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Cancer of the Pancreas

Pancreatic cancer is a disease in which the cells of the pancreas become malignant. The pancreas has two main functions; (i) it makes juices that help digest food and (ii) produces hormones (including insulin) that conrol how food is used and stored in the body. The vast majority of pancreatic cancers are associated with the part of the pancreas that makes digestive juices - these are known as "exocrine" pancreatic cancers. Only about 1/20 pancreatic cancers start in the hormone producing part of the pancreas ; these are known as "endocrine" pancreatic cancer or "islet cell cancer". There are several types of exocrine pancreatic cancers (based on how the cells appear under the microsope), most are classed as "ductal adenocarcinomas". Pancreatic cancer is rare before the age of 40 years, incidence increases sharply with increasing age.

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Pancreatic Neuroendocrine Tumours (Islet Cell Tumours)
Familial Pancreatic Cancer

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  • PubMed search for publications about Pancreatic Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Pancreatic Cancer
    MeSH term: Pancreatic Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Fox RG, Lytle NK, Jaquish DV, et al.
Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Nature. 2016; 534(7607):407-11 [PubMed] Related Publications
Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

Preechasuk L, Pongpaibul A, Kunavisarut T
Non-insulinoma Pancreatogeneous Hypoglycemia Syndrome with False-Positive Somatostatin Receptor Scintigraphy: A Case Report and Review of Literature.
J Med Assoc Thai. 2016; 99(3):354-9 [PubMed] Related Publications
Non-insulinoma pancreatogeneous hypoglycemia syndrome (NIPHS) is a rare cause of hypoglycemia in adults. The cause of NIPHS is diffuse hyperinsulinism. As a result, computed tomography (CT) of pancreas, endoscopic pancreatic ultrasonography (EUS), and somatostatin receptor scintigraphy (SSRS), which are usually performed to locate an insulinoma, are not able to diagnose NIPHS. Moreover, SSRS can give a false-positive result. In this case report, we introduce a 22-year-old Thai woman who presented with fasting and postprandial hyperinsulinemic hypoglycemia. Accordingly, an insulinoma was suspected. She underwent several studies to locate the lesion. Pancreatic CT and EUS failed to locate a lesion; however, SSRS showed a faint focus of increased uptake at the pancreatic head. The suspected insulinoma was not identified during a first operation. Thereafter other diagnostic methods were performed in an effort to locate the suspected insulinoma, including selective arterial calcium stimulation test. The result of the selective arterial calcium stimulation test was negative. Intraoperative ultrasonography during a second operation also failed to locate a tumor. Finally, a pancreatic head resection was performed according to SSRS result, yet capillary blood glucose levels did not increase after resection. In response, a 95% pancreatectomy was performed. The pathology report was consistent with diffuse hyperinsulinism. This report emphasizes that SSRS can give false positive result in NIPHS.

Stark A, Donahue TR, Reber HA, Hines OJ
Pancreatic Cyst Disease: A Review.
JAMA. 2016; 315(17):1882-93 [PubMed] Related Publications
IMPORTANCE: Cystic lesions of the pancreas are common and increasingly detected in the primary care setting. Some patients have a low risk for developing a malignancy and others have a high risk and need further testing and interventions.
OBSERVATIONS: Pancreatic cysts may be intraductal mucinous neoplasms, mucinous cystic neoplasms, serous cystadenomas, solid pseudopapillary neoplasms, cystic variations of pancreatic neuroendocrine tumors, pancreatic ductal adenocarcinomas, or 1 of several types of nonneoplastic cysts. Mucinous (intraductal mucinous neoplasm or mucinous cystic neoplasm) lesions have malignant potential and should be distinguished from serous lesions (serous cystadenomas) that are nearly always benign. Symptomatic patients or those having high-risk features on initial imaging (eg, main pancreatic duct dilatation, a solid component, or mural nodule) require further evaluation with advanced imaging, possibly followed by surgical resection. Advanced imaging includes endoscopic ultrasound with cyst fluid analysis and cytology to confirm the type of cyst and determine the risk of malignancy. Small cysts (size <3 cm) in asymptomatic patients without any suspicious features may be observed with serial imaging because the risk for malignancy is low.
CONCLUSIONS AND RELEVANCE: The management of pancreatic cysts requires risk stratification for malignant potential based on the presence or absence of symptoms and high-risk features on cross-sectional imaging. Because pancreatic cysts are becoming more frequently diagnosed, clinicians should have a systematic approach for establishing a diagnosis and determining which patients require treatment.

Hammel P, Huguet F, van Laethem JL, et al.
Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial.
JAMA. 2016; 315(17):1844-53 [PubMed] Related Publications
IMPORTANCE: In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown.
OBJECTIVES: To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.
DESIGN, SETTING, AND PARTICIPANTS: In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013.
INTERVENTIONS: In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine).
MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects.
RESULTS: A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.
CONCLUSIONS AND RELEVANCE: In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00634725.

Seifert L, Werba G, Tiwari S, et al.
The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.
Nature. 2016; 532(7598):245-9 [PubMed] Article available free on PMC after 06/10/2016 Related Publications
Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

Husen Y, Saeed MA, Siddiqui S
J Ayub Med Coll Abbottabad. 2015 Oct-Dec; 27(4):936-7 [PubMed] Related Publications
Acinar cell carcinoma is a rare tumour arising from pancreatic acinar cells. Typical radiological patterns associated with it may suggest the unusual diagnosis even before final confirmation by histopathology. We present a case of an 8 year old boy who presented to clinic with symptoms of abdominal pain without associated jaundice or vomiting. Imaging revealed an atypical mass arising from head of the pancreas. Histopathology confirmed the diagnosis of acinar cell carcinoma. An idea about atypical and rare pancreatic masses is necessary to help direct the diagnosis and guide the pathologist for suspecting atypical pathology.

Nakamoto M, Hisaoka M
Clinicopathological Implications of Wingless/int1 (WNT) Signaling Pathway in Pancreatic Ductal Adenocarcinoma.
J UOEH. 2016; 38(1):1-8 [PubMed] Related Publications
Pancreatic cancer is still one of the most lethal malignancies in the world, and a more thorough understanding of its detailed pathogenetic mechanisms and the development of more effective therapeutic strategies are urgently required. Pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer, is characterized by consistent genetic abnormalities such as point mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) and in the tumor suppressor protein p53 (TP53) genes. Alterations in intracellular core signal pathways have also been shown to induce the development or progression of PDA. The Wingless/int1 (WNT) signal pathway plays a pivotal role in embryonic development, cellular proliferation and differentiation, and dysregulation of WNT signaling can lead to neoplastic transformation in a variety of organ systems, including the pancreas. Recent studies have shown that altered WNT signaling is associated with a poor prognosis in patients with PDA, suggesting that the pathway is a predictor of patients' survival and a potential therapeutic target of PDA. In this review, the clinicopathological implications of WNT signaling in PDA are highlighted.

Javle M, Golan T, Maitra A
Changing the course of pancreatic cancer--Focus on recent translational advances.
Cancer Treat Rev. 2016; 44:17-25 [PubMed] Related Publications
In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway. While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles. While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed at manipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition. DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer. Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer.

Liu IH, Ford JM, Kunz PL
DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications.
Cancer Treat Rev. 2016; 44:1-9 [PubMed] Related Publications
BACKGROUND: The role of DNA repair in pathogenesis and response to treatment is not well understood in pancreatic neuroendocrine tumors (pNETs). However, the existing literature reveals important preliminary trends and targets in the genetic landscape of pNETs. Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the DNA mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies.
METHODS: PubMed searches were conducted for original studies assessing the DNA repair genes MGMT and MMR in pNETs, as well as for PTEN and MEN1, which are not directly DNA repair genes but are involved in DNA repair pathways. Searches were specific to pNETs, yielding five original studies on MGMT and four on MMR. Six original papers studied PTEN in pNETs. Five studied MEN1 in pNETs, and two others implicated MEN1 in DNA repair processes.
RESULTS: The five studies on MGMT in pNET tumor samples found MGMT loss of between 24% and 51% of tumor samples by IHC staining and between 0% and 40% by promoter hypermethylation, revealing discrepancies in methods assessing MGMT expression as well as potential weaknesses in the correlation between MGMT IHC expression and promoter hypermethylation rates. Four studies on MMR in pNET tumor samples indicated similar ambiguities, as promoter hypermethylation of the MLH1 MMR gene ranged from 0% to 31% of pNETs, while IHC staining revealed loss of MMR genes in between 0% and 36% of pNETs sampled. Studies also indicated that PTEN and MEN1 are commonly mutated or underexpressed genes in pNETs, although frequency of mutation or loss of expression was again variable among different studies.
CONCLUSION: Further studies are essential in determining a more thorough repertoire of DNA repair defects in pNETs and the clinical significance of these defects. This literature review synthesises the existing knowledge of relevant DNA repair pathways and studies of the specific genes that carry out these repair mechanisms in pNETs.

Davies L, Weickert MO
Gastroenteropancreatic neuroendocrine tumours: an overview.
Br J Nurs. 2016 Feb 25-Mar 9; 25(4):S12-5 [PubMed] Related Publications
Gastroenteropancreatic neuroendocrine tumours (GEP-NET) represent a heterogeneous family of diseases of often challenging clinical management. Although many GEP-NET are slow progressing and frequently less aggressive than neoplasms of other origin, they can metastasise and reduce the life span of the patient. GEP-NET can be functioning (secreting hormones that may cause symptoms and organ damage), but some 60% are non-functioning. Thorough clinical assessment including family history, biochemical tests, radiology and nuclear medicine scans, and histological confirmation are important to tailor the optimal treatment of GEP-NET, which should be managed with a multidisciplinary approach and mainly guided by tumour grading and staging, functioning status, and location of the primary lesion.

Bailey P, Chang DK, Nones K, et al.
Genomic analyses identify molecular subtypes of pancreatic cancer.
Nature. 2016; 531(7592):47-52 [PubMed] Related Publications
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Hüttner FJ, Fitzmaurice C, Schwarzer G, et al.
Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma.
Cochrane Database Syst Rev. 2016; 2:CD006053 [PubMed] Related Publications
BACKGROUND: Pancreatic cancer is the fourth-leading cause of cancer death for both, men and women. The standard treatment for resectable tumours consists of a classic Whipple (CW) operation or a pylorus-preserving pancreaticoduodenectomy (PPW). It is unclear which of these procedures is more favourable in terms of survival, postoperative mortality, complications, and quality of life.
OBJECTIVES: The objective of this systematic review was to compare the effectiveness of CW and PPW techniques for surgical treatment of cancer of the pancreatic head and the periampullary region.
SEARCH METHODS: We conducted searches on 28 March 2006, 11 January 2011, 9 January 2014, and 18 August 2015 to identify all randomised controlled trials (RCTs), while applying no language restrictions. We searched the following electronic databases on 18 August 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE) from the Cochrane Library (2015, Issue 8); MEDLINE (1946 to August 2015); and EMBASE (1980 to August 2015). We also searched abstracts from Digestive Disease Week and United European Gastroenterology Week (1995 to 2010); we did not update this part of the search for the 2014 and 2015 updates because the prior searches did not contribute any additional information. We identified two additional trials through the updated search in 2015.
SELECTION CRITERIA: RCTs comparing CW versus PPW including participants with periampullary or pancreatic carcinoma.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used a random-effects model for pooling data. We compared binary outcomes using odds ratios (ORs), pooled continuous outcomes using mean differences (MDs), and used hazard ratios (HRs) for meta-analysis of survival. Two review authors independently evaluated the methodological quality and risk of bias of included trials according to the standards of The Cochrane Collaboration.
MAIN RESULTS: We included eight RCTs with a total of 512 participants. Our critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters. Postoperative mortality (OR 0.64, 95% confidence interval (CI) 0.26 to 1.54; P = 0.32), overall survival (HR 0.84, 95% CI 0.61 to 1.16; P = 0.29), and morbidity showed no significant differences, except of delayed gastric emptying, which significantly favoured CW (OR 3.03, 95% CI 1.05 to 8.70; P = 0.04). Furthermore, we noted that operating time (MD -45.22 minutes, 95% CI -74.67 to -15.78; P = 0.003), intraoperative blood loss (MD -0.32 L, 95% CI -0.62 to -0.03; P = 0.03), and red blood cell transfusion (MD -0.47 units, 95% CI -0.86 to -0.07; P = 0.02) were significantly reduced in the PPW group. All significant results were associated with low-quality evidence based on GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria.
AUTHORS' CONCLUSIONS: Current evidence suggests no relevant differences in mortality, morbidity, and survival between the two operations. However, some perioperative outcome measures significantly favour the PPW procedure. Given obvious clinical and methodological heterogeneity, future high-quality RCTs of complex surgical interventions based on well-defined outcome parameters are required.

Nagakawa Y, Hosokawa Y, Sahara Y, et al.
A Novel "Artery First" Approach Allowing Safe Resection in Laparoscopic Pancreaticoduodenectomy: The Uncinate Process First Approach.
Hepatogastroenterology. 2015; 62(140):1037-40 [PubMed] Related Publications
BACKGROUND/AIMS: Laparoscopic pancreaticoduodenectomy (LPD) is still a challenging operation, particularly because the dissection around the superior mesenteric artery (SMA) and bleeding control are difficult. Although it has been reported that early ligation of the origin of the inferior pancreaticoduodenal artery (IPDA) reduces blood loss, it is difficult to laparoscopically expose the origin of the IPDA. We sought to develop a novel approach to simplify the dissection of the IPDA and reduce bleeding.
METHODOLOGY: The uncinate process was exposed at the left posterior side of the SMA, and the branches of the IPDA were divided at positions where they enter and exit the uncinate process before isolating the pancreatic head from the right aspect of the SMA. Ten patients were operated using this new approach, and the results were retrospectively compared to those of 22 patients treated with conventional LPD.
RESULTS: The operation times did not differ significantly between the two groups. However, the intraoperative blood loss was significantly lower in the "uncinate process first" group than in the conventional LPD group. (162.7 ml vs. 463.8 ml, respectively; P = 0.023).
CONCLUSIONS: The new approach facilitates the initial dissection of the IPDA at the right side of the SMA, reducing intraopera- tive blood loss.

Kobayashi S, Honda G, Kurata M, et al.
A Phase I Study of S-1 and Gemcitabine with Concurrent Radiotherapy in Patients with Non-Metastatic Advanced Pancreatic Cancer.
Hepatogastroenterology. 2015; 62(140):1031-6 [PubMed] Related Publications
BACKGROUND/AIMS: To determine the recommended dose (RD) for full-dose S-1 and low-dose gemcitabine combined with radiotherapy in patients with non-metastatic advanced pancreatic cancer.
METHODOLOGY: Adult patients with non-metastatic advanced pancreatic cancer (Union for International Cancer Control T stage 3 or 4) were eligible. The weekly intravenous gemcitabine (level 0-1: 200 mg/ml,level 2: 300 mg/m on Days 1, 8, 15, 22, 29, 36) dose was escalated starting from level 1 in a 3+3 design along with full dose twice-daily oral S-1 (level 0: 60 mg/m2/day, level 1-2: 80 mg/ml/day), and was administered on the same days as radiotherapy (1.8 Gy x 28 days).
RESULTS: Eight patients were included in this study. A dose-limiting toxicity (DLT) (grade 4 neutropenia) was observed in one of the first three patients in level 1, and three additional patients received the level 1 dose without any severe adverse events. DLTs (grade 3/4 neutropenia) were then observed in the first two patients given level 2 dose. Therefore, level 1 was designated as the RD. Common grade 3/4 toxicities included neutropenia (62.5%), anorexia (37.5%), and pneumonitis (12.5%).
CONCLUSIONS: The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Chen FM, Ni JM, Zhang ZY, et al.
Presurgical Evaluation of Pancreatic Cancer: A Comprehensive Imaging Comparison of CT Versus MRI.
AJR Am J Roentgenol. 2016; 206(3):526-35 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to compare comprehensive CT and MRI in the presurgical evaluation of pancreatic cancer.
MATERIALS AND METHODS: Thirty-eight patients with pathologically proven pancreatic cancer were included in a retrospective study. CT with negative-contrast CT cholangiopancreatography and CT angiography (CTA) (CT image set) versus MRI with MRCP and MR angiography (MRI image set) were analyzed independently by two reviewers for tumor detection, extension, metastasis, vascular invasion, and resectability. These results were compared with the surgical and pathologic findings.
RESULTS: The rate of detection of tumors was higher with MRI than with CT but not significantly so (reviewer 1, p = 1.000; reviewer 2, p = 0.500). In the evaluation of vessel involvement, nodal status, and resectability, although CT had higher ROC AUC values than did MRI (reviewer 1, 0.913 vs 0.858, 0.613 vs 0.503, and 0.866 vs 0.774; reviewer 2, 0.879 vs 0.849, 0.640 vs 0.583, and 0.830 vs 0.815), the differences were not statistically significant (p = 0.189 vs 0.494, 0.328 vs 0.244, and 0.193 vs 0.813 for reviewers 1 and 2). In the evaluation of tumor extension and organ metastases in the 38 patients, correct diagnosis of one of two liver metastases was achieved with both image sets, one case of omental and one case of peritoneal seeding were underestimated, and one case of stomach invasion was overestimated.
CONCLUSION: MRI and CT had similar performance in the presurgical evaluation of pancreatic cancer.

Fu W, Li J, Wen J, et al.
Management of Islet Cell Tumours: A Single Hospital Experience.
Hepatogastroenterology. 2015; 62(139):773-6 [PubMed] Related Publications
BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs.
METHODS: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed.
RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma. The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia.
CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

Fu W, Li J, Wen J, et al.
Management of Islet Cell Tumours: A Single Hospital Experience.
Hepatogastroenterology. 2015; 62(139):723-6 [PubMed] Related Publications
BACKGROUND/AIMS: Islet cell tumours (ICTs) are uncommon tumours in clinical practice. Surgical resection is the treatment of choice for ICTs, but localisation of these lesions can be challenging. The aim of this study was to analyse the clinical diagnosis and treatment for ICTs.
METHODOLOGY: Thirty-one patients with ICTs who were diagnosed and who underwent surgical treatment in the affiliate hospital of Luzhou Medical College from 1 January 2000 to 31 July 2013 were enrolled. The clinical data of these patients were retrospectively reviewed.
RESULTS: Among 31 patients (6 males, 25 females), 15 cases (48.39%) had non-functional ICTs and 16 (51.61%) cases were insulinoma: The mean age of patients with non-functional ICTs was 42.73 ± 12.34 years and of those with insulinoma was 48.88 ± 13 years. Non-functional ICTs had a non-specific presentation. Insulinoma makes different clinical presentations mostly with symptoms of hypoglycaemia.
CONCLUSIONS: Preoperative and/or intra-operative localisation is needed for ICTs; CT scan or MRI is used routinely as the first choice. If the lesion is very small, DSA is also good for localisation before operation. IOUS is a reliable technique in exactly localising insulinoma. ICTs are considered to be cured with successful surgical removal.

Bouvet M, Hoffman RM
Toward Curative Fluorescence-Guided Surgery of Pancreatic Cancer.
Hepatogastroenterology. 2015; 62(139):715-22 [PubMed] Related Publications
BACKGROUND/AIMS: Negative surgical margins are critical to prevent recurrence in cancer surgery. We review the use of fluorophore-labeled monoclonal antibodies to aid in cancer visualization in orthotopic nude mouse models of human pancreatic cancer in order to achieve negative margins in fluorescence-guided surgery (FGS).
METHODOLOGY: Anti-CEA or anti-CA 19-9 antibodies were conjugated with fluorophores of visible and near-infrared wavelengths. Orthotopic primary and metastatic human pancreatic tumors in nude mouse models were readily visualized with fluorescence imaging after administration of fluorophore conjugated anti-CEA or anti-CA 19-9.
RESULTS: The fluorescence signal was detectable 30 minutes after systemic antibody delivery and remained present for two weeks, with minimal in vivo photobleaching after exposure to standard operating room lighting. There was greatly improved ability to resect labeled tumor tissue using FGS.
CONCLUSIONS: Fluorophore-labeled anti-CEA or anti-CA 19-9 antibodies enable enhanced visualization of tumors for FGS of pancreatic cancer when CEA or CA 19-9 expression is present. The choice of fluorophore significantly affects the signal intensity in the labeled tumor. The technologies described herein have the potential to change the paradigm of surgical oncology to engender significantly improved outcomes.

Azoulay L, Filion KB, Platt RW, et al.
Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study.
BMJ. 2016; 352:i581 [PubMed] Article available free on PMC after 06/10/2016 Related Publications
OBJECTIVE: To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes.
DESIGN: Population based cohort.
SETTING: Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom.
PARTICIPANTS: A cohort of 972,384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014.
MAIN OUTCOME MEASURES: Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models.
RESULTS: During 2,024,441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.
CONCLUSIONS: In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Zhu LM, Tang L, Qiao XW, et al.
Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study.
Medicine (Baltimore). 2016; 95(7):e2836 [PubMed] Related Publications
The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.

Ying H, Dey P, Yao W, et al.
Genetics and biology of pancreatic ductal adenocarcinoma.
Genes Dev. 2016; 30(4):355-85 [PubMed] Article available free on PMC after 15/08/2016 Related Publications
With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival.

Che X, Yu D, Wu Z, et al.
Association of Genetic Polymorphisms in UDP-Glucuronosyltransferases 2B17 with the Risk of Pancreatic Cancer in Chinese Han Population.
Clin Lab. 2015; 61(12):1905-10 [PubMed] Related Publications
BACKGROUND: This study is aimed to investigate the association between polymorphisms in UGT2B17 and the risk of developing pancreatic cancer in Chinese Han population.
METHODS: A hospital-based case-control study was conducted, and 1579 healthy controls and 406 pancreatic cancer patients were enrolled. Real-time PCR was applied to identify the genetic polymorphisms in the subjects, and multivariable logistic regression analysis was performed to investigate the association between UGT2B17 polymorphisms and susceptibility to pancreatic cancer.
RESULTS: The prevalence of the UGT2B17 del/del, del/ins, and ins/ins in cases were 72.9%, 24.0%, and 3.1%, respectively, and in controls 66.6%, 30.7%, and 2.7%, respectively. Multivariable logistic regression revealed that, compared with the del/del genotype, the del/ins genotype in UGT2B17 is related to a significant reduction in pancreatic cancer risk (OR = 0.77, 95% CI = 0.60 - 0.99; P = 0.04). In the female subjects, compared with the del/del genotype, the del/ins genotype was related to a substantial reduction in pancreatic cancer risk (OR = 0.59, 95% CI = 0.39 - 0.90, P = 0.01).
CONCLUSIONS: All these results indicate a higher ratio of UGT2B17 deletion polymorphisms in Asians. UGT2B17 deletion polymorphisms are associated with the risk of developing pancreatic cancer in Chinese Han population, especially in the female population.

Jeong SM, Hwang S, Seong RH
Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation.
Biochem Biophys Res Commun. 2016; 471(3):373-9 [PubMed] Related Publications
The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer.

Wild AT, Herman JM, Dholakia AS, et al.
Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer.
Int J Radiat Oncol Biol Phys. 2016; 94(3):571-9 [PubMed] Article available free on PMC after 15/08/2016 Related Publications
PURPOSE: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC).
METHODS AND MATERIALS: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival.
RESULTS: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002).
CONCLUSIONS: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Merrell KW, Haddock MG, Quevedo JF, et al.
Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer.
Int J Radiat Oncol Biol Phys. 2016; 94(3):561-70 [PubMed] Related Publications
PURPOSE: Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS).
METHODS AND MATERIALS: We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score.
RESULTS: Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3).
CONCLUSIONS: In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as adjuvant locoregional treatment following pancreatic cancer resection.

Chang MC, Chang YT, Chen JY, et al.
Clinical Significance of Circulating Tumor Microemboli as a Prognostic Marker in Patients with Pancreatic Ductal Adenocarcinoma.
Clin Chem. 2016; 62(3):505-13 [PubMed] Related Publications
BACKGROUND: Characterization of circulating tumor cells (CTCs) has been used to provide prognostic, predictive, and pharmacodynamic information in many different cancers. However, the clinical significance of CTCs and circulating tumor microemboli (CTM) in patients with pancreatic ductal adenocarcinoma (PDAC) has yet to be determined.
METHODS: In this prospective study, CTCs and CTM were enumerated in the peripheral blood of 63 patients with PDAC before treatment using anti-EpCAM (epithelial cell adhesion molecule)-conjugated supported lipid bilayer-coated microfluidic chips. Associations of CTCs and CTM with patients' clinical factors and prognosis were determined.
RESULTS: CTCs were abundant [mean (SD), 70.2 (107.6)] and present in 81% (51 of 63) of patients with PDAC. CTM were present in 81% (51 of 63) of patients with mean (SD) 29.7 (1101.4). CTM was an independent prognostic factor of overall survival (OS) and progression free survival (PFS). Patients were stratified into unfavorable and favorable CTM groups on the basis of CTM more or less than 30 per 2 mL blood, respectively. Patients with baseline unfavorable CTM, compared with patients with favorable CTM, had shorter PFS (2.7 vs 12.1 months; P < 0.0001) and OS (6.4 vs 19.8 months; P < 0.0001). Differences persisted if we stratified patients into early and advanced diseases. The number of CTM before treatment was an independent predictor of PFS and OS after adjustment for clinically significant factors.
CONCLUSIONS: The number of CTM, instead of CTCs, before treatment is an independent predictor of PFS and OS in patients with PDAC.

Tan J, Tan P, Teh BT
Defining the Molecular Alterations of Ampullary Carcinoma.
Cancer Cell. 2016; 29(2):135-6 [PubMed] Related Publications
Ampullary carcinomas represent a group of heterogeneous tumors that can be histologically divided into two subtypes with distinct pathogenic and clinical characteristics. Yachida et al. (2016) and Gingras et al. (2016) now report the genomic landscape of ampullary carcinoma, providing insights into molecular drivers with clinical implications for diagnosis and therapeutics.

Schirmer MA, Lüske CM, Roppel S, et al.
Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer.
J Natl Cancer Inst. 2016; 108(5) [PubMed] Article available free on PMC after 15/08/2016 Related Publications
BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects.
METHODS: This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided.
RESULTS: The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval [CI] = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P trend < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P trend < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3.
CONCLUSIONS: WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations.

Lee YH, Gyu Song G
Genome-wide pathway analysis in pancreatic cancer.
J BUON. 2015 Nov-Dec; 20(6):1565-75 [PubMed] Related Publications
PURPOSE: The purpose of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might play a role in susceptibility to pancreatic cancer, elucidate their potential mechanisms, and generate SNP-to-gene-to-pathway hypotheses.
METHODS: A genome-wide association study (GWAS) dataset of pancreatic cancer that included 496,959 SNPs from 3,851 pancreatic cancer patients and 3,934 control subjects of European descent was used in this study. The Identify candidate Causal SNPs and Pathways (ICSNPathway) method was applied to the GWAS dataset.
RESULTS: ICSNPathway analysis identified 18 candidate SNPs, 11 genes (including HNF1A and HNF4G), and 30 pathways, which revealed 11 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was one wherein rs2230739 alters the role of ADCY9 in various pathways and processes, including cyclase activity, phosphorus oxygen lyase activity, hsa04912, hsa04540, hsa04020, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ false discovery rate (FDR) ≤ 0.016). The second strongest mechanism was that rs16859886 modulates ADCY10 to affect its role in pathways including cyclase activity, phosphorus oxygen lyase activity, nucleobase, nucleoside, and nucleotide metabolic processing, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ FDR ≤ 0.016).
CONCLUSIONS: By using the ICSNPathway to analyze pancreatic cancer GWAS data, 18 candidate SNPs, 11 genes (including ADCY9, ADCY10, HNF1A, and HNF4G), and 30 pathways were identified that might contribute to the susceptibility of patients to pancreatic cancer.

Imaizumi A, Onishi H, Yamasaki A, et al.
Hypoxic Conditions Promote Gemcitabine Sensitivity in a Pancreatic Cancer Stem Cell Line.
Anticancer Res. 2016; 36(2):653-7 [PubMed] Related Publications
Development of an effective therapeutic strategy for refractory pancreatic cancer must consider whether chemosensitivity can be induced in chemoresistant cells. We established a pancreatic cancer stem cell-rich cell line using TIG-1 feeder cells and leukemia inhibitory factor (LIF)-rich SNL76/7 conditioned medium. We generated a cell line, namely YNPC031312-B, following isolation of cells from the malignant ascites of a patient with gemcitabine-resistant pancreatic cancer. A YNPC031312-B-Hypoxia cell line was established by maintaining YNPC031312-B cells under tumor-like hypoxic conditions (1% O2). Both cell lines exhibited a pancreatic cancer stem cell phenotype: YNPC031312-B cells were CD24(+)CD44(-)CD133(+)epithelial cell adhesion molecule (EpCAM)(+)alkaline phosphatase(+)Octamer-binding transcription factor (OCT)3/4+and YNPC031312-B-Hypoxia cells were CD24(+)CD44(+)CD133(+)EpCAM(+). YNPC031312-B-Hypoxia cells were larger, had superior migratory ability, and higher gemcitabine sensitivity compared to YNPC031312-B cells. The use of LIF or other factors with similar bioactivity under hypoxic conditions may contribute to the phenotypic change to gemcitabine sensitivity. Our results may aid development of new therapeutic strategies targeting refractory pancreatic cancer.

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