Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr. Opin. Cell Biol. 19, 124–134 (2007).
Matsushita, A., Gotze, T. & Korc, M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 67, 10309–10316 (2007). Together with reference 33, this paper demonstrates that pancreatic cancer cells are characterized by multiple aberrant signalling pathways that enhance mitogenic signalling, underscoring the need for combinatorial therapies.
Morello, V. et al. β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene 30, 4087–4096 (2011).
Kleeff, J. et al. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J. Clin. Invest. 102, 1662–1673 (1998).
Hruban, R. H., Goggins, M. & Kern, S. E. Molecular genetics and related developments in pancreatic cancer. Curr. Opin. Gastroenterol. 15, 404–409 (1999).
Doherty, J. R. & Cleveland, J. L. Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest. 123, 3685–3692 (2013).
Ma, Z., Vocadlo, D. J. & Vosseller, K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. J. Biol. Chem. 288, 15121–15130 (2013).
Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).
Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).
Walter, K. et al. Serum fatty acid synthase as a marker of pancreatic neoplasia. Cancer Epidemiol. Biomarkers Prev. 18, 2380–2385 (2009).
Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000).
Lowenfels, A. B. et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J. Natl Cancer Inst. 89, 442–446 (1997).
Howes, N. et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin. Gastroenterol. Hepatol. 2, 252–261 (2004).
Goldstein, A. M. et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N. Engl. J. Med. 333, 970–974 (1995).
Borg, A. et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl Cancer Inst. 92, 1260–1266 (2000).
Kastrinos, F. et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302, 1790–1795 (2009).
Maisonneuve, P., Marshall, B. C. & Lowenfels, A. B. Risk of pancreatic cancer in patients with cystic fibrosis. Gut 56, 1327–1328 (2007).
Iqbal, J. et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 107, 2005–2009 (2012).
Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).
Geoffroy-Perez, B. et al. Cancer risk in heterozygotes for ataxia-telangiectasia. Int. J. Cancer 93, 288–293 (2001).
Ruijs, M. W. et al. TP53 germline mutation testing in 180 families suspected of Li–Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 47, 421–428 (2010).
Giardiello, F. M. et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 34, 1394–1396 (1993).