Biology and management of pancreatic cancer

Pancreatic cancer continues to pose an enormous challenge to clinicians and cancer scientists. With a more affluent world the global incidence of pancreatic cancer is rising. For the first time significant advances are now being made into the management of the disease. There is a more sophisticated approach to palliative care and the centralisation of pancreatic cancer services is leading to greater tumour resection rates. Newer adjuvant modalities are also greatly increasing the 5 year survival rates. The molecular basis of pancreatic cancer is now better understood than ever before, leading to the development of new diagnostic approaches and the introduction of mechanistic based treatments. Technical advances in imaging and great improvements in conventional and molecular pathology have led to a deeper understanding of the pathological variables of the disease. This is now an important time for making big inroads into what still remains the most lethal of the common cancers. Pancreatic ductal adenocarcinoma remains one of the most difficult cancers to treat. It is the commonest cancer affecting the exocrine pancreas. In 2000, there were 217 000 new cases of pancreatic cancer and 213 000 deaths world wide and in Europe 60 139 new patients (10.4% of all digestive tract cancers) and 64 801 deaths.1 In 2002 there were 7152 new cases in the UK, with similar numbers in men and women.2 In the USA in 2006 there were 33 730 new cases and 32 300 deaths.3 Without active treatment, metastatic pancreatic cancer has a median survival of 3–5 months and 6–10 months for locally advanced disease, which increases to around 11–15 months with resectional surgery.4 The late presentation and aggressive tumour biology of this disease mean that only a minority (10–15%) of patients can undergo potentially curative surgery. Major advances in the past decade …

[1]  S. Richard,et al.  Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau. , 2000, Gastroenterology.

[2]  Steven Piantadosi,et al.  Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[3]  P. Ruszniewski,et al.  Long-term Outcome of Biliary and Duodenal Stents in Palliative Treatment of Patients with Unresectable Adenocarcinoma of the Head of Pancreas , 2006, The American Journal of Gastroenterology.

[4]  H. Friess,et al.  Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer , 2004, International journal of cancer.

[5]  R. Sutton,et al.  Survival of patients with periampullary carcinoma is predicted by lymph node 8a but not by lymph node 16b1 status , 2004, British Journal of Surgery.

[6]  Jussi Taipale,et al.  Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. , 2002, Genes & development.

[7]  L. Beckett,et al.  Incidence, mechanism and prognostic value of activated AKT in pancreas cancer , 2003, British Journal of Cancer.

[8]  T. Takada,et al.  Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. , 2008, Archives of surgery.

[9]  D. Jaffe Methionine and Vitamin B6 Intake and Risk of Pancreatic Cancer: A Prospective Study of Swedish Women and Men , 2008 .

[10]  H. Tsukuma,et al.  Patients with pancreatic intraductal papillary mucinous neoplasms are at high risk of colorectal cancer development. , 2006, Surgery.

[11]  V. Yajnik,et al.  Pathology and genetics of tumors of the digestive system , 2001 .

[12]  K. Takagi,et al.  Ataxia–telangiectasia with dysgerminoma of right ovary, papillary carcinoma of thyroid, and adenocarcinoma of pancreas , 1984, Cancer.

[13]  Irving L Weissman,et al.  The cancer stem cell hypothesis: a work in progress , 2006, Laboratory Investigation.

[14]  Scott E. Kern,et al.  DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1 , 1996, Science.

[15]  D. Sargent,et al.  A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. , 2005, Surgery.

[16]  Alison P. Klein,et al.  Prospective Risk of Pancreatic Cancer in Familial Pancreatic Cancer Kindreds , 2004, Cancer Research.

[17]  R H Hruban,et al.  Progression model for pancreatic cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  D. Kerr,et al.  Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial , 2001, The Lancet.

[19]  Tobias Schmelzle,et al.  TOR, a Central Controller of Cell Growth , 2000, Cell.

[20]  J. Neoptolemos,et al.  Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer , 2004, Clinical Cancer Research.

[21]  H. Çamlıca,et al.  Efficacy of coeliac plexus and splanchnic nerve blockades in body and tail located pancreatic cancer pain , 2004, European journal of pain.

[22]  J. Neoptolemos,et al.  Capecitabine in carcinoma of the pancreas , 2006, Expert Opinion on Pharmacotherapy.

[23]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[24]  W. Schmiegel,et al.  Basement membrane component laminin-5 is a target of the tumor suppressor Smad4 , 2007, Oncogene.

[25]  Yusuke Nakamura,et al.  Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4 , 2006, Cancer science.

[26]  J. Neoptolemos,et al.  Diagnosis, Treatment and Outcome of Pancreatoblastoma , 2004, Pancreatology.

[27]  Gerald C. Chu,et al.  Stromal biology of pancreatic cancer , 2007, Journal of cellular biochemistry.

[28]  Y. Ogata,et al.  Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings , 2006, Journal of Gastrointestinal Surgery.

[29]  R. Schmid,et al.  Pancreatic cancer: a review of recent advances , 2006, Expert opinion on investigational drugs.

[30]  A. Sauvanet,et al.  Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[31]  H. Friess,et al.  Overexpression of HER2/neu oncogene in human pancreatic carcinoma. , 1993, Human pathology.

[32]  Donghui Li,et al.  The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. , 2005, Biochemical and biophysical research communications.

[33]  G. Evan,et al.  The pathological response to DNA damage does not contribute to p53-mediated tumour suppression , 2006, Nature.

[34]  N. Gruis,et al.  Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16‐Leiden) , 2000, International journal of cancer.

[35]  M. Imamura,et al.  A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer. , 2004, Surgery.

[36]  J. Fleming,et al.  Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras–Directed Therapy , 2005, Molecular Cancer Research.

[37]  Tomoko Umaki,et al.  Possible detection of pancreatic cancer by plasma protein profiling. , 2005, Cancer research.

[38]  U. Settmacher,et al.  [Reconstruction of visceral arteries with homografts in excision of the pancreas]. , 2004, Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen.

[39]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[40]  H. Friess,et al.  Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  Greco Fa,et al.  Adjuvant Combination Chemotherapy (AMF) Following Radical Resection of Carcinoma of the Pancreas and Papilla of Vater Results of a Controlled, Prospective, Randomised Multicentre Study , 1993 .

[42]  H. Ohge,et al.  Re: "Intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms of the pancreas differentiated by ovarian-type stroma". , 2006, Surgery.

[43]  R. Kapur,et al.  The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. , 1998, Development.

[44]  Michael A. Choti,et al.  1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience , 2006, Journal of Gastrointestinal Surgery.

[45]  W. Greenhalf,et al.  RNASEL germline variants are associated with pancreatic cancer , 2005, International journal of cancer.

[46]  G. Lomberk,et al.  When developmental signaling pathways go wrong and their impact on pancreatic cancer development , 2005, Current opinion in gastroenterology.

[47]  Leonid Kruglyak,et al.  A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34. , 2002, American journal of human genetics.

[48]  E. Holly,et al.  A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. , 2002, Journal of the National Cancer Institute.

[49]  M. Kalser,et al.  Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer , 1987, Cancer.

[50]  A. Knudson Retinoblastoma: a prototypic hereditary neoplasm. , 1978, Seminars in oncology.

[51]  A. Yanagisawa,et al.  Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. , 1993, Cancer research.

[52]  H. Ohge,et al.  Intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms of the pancreas differentiated by ovarian-type stroma. , 2006, Surgery.

[53]  J. Birkmeyer,et al.  Relationship between hospital volume and late survival after pancreaticoduodenectomy. , 1999, Surgery.

[54]  Jin‐Young Jang,et al.  Analysis of Long-term Survivors After Surgical Resection for Pancreatic Cancer , 2006, Pancreas.

[55]  Cun-Yu Wang,et al.  Notch signaling in the regulation of tumor angiogenesis. , 2006, Trends in cell biology.

[56]  N. Lemoine,et al.  Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer , 1991, The Journal of pathology.

[57]  J. Jeekel,et al.  Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. , 1999, Annals of surgery.

[58]  C. Catalano,et al.  Pancreatic carcinoma: the role of high-resolution multislice spiral CT in the diagnosis and assessment of resectability , 2002, European Radiology.

[59]  P. Murawa,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 , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  E. Vokes,et al.  Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium , 2007 .

[61]  L. Sobin,et al.  TNM Classification of Malignant Tumours , 1987, UICC International Union Against Cancer.

[62]  S. Richard,et al.  Pancreatic involvement in von Hippel–Lindau disease , 2000 .

[63]  Jeffrey W. Clark,et al.  A Phase I study of bortezomib plus irinotecan in patients with advanced solid tumors , 2006, Cancer.

[64]  D. Gouma,et al.  Value of CT criteria in predicting survival in patients with potentially resectable pancreatic head carcinoma , 2005, Journal of surgical oncology.

[65]  H. Friess,et al.  Influence of Surgical Resection and Post-Operative Complications on Survival following Adjuvant Treatment for Pancreatic Cancer in the ESPAC-1 Randomized Controlled Trial , 2006, Digestive Surgery.

[66]  K. Chayama,et al.  Management of Intraductal Papillary-mucinous Neoplasm of the Pancreas: Treatment Strategy Based on Morphologic Classification , 2006, Journal of clinical gastroenterology.

[67]  S. Chari,et al.  International Consensus Guidelines for Management of Intraductal Papillary Mucinous Neoplasms and Mucinous Cystic Neoplasms of the Pancreas , 2006, Pancreatology.

[68]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[69]  Y. Takeda,et al.  Surgical Outcomes of Noninvasive and Minimally Invasive Intraductal Papillary-Mucinous Neoplasms of the Pancreas , 2006, Annals of Surgical Oncology.

[70]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  R. Pazdur,et al.  Sorafenib for the Treatment of Advanced Renal Cell Carcinoma , 2006, Clinical Cancer Research.

[72]  R. Urrutia,et al.  Molecular pathways of pancreatic carcinogenesis , 2004 .

[73]  H. Friess,et al.  Randomized clinical trial of pylorus‐preserving duodenopancreatectomy versus classical Whipple resection—long term results , 2005, The British journal of surgery.

[74]  J. Rykowski,et al.  Efficacy of Neurolytic Celiac Plexus Block in Varying Locations of Pancreatic Cancer: Influence on Pain Relief , 2000, Anesthesiology.

[75]  J. Neoptolemos,et al.  Absence of the palladin P239S mutation in European pancreatic cancer families. , 2007 .

[76]  B. Chauffert,et al.  Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  R. Herrmann,et al.  Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  M. Clarke,et al.  Identification of pancreatic cancer stem cells. , 2007, Cancer research.

[79]  K. Sheahan,et al.  Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene. , 2006, Human pathology.

[80]  O. Volpert,et al.  Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[81]  S. Köklü,et al.  Significance of Serum Receptor-Binding Cancer Antigen (RCAS1) in Pancreatic Cancer and Benign Pancreatobiliary Diseases , 2006, Pancreatology.

[82]  S. Goodman,et al.  K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. , 1993, The American journal of pathology.

[83]  B. Spike,et al.  New roles for the RB tumor suppressor protein. , 2004, Current opinion in genetics & development.

[84]  J. Neoptolemos,et al.  Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis , 2002, Gut.

[85]  D. Fraker,et al.  Pancreatic cancer cell radiation survival and prenyltransferase inhibition: the role of K-Ras. , 2005, Cancer research.

[86]  S. Gallinger,et al.  Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. , 2000, Cancer research.

[87]  D. Longnecker Intraductal papillary-mucinous neoplasms of the pancreas , 2000 .

[88]  M. Manns,et al.  UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. , 2003, Gastroenterology.

[89]  R H Hruban,et al.  Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. , 1997, Annals of surgery.

[90]  Michael A. Choti,et al.  Does pancreatic duct stenting decrease the rate of pancreatic fistula following pancreaticoduodenectomy? Results of a prospective randomized trial , 2006, Journal of Gastrointestinal Surgery.

[91]  R. Hruban,et al.  Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. , 2003, Cancer cell.

[92]  M. Tempero,et al.  Systemic therapy for pancreatic cancer. , 2005, Seminars in radiation oncology.

[93]  R. Santoro,et al.  Cystic pancreatic neoplasms: 12-year surgical experience. , 2006, Journal of experimental & clinical cancer research : CR.

[94]  P. Neuhaus,et al.  Viszeralarterienrekonstruktionen mit Homografts bei Resektionen des Pankreas , 2004, Der Chirurg.

[95]  Kevin R Coombes,et al.  Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[96]  M. de Andrade,et al.  Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma , 2005, Gut.

[97]  Y. Murakami,et al.  Development of an intraductal papillary-mucinous neoplasm of the pancreas in a patient with familial adenomatous polyposis. , 2005, Pancreas.

[98]  J. Scoazec,et al.  Carcinome pancréatique à cellules acineuses et polypose adénomateuse familiale , 2003 .

[99]  Mariza de Andrade,et al.  Probability of pancreatic cancer following diabetes: a population-based study. , 2005, Gastroenterology.

[100]  G. Klöppel,et al.  The K‐ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium , 1999, Cancer.

[101]  S. Ellenberg,et al.  Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. , 1985, Archives of surgery.

[102]  W. Greenhalf,et al.  Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. , 2005, Gastroenterology.

[103]  J. Marshall Clinical implications of the mechanism of epidermal growth factor receptor inhibitors , 2006, Cancer.

[104]  H. Friess,et al.  Adjuvant therapy in pancreatic cancer: historical and current perspectives. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[105]  J. Birkmeyer,et al.  Hospital volume and surgical mortality in the United States. , 2002, The New England journal of medicine.

[106]  P. Maisonneuve,et al.  Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds. , 2003, Gastroenterology.

[107]  N. Fusenig,et al.  Friends or foes — bipolar effects of the tumour stroma in cancer , 2004, Nature Reviews Cancer.

[108]  Tatjana Crnogorac-Jurcevic,et al.  Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism , 2006, PLoS medicine.

[109]  J. Cheng,et al.  Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[110]  C. Hill,et al.  Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. , 2005, Molecular and cellular biology.

[111]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[112]  Brian E Henderson,et al.  Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. , 2005, Journal of the National Cancer Institute.

[113]  Jin‐Young Jang,et al.  High incidence of extrapancreatic neoplasms in patients with intraductal papillary mucinous neoplasms. , 2006, Archives of surgery.

[114]  Caj Haglund,et al.  Serum HCGβ and CA 72-4 Are Stronger Prognostic Factors than CEA, CA 19-9 and CA 242 in Pancreatic Cancer , 2004, Oncology.

[115]  D. Jäger,et al.  Chemotherapy for pancreatic cancer , 2003, Alimentary pharmacology & therapeutics.

[116]  S Pancreatic,et al.  Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas , 2005, Gut.

[117]  A. Scarpa,et al.  Branch-duct intraductal papillary mucinous neoplasms of the pancreas: to operate or not to operate? , 2006, Gut.

[118]  M. Leslie,et al.  Chemotherapy for pancreatic cancer. , 2004, The New England journal of medicine.

[119]  E. Jaffee,et al.  Immunotherapy for pancreatic cancer — science driving clinical progress , 2005, Nature Reviews Cancer.

[120]  N. Sasahira,et al.  Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[121]  G. Y. Wong,et al.  Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. , 2004, JAMA.

[122]  R. Hruban,et al.  The Genetics of FANCC and FANCG in Familial Pancreatic Cancer , 2004, Cancer biology & therapy.

[123]  K. Campbell,et al.  Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinomad—part 3: Update on 5-year survival , 2005, Journal of Gastrointestinal Surgery.

[124]  T. Seufferlein,et al.  Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. , 1999, Cancer research.

[125]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[126]  J. Riemann,et al.  Magnetic Resonance Cholangiopancreatography , 2002, Pancreatology.

[127]  Stephen P. Pereira,et al.  Endoscopic ultrasound‐guided tissue sampling by combined fine needle aspiration and trucut needle biopsy: a prospective study , 2006, Cytopathology : official journal of the British Society for Clinical Cytology.

[128]  P. Andersen,et al.  Preoperative endoscopic stent placement before pancreaticoduodenectomy: a meta-analysis of the effect on morbidity and mortality. , 2002, Gastrointestinal endoscopy.

[129]  Ireland,et al.  Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. , 2005 .

[130]  K. Dhaene,et al.  Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. , 1998, Annals of surgery.

[131]  G. Tytgat,et al.  Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region , 1998, Gut.

[132]  R. Perugini,et al.  FRAP-p70s6K signaling is required for pancreatic cancer cell proliferation. , 2001, The Journal of surgical research.

[133]  R. Wolff,et al.  Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[134]  H. Friess,et al.  Hedgehog signaling in the normal and diseased pancreas. , 2006, Pancreas.

[135]  D. Ito,et al.  In vivo antitumor effect of the mTOR inhibitor CCI‐779 and gemcitabine in xenograft models of human pancreatic cancer , 2006, International journal of cancer.

[136]  J. Neoptolemos,et al.  Positron Emission Tomography Does Not Add to Computed Tomography for the Diagnosis and Staging of Pancreatic Cancer , 2005, Digestive Surgery.

[137]  Helen Hickey,et al.  A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. , 2004, The New England journal of medicine.

[138]  P. Malfertheiner,et al.  Is endoscopic ultrasonography superior to multidetector CT for assessing pancreatic cancer? , 2005, Nature Clinical Practice Gastroenterology &Hepatology.

[139]  C. Pilarsky,et al.  No evidence for germline mutations of the LKB1/STK11 gene in familial pancreatic carcinoma. , 2004, Cancer letters.

[140]  F. Motoi,et al.  Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells , 2003, Oncogene.

[141]  C. Sherr Divorcing ARF and p53: an unsettled case , 2006, Nature Reviews Cancer.

[142]  J. Neoptolemos,et al.  Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses , 2008, British Journal of Cancer.

[143]  Steven S. Coughlin,et al.  Predictors of pancreatic cancer mortality among a large cohort of United States adults , 2000, Cancer Causes & Control.

[144]  H. Friess,et al.  Enhanced expression of transforming growth factor β isoforms in pancreatic cancer correlates with decreased survival , 1993 .

[145]  Y. Shiratori,et al.  Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. , 1996, Gastroenterology.

[146]  Hans A. Kestler,et al.  Specialized DNA Arrays for the Differentiation of Pancreatic Tumors , 2005, Clinical Cancer Research.

[147]  I. Eyre-Brook Low mortality following resection for pancreatic and periampullary tumours in 1026 patients: UK survey of specialist pancreatic units. , 1998, The British journal of surgery.

[148]  Brian Bierie,et al.  Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer , 2006, Nature Reviews Cancer.

[149]  Arlene M Correa,et al.  Endoscopic Ultrasound-Guided Fine Needle Aspiration and Multidetector Spiral CT in the Diagnosis of Pancreatic Cancer , 2004, American Journal of Gastroenterology.

[150]  J. Neoptolemos,et al.  Laparoscopy and Laparoscopic Ultrasound in the Evaluation of Pancreatic and Periampullary Tumours , 2004, Digestive Surgery.

[151]  R. Hruban,et al.  Precursors to Invasive Pancreatic Cancer , 2005, Advances in anatomic pathology.

[152]  K. Leksowski Thoracoscopic splanchnicectomy for control of intractable pain due to advanced pancreatic cancer , 2001, Surgical Endoscopy.

[153]  R. Hruban,et al.  Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma , 1994, Nature Genetics.

[154]  J. Neoptolemos Is endoscopic ultrasonography superior to multidetector CT for assessing pancreatic cancer? , 2005, Nature Clinical Practice Oncology.

[155]  J. Saurin,et al.  [Pancreatic acinar cell carcinoma in a patient with familial adenomatous polyposis]. , 2003, Gastroenterologie clinique et biologique.

[156]  Dong Wook Choi,et al.  Prognostic Factors and Adjuvant Chemoradiation Therapy After Pancreaticoduodenectomy for Pancreatic Adenocarcinoma , 2009, Journal of Gastrointestinal Surgery.

[157]  Michael Goggins,et al.  Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. , 2005, Cancer research.

[158]  T. Fukuda,et al.  High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma , 2000, Cancer.

[159]  A. Dachman,et al.  Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[160]  M. Tempero,et al.  Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer , 2005, British Journal of Cancer.

[161]  H. Amthauer,et al.  Retrospective digital image fusion of multidetector CT and 18F-FDG PET: clinical value in pancreatic lesions--a prospective study with 104 patients. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[162]  D. Tait,et al.  Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy , 2007, British Journal of Cancer.

[163]  J. Cheng,et al.  Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas , 1998, Molecular carcinogenesis.

[164]  S. Larsson,et al.  Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. , 2006, Journal of the National Cancer Institute.

[165]  I Ihse,et al.  Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial , 2001, Annals of surgery.

[166]  A. Ziegler,et al.  BRCA2 germline mutations in familial pancreatic carcinoma. , 2003, Journal of the National Cancer Institute.

[167]  W. Scheithauer,et al.  Gemcitabine (G) plus capecitabine (C) versus G alone in locally advanced or metastatic pancreatic cancer. A randomized phase III study of the Swiss Group for Clinical Cancer Research (SAKK) and the Central European Cooperative Oncology Group (CECOG) , 2005 .

[168]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[169]  R. Schilsky,et al.  A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB , 2007 .

[170]  Jeffrey E. Lee,et al.  Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer , 2003, Journal of Gastrointestinal Surgery.

[171]  P. Ruszniewski,et al.  Risk of pancreatic adenocarcinoma in chronic pancreatitis , 2002, Gut.

[172]  Martin H. Prins,et al.  A Meta-analysis on the Efficacy of Preoperative Biliary Drainage for Tumors Causing Obstructive Jaundice , 2002, Annals of surgery.

[173]  R. Hruban,et al.  Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. , 1999, The American journal of pathology.

[174]  J. Varley,et al.  Relative frequency and morphology of cancers in carriers of germline TP53 mutations , 2001, Oncogene.

[175]  G. Gaudernack,et al.  Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study , 2006, British Journal of Cancer.

[176]  E. Van Cutsem,et al.  Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[177]  J. Nemunaitis,et al.  A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer , 2002, British Journal of Cancer.

[178]  M. Falconi,et al.  Sonography versus helical CT in identification and staging of pancreatic ductal adenocarcinoma , 2003, Journal of clinical ultrasound : JCU.

[179]  P. Loehrer Meta-analysis of Randomised Adjuvant Therapy Trials for Pancreatic Cancer , 2006 .

[180]  W. Greenhalf,et al.  Anticipation in familial pancreatic cancer , 2005, Gut.

[181]  S. Goodman,et al.  Tumor-suppressive pathways in pancreatic carcinoma. , 1997, Cancer research.

[182]  J. Neoptolemos,et al.  Serum CA19-9 Measurement Increases the Effectiveness of Staging Laparoscopy in Patients with Suspected Pancreatic Malignancy , 2005, Digestive Surgery.

[183]  J. Neoptolemos,et al.  CT and pathologic assessment of prospective nodal staging in patients with ductal adenocarcinoma of the head of the pancreas. , 2003, AJR. American journal of roentgenology.

[184]  BRCA2 Germline Mutations in Familial Pancreatic Carcinoma , 2003 .

[185]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[186]  H. Xiong Molecular targeting therapy for pancreatic cancer , 2004, Cancer Chemotherapy and Pharmacology.

[187]  S. Connor,et al.  Meta‐analysis of the value of somatostatin and its analogues in reducing complications associated with pancreatic surgery , 2005, The British journal of surgery.

[188]  C. Hill,et al.  Smad4 Dependency Defines Two Classes of Transforming Growth Factor β (TGF-β) Target Genes and Distinguishes TGF-β-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses , 2005, Molecular and Cellular Biology.

[189]  J. Taipale,et al.  Patched acts catalytically to suppress the activity of Smoothened , 2002, Nature.

[190]  W. Greenhalf,et al.  Increasing survival rates of patients with pancreatic cancer by earlier identification , 2006, Nature Clinical Practice Oncology.

[191]  Peter Neuhaus,et al.  Prospective evaluation of pancreatic tumors: accuracy of MR imaging with MR cholangiopancreatography and MR angiography. , 2002, Radiology.

[192]  S. Kirzin,et al.  Risk factors for mortality and intra-abdominal complications after pancreatoduodenectomy: multivariate analysis in 300 patients. , 2006, Surgery.

[193]  W. Greenhalf,et al.  Evaluation of the 4q32-34 Locus in European Familial Pancreatic Cancer , 2006, Cancer Epidemiology Biomarkers & Prevention.

[194]  T. Imperiale,et al.  Comparison of endoscopic ultrasound and computed tomography for the preoperative evaluation of pancreatic cancer: a systematic review. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[195]  T. Takada,et al.  Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? , 2002, Cancer.

[196]  W. Hop,et al.  Pylorus Preserving Pancreaticoduodenectomy Versus Standard Whipple Procedure: A Prospective, Randomized, Multicenter Analysis of 170 Patients With Pancreatic and Periampullary Tumors , 2004, Annals of surgery.

[197]  R. Abrams,et al.  RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[198]  U. Boggi,et al.  Standard Kausch-Whipple Pancreatoduodenectomy , 1999, Digestive Surgery.

[199]  S. Leach Epithelial differentiation in pancreatic development and neoplasia: new niches for nestin and Notch. , 2005, Journal of clinical gastroenterology.

[200]  R. Nelson,et al.  Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. , 2003, Gastrointestinal endoscopy.

[201]  J. Testa,et al.  Frequent activation of AKT2 kinase in human pancreatic carcinomas , 2002, Journal of cellular biochemistry.

[202]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[203]  C. Sherr,et al.  Principles of Tumor Suppression , 2004, Cell.

[204]  J. Neoptolemos,et al.  Current standards of surgery for pancreatic cancer , 2004, The British journal of surgery.

[205]  F. Bray,et al.  Cancer burden in the year 2000. The global picture. , 2001, European journal of cancer.

[206]  Michio Shimizu,et al.  An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms , 2004, The American journal of surgical pathology.

[207]  Peter Neuhaus,et al.  Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. , 2007, JAMA.

[208]  P. Lin,et al.  Prospective randomized comparison between pylorus‐preserving and standard pancreaticoduodenectomy , 1999, The British journal of surgery.

[209]  T. Ponchon,et al.  Predictive factors for survival of patients with inoperable malignant distal biliary strictures: a practical management guideline , 1998, Gut.

[210]  A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma , 2006 .

[211]  H. Friess,et al.  Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. , 1992, The Journal of clinical investigation.

[212]  S. Larsson,et al.  Methionine and vitamin B6 intake and risk of pancreatic cancer: a prospective study of Swedish women and men. , 2007, Gastroenterology.

[213]  T. Sauerbruch,et al.  Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine , 2003, British Journal of Cancer.

[214]  D. Chan,et al.  SerumMarkers in Patients with Resectable Pancreatic Adenocarcinoma : Macrophage Inhibitory Cytokine 1 versus CA 19-9 , 2006 .

[215]  R H Hruban,et al.  Pancreatic Intraepithelial Neoplasia: A New Nomenclature and Classification System for Pancreatic Duct Lesions , 2001, The American journal of surgical pathology.

[216]  T. Kosuge,et al.  A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer. , 2006, Japanese journal of clinical oncology.

[217]  W. Greenhalf,et al.  Peutz–Jeghers syndrome and screening for pancreatic cancer , 2006, The British journal of surgery.

[218]  Ming-Sound Tsao,et al.  A review of erlotinib and its clinical use , 2006, Expert opinion on pharmacotherapy.

[219]  H. Friess,et al.  Growth factors and their receptors in pancreatic cancer. , 2001, Teratogenesis, carcinogenesis, and mutagenesis.

[220]  W. Greenhalf,et al.  The inherited genetics of pancreatic cancer and prospects for secondary screening. , 2006, Best practice & research. Clinical gastroenterology.

[221]  T. Beaty,et al.  Evidence for a major gene influencing risk of pancreatic cancer , 2002, Genetic epidemiology.

[222]  Michelle A. Anderson,et al.  Comparative serum glycoproteomics using lectin selected sialic acid glycoproteins with mass spectrometric analysis: application to pancreatic cancer serum. , 2006, Journal of proteome research.

[223]  A. Rosemurgy,et al.  Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[224]  C. Doig,et al.  Meta‐analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy , 2006, The British journal of surgery.

[225]  J. Neoptolemos,et al.  Low mortality following resection for pancreatic and periampullary tumours in 1026 patients: UK survey of specialist pancreatic units , 1997, The British journal of surgery.

[226]  Pablo R Ros,et al.  Differentiation of Chronic Focal Pancreatitis From Pancreatic Carcinoma by In Vivo Proton Magnetic Resonance Spectroscopy , 2005, Journal of computer assisted tomography.

[227]  J. Verweij,et al.  Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all? , 2006, European journal of cancer.

[228]  P. Boyle,et al.  Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase in relation to malignant and benign pancreatic disease risk , 1998, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[229]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[230]  W. Greenhalf,et al.  Clinical and genetic characteristics of hereditary pancreatitis in Europe. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[231]  K. Lillemoe,et al.  Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. , 1999, Journal of the American College of Surgeons.

[232]  N. Sharpless,et al.  INK4a/ARF: a multifunctional tumor suppressor locus. , 2005, Mutation research.

[233]  R. Hruban,et al.  Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[234]  J. Neoptolemos,et al.  PHASE III RANDOMISED COMPARISON OF GEMCITABINE (GEM) WITH GEMCITABINE PLUS CAPECITABINE (GEM-CAP) IN PATIENTS WITH ADVANCED PANCREATIC CANCER , 2005 .

[235]  S. Rane,et al.  Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease. , 2006, Cytokine & growth factor reviews.

[236]  L. Traverso,et al.  Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. , 2003, American journal of surgery.

[237]  M. Gonen,et al.  Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[238]  J. Furuse,et al.  Needle Tract Implantation of Hepatocellular Carcinoma and Pancreatic Carcinoma after Ultrasound-guided Percutaneous Puncture: Clinical and Pathologic Characteristics and the Treatment of Needle Tract Implantation , 2003, World Journal of Surgery.

[239]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[240]  S. Jeon,et al.  Solid-pseudopapillary Tumor of the Pancreas , 2006, Journal of clinical gastroenterology.

[241]  Christopher H. Crane,et al.  Pancreaticoduodenectomy with vascular resection: margin status and survival duration , 2004, Journal of Gastrointestinal Surgery.