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Find video protocols related to scientific articles indexed in Pubmed.
Biomarkers for early diagnosis of pancreatic cancer.
Expert Rev Gastroenterol Hepatol
PUBLISHED: 11-07-2014
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Pancreatic ductal adenocarcinoma is an aggressive malignancy with a 5-year survival rate of approximately 5%.The lack of established strategies for early detection contributes to this poor prognosis. Although several novel candidate biomarkers have been proposed for earlier diagnosis, none have been adopted into routine clinical use. In this review, the authors examine the challenges associated with finding new pancreatic cancer diagnostic biomarkers and explore why translation of biomarker research for patient benefit has thus far failed. The authors also review recent progress and highlight advances in the understanding of the biology of pancreatic cancer that may lead to improvements in biomarker detection and implementation.
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Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).
Eur. J. Cancer
PUBLISHED: 07-07-2014
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Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer.
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Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS).
Surgery
PUBLISHED: 06-17-2014
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The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy.
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Serum cytokine biomarker panels for discriminating pancreatic cancer from benign pancreatic disease.
Mol. Cancer
PUBLISHED: 04-23-2014
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We investigated whether combinations of serum cytokines, used with logistic disease predictor models, could facilitate the detection of pancreatic ductal adenocarcinoma (PDAC).
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Prognostic markers in acute pancreatitis.
Expert Rev. Mol. Diagn.
PUBLISHED: 03-22-2014
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Acute pancreatitis has a mortality rate of 5-10%. Early deaths are mainly due to multiorgan failure and late deaths are due to septic complications from pancreatic necrosis. The recently described 2012 Revised Atlanta Classification and the Determinant Classification both provide a more accurate description of edematous and necrotizing pancreatitis and local complications. The 2012 Revised Atlanta Classification uses the modified Marshall scoring system for assessing organ dysfunction. The Determinant Classification uses the sepsis-related organ failure assessment scoring system for organ dysfunction and, unlike the 2012 Revised Atlanta Classification, includes infected necrosis as a criterion of severity. These scoring systems are used to assess systemic complications requiring intensive therapy unit support and intra-abdominal complications requiring minimally invasive interventions. Numerous prognostic systems and markers have been evaluated but only the Glasgow system and serum CRP levels provide pragmatic prognostic accuracy early on. Novel concepts using genetic, transcriptomic and proteomic profiling and also functional imaging for the identification of specific disease patterns are now required.
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Extended pancreatectomy in pancreatic ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS).
Surgery
PUBLISHED: 02-01-2014
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Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer.
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When to perform a pancreatoduodenectomy in the absence of positive histology? A consensus statement by the International Study Group of Pancreatic Surgery.
Surgery
PUBLISHED: 01-02-2014
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Pancreatoduodenectomy (PD) provides the best chance for cure in the treatment of patients with localized pancreatic head cancer. In patients with a suspected, clinically resectable pancreatic head malignancy, the need for histologic confirmation before proceeding with PD has not historically been required, but remains controversial.
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The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer.
Cancer Immunol. Immunother.
PUBLISHED: 09-13-2013
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In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
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cAMP inhibits migration, ruffling and paxillin accumulation in focal adhesions of pancreatic ductal adenocarcinoma cells: Effects of PKA and EPAC.
Biochim. Biophys. Acta
PUBLISHED: 04-23-2013
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We demonstrated that increasing intracellular cAMP concentrations result in the inhibition of migration of PANC-1 and other pancreatic ductal adenocarcinoma (PDAC) cell types. The rise of cAMP was accompanied by rapid and reversible cessation of ruffling, by inhibition of focal adhesion turnover and by prominent loss of paxillin from focal adhesions. All these phenomena develop rapidly suggesting that cAMP effectors have a direct influence on the cellular migratory apparatus. The role of two primary cAMP effectors, exchange protein activated by cAMP (EPAC) and protein kinase A (PKA), in cAMP-mediated inhibition of PDAC cell migration and migration-associated processes was investigated. Experiments with selective activators of EPAC and PKA demonstrated that the inhibitory effect of cAMP on migration, ruffling, focal adhesion dynamics and paxillin localisation is mediated by PKA, whilst EPAC potentiates migration.
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Somatic mutations in exocrine pancreatic tumors: association with patient survival.
PLoS ONE
PUBLISHED: 03-04-2013
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KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P?=?0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P?=?0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P?=?0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.
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ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium.
Oncol. Rep.
PUBLISHED: 01-24-2013
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There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or B allele in comparison with the O allele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.
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Circulating microRNAs as potential markers of human drug-induced liver injury.
Hepatology
PUBLISHED: 11-03-2011
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New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ??Ct [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied Kings College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15).
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Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study.
Pancreatology
PUBLISHED: 08-08-2011
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Pancreatic resection for cancer may produce pancreatic exocrine insufficiency (PEI), which is poorly understood. This study examined the coefficient of fat absorption (CFA), symptoms, quality of life (QoL) and the accuracy of faecal elastase-1 (FE-1) measurement to predict PEI.
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Pancreatic cancer susceptibility loci and their role in survival.
PLoS ONE
PUBLISHED: 06-27-2011
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Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.
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Tetracycline-inducible protein expression in pancreatic cancer cells: effects of CapG overexpression.
World J. Gastroenterol.
PUBLISHED: 04-30-2011
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To establish stable tetracycline-inducible pancreatic cancer cell lines.
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Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy.
Mol. Cancer
PUBLISHED: 04-13-2011
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Nrf2 is a key transcriptional regulator of a battery of genes that facilitate phase II/III drug metabolism and defence against oxidative stress. Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation. The Nrf2/Keap1 system is dysregulated in lung, head and neck, and breast cancers and this affects cellular proliferation and response to therapy. Here, we have investigated the integrity of the Nrf2/Keap1 system in pancreatic cancer.
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Pancreatic cancer in 2010: new insights for early intervention and detection.
Nat Rev Gastroenterol Hepatol
PUBLISHED: 02-05-2011
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Pancreatic cancer is usually detected at an advanced stage and responds poorly to treatment. In 2010 new insights were gained into understanding the complex biology of pancreatic cancer. Importantly, these insights offer novel opportunities for early diagnosis and treatment of this disease.
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Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells.
Gastroenterology
PUBLISHED: 01-14-2011
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Oxidative stress is implicated in the pathogenesis of pancreatitis, but clinical trials of antioxidants have produced conflicting results. We examined the role of intracellular reactive oxygen species (ROS) in pancreatic acinar cell injury.
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Adjuvant therapy in pancreatic cancer.
Dig Dis
PUBLISHED: 11-18-2010
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Pancreatic cancer is one of the major causes of cancer death in Europe with a 5-year survival rate of less than 5%. Although surgery cannot guarantee a cure, the 5-year survival does improve to around 10% following resection and increases to 20-30% with adjuvant chemotherapy. The European Study Group for Pancreatic Cancer (ESPAC) 1 trial was the first adequately powered, randomized study to assess chemoradiotherapy (CRT), concurrent with 5-fluorouracil (5-FU) and chemotherapy [5-FU/folinic acid (FA)] in resected pancreatic cancer. There was a survival benefit for adjuvant chemotherapy, but not for adjuvant CRT. Adjuvant CRT also did not improve survival in the EORTC multicenter prospective randomized trial by Klinkenbijl et al. (1999). The phase 3 RTOG 9704 trial compared pre- and postchemoradiation gemcitabine to pre- and postchemoradiation 5-FU. Overall there was no difference in overall survival between the 2 arms. Adjuvant gemcitabine significantly improved disease-free survival and later overall survival compared to surgery alone in the CONKO-001 randomized trial. The ESPAC-3(v2) trial compared adjuvant gemcitabine versus 5-FU/FA. The final 2-year analysis demonstrated median survival from resection of patients treated with 5-FU/FA was 23.0 months (95% CI: 21.1, 25.0) and 23.6 months (95% CI: 21.4, 26.4) for patients treated with gemcitabine. Further randomized studies will assess the role of adjuvant combination chemotherapy (ESPAC-4). The key to the future of adjuvant therapy in pancreatic cancer will be the identification of novel and effective agents, and better biomarker technology underpinned by translational research which will inform the design of future trials.
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Low molecular weight heat shock protein HSP27 is a prognostic indicator in rectal cancer but not colon cancer.
Gut
PUBLISHED: 10-16-2010
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There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis.
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Analysis of serum proteins by LC-MS/MS.
Methods Mol. Biol.
PUBLISHED: 09-15-2010
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Serum contains a vast array of proteins, some of which are specific to blood whilst others are secreted into blood from tissues and organs. The so-called tissue leakage factors reveal information about the tissue from which they originate and are therefore of great potential importance as disease biomarkers. There are already a number of blood-borne biomarkers in routine clinical use that aid in the diagnosis or management of cancer. However, there is a pressing need for additional markers, and new methods to find them are under development. Here we provide a protocol for serum protein profiling using liquid chromatography tandem mass spectrometry (LC-MS/MS). Included in this procedure, we detail the pre-processing steps of lipid and high-abundance protein removal. These procedures can also be employed up-stream of quantification methods such as isobaric tags for relative and absolute quantification (iTRAQ). Chapter 12 is devoted to the iTRAQ approach for quantifying proteins, and it is therefore not described in this chapter.
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Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells.
Carcinogenesis
PUBLISHED: 07-09-2010
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S100A8 and its dimerization partner S100A9 are emerging as important chemokines in cancer. We previously reported that Smad4-negative pancreatic tumors contain fewer stromal S100A8-positive monocytes than their Smad4-positive counterparts. Here, we studied S100A8/A9-expressing cells in colorectal tumors relating their presence to clinicopathological parameters and Smad4 status. Two-dimensional gel electrophoresis (n = 12) revealed variation in the levels of S100A8 protein in colorectal cancer tumors, whereas immunohistochemical analysis (n = 313) showed variation in the numbers of stromal S100A8-positive and S100A9-positive cells. Loss of Smad4 expression was observed in 42/304 (14%) colorectal tumors and was associated with reduced numbers of S100A8-positive (P = 0.03) but not S100A9-positive stromal cells (P = 0.26). High S100A9 cell counts were associated with large tumor sizes (P = 0.0006) and poor differentiation grade (P = 0.036). However, neither S100A8 nor S100A9 cell counts predicted poor survival, except for patients with Smad4-negative tumors (P = 0.02). To address the impact of environmental S100A8/A9 chemokines on tumor cells, we examined the effects of exogenously added S100A8 and S100A9 proteins on cellular migration and proliferation of colorectal and pancreatic cancer cells. S100A8 and S100A9 enhanced migration and proliferation in Smad4-positive and Smad4-negative cancer cells. However, transient depletion of Smad4 resulted in loss of responsiveness to exogenous S100A8, but not S100A9. S100A8 and S100A9 activated Smad4 signaling as evidenced by phosphorylation of Smad2/3; blockade of the receptor for the advanced glycation end products inhibited this response. In conclusion, Smad4 loss alters the tumors interaction with stromal myeloid cells and the tumor cells response to the stromal chemokine, S100A8.
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Minimal access retroperitoneal pancreatic necrosectomy: improvement in morbidity and mortality with a less invasive approach.
Ann. Surg.
PUBLISHED: 04-17-2010
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Comparison of minimal access retroperitoneal pancreatic necrosectomy (MARPN) versus open necrosectomy in the treatment of infected or nonresolving pancreatic necrosis.
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Dual-color proteomic profiling of complex samples with a microarray of 810 cancer-related antibodies.
Mol. Cell Proteomics
PUBLISHED: 02-16-2010
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Antibody microarrays have the potential to enable comprehensive proteomic analysis of small amounts of sample material. Here, protocols are presented for the production, quality assessment, and reproducible application of antibody microarrays in a two-color mode with an array of 1,800 features, representing 810 antibodies that were directed at 741 cancer-related proteins. In addition to measures of array quality, we implemented indicators for the accuracy and significance of dual-color detection. Dual-color measurements outperform a single-color approach concerning assay reproducibility and discriminative power. In the analysis of serum samples, depletion of high-abundance proteins did not improve technical assay quality. On the contrary, depletion introduced a strong bias in protein representation. In an initial study, we demonstrated the applicability of the protocols to proteins derived from urine samples. We identified differences between urine samples from pancreatic cancer patients and healthy subjects and between sexes. This study demonstrates that biomedically relevant data can be produced. As demonstrated by the thorough quality analysis, the dual-color antibody array approach proved to be competitive with other proteomic techniques and comparable in performance to transcriptional microarray analyses.
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Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer.
J. Clin. Oncol.
PUBLISHED: 10-26-2009
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Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP).
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Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin.
Histopathology
PUBLISHED: 09-03-2009
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The current Royal College of Pathologists guidelines for pancreatoduodenectomy specimen reporting recommend that microscopic evidence of tumour within 1 mm of a resection margin (RM) should be classified as R1. No clinical evidence exists to justify this classification. The aim of this study was to identify the proportion of pancreatoduodenectomy specimens in which equivocal RMs are present (tumour involvement within 1 mm of, but not directly reaching, one or more resection margins) and whether the survival of these patients was similar to that of patients with unequivocal RM involvement.
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A preoperative prognostic score for resected pancreatic and periampullary neuroendocrine tumours.
Pancreatology
PUBLISHED: 08-14-2009
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To identify potential preoperative prognostic factors in resected pancreatic and periampullary neuroendocrine tumours.
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Pancreatic cancer: proteomic approaches to a challenging disease.
Pancreatology
PUBLISHED: 08-04-2009
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To describe progress in the application of proteomic approaches to advance our understanding of the biology of pancreatic cancer as well as contribute potential protein biomarkers for this disease.
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A technically detailed and pragmatic protocol for quantitative serum proteomics using iTRAQ.
J Proteomics
PUBLISHED: 05-01-2009
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Blood is recognised as a highly important source of disease-related biomarkers, and proteomic approaches for identifying novel blood-borne biomarkers are in demand. The complexity and dynamic protein concentration range of plasma/serum however complicates the analysis process. A number of strategies for simplification of blood prior to proteomic analysis have been developed. In addition, methods for quantifying the levels of proteins in samples, such as isobaric tags for relative and absolute quantification (iTRAQ) are emerging. However, the successful application of these procedures is not always straightforward and technical hurdles must be overcome. Here we provide a technically detailed working protocol for iTRAQ-based quantification of serum proteins following immunodepletion of high abundance proteins. To improve the number of proteins identified and quantified we have introduced several modifications to the standard iTRAQ protocol. We report identifications of 217 proteins (5773 peptides) with a false discovery rate of 1% or 254 proteins with 95% confidence, respectively. Relative quantification data were obtained for 234 (95% confidence) serum proteins, including species present in the concentration range of tissue leakage factors. The samples described here relate to pancreatic cancer; however the protocol can be applied to serum from other control or disease types.
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Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma.
Am. J. Surg.
PUBLISHED: 04-15-2009
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The objective of this study was to investigate whether the preoperative platelet-lymphocyte (P/L) ratio represents a significant prognostic index in resected pancreatic ductal adenocarcinoma.
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Longitudinal quality of life data can provide insights on the impact of adjuvant treatment for pancreatic cancer-Subset analysis of the ESPAC-1 data.
Int. J. Cancer
PUBLISHED: 03-31-2009
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The European Study Group for Pancreatic Cancer (ESPAC-1) study is the largest study of adjuvant treatment for pancreatic ductal adenocarcinoma to date and confirmed a survival advantage for adjuvant chemotherapy but not for chemoradiation. The importance of parallel evaluation of survival and quality of life (QoL) has been recognized as fundamental and the aim was to assess QoL and quality adjusted survival. A longitudinal QoL study on a subset of ESPAC-1 patients who prospectively completed the EORTC QLQ C-30 questionnaire during treatment and follow-up. An integrated quality-survival product method was used to adjust any treatment effect on survival by a function of measured QoL, calculated over a restricted 24-month-period (QALM-24). Three hundred and sixteen patients completed 1,201 questionnaires. There were no differences between treatment groups in dimension scores at baseline (randomization). For the chemotherapy group, the mean Quality Adjusted Life Months over 24 months (QALM-24) was 9.6 (95% CI: 8.7, 11.2) months compared with the mean QALM-24 of 8.6 (95% CI: 7.6, 10.5) months for the no chemotherapy group. For the chemoradiation group, the mean QALM-24 was 7.1 (95% CI: 6.0, 9.0) months compared with the mean QALM-24 of 8.1 (95% CI: 7.0, 10.0) months for the no chemoradiation group. The previously reported survival advantage supporting the use of adjuvant chemotherapy is maintained when adjusted using quality adjusted survival methodology. Chemotherapy provided on average an additional 1.0 quality-adjusted life months within a restricted 2-year time period from the time of resection.
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Confounding effect of obstructive jaundice in the interpretation of proteomic plasma profiling data for pancreatic cancer.
J. Proteome Res.
PUBLISHED: 02-28-2009
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It is well established that variation in sampling, processing and storage protocols can alter the levels of potential biomarkers in serum and plasma. Here, using pancreatic cancer as an example, we demonstrate that consideration of clinical parameters related to the patients illness is equally important when seeking cancer-specific biomarkers. Bile duct-obstruction is a feature of pancreatic disease that can cause jaundice. Comparing patients with pancreatic cancer, chronic pancreatitis or biliary duct obstruction, we observed that the plasma levels of apolipoprotein A1, transthyretin, and apolipoprotein E, when examined in isolation, were each associated with pancreatic cancer. However, when the effect of bile duct obstruction was considered, only transthyretin levels were independently associated with cancer likelihood. Our results demonstrate the importance of accounting for disease-related confounding factors when analyzing data for the detection of cancer biomarkers.
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Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma.
BMC Cancer
PUBLISHED: 02-25-2009
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Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I(131) in pancreatic cancer (ISRCTN 16857581).
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The value of source data verification in a cancer clinical trial.
PLoS ONE
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Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial.
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Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium.
Dig Liver Dis
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Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.
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Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.
Nat. Genet.
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Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
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Adjuvant therapy for pancreatic cancer.
Recent Results Cancer Res.
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Pancreatic cancer is a challenging malignancy to treat, as less than one-fifth of diagnosed cases are resectable, surgery is complex and postoperative recovery slow, treated patients tend to relapse and overall survival rates are low. It is one of the leading causes of cancer-related mortality. Adjuvant therapy has been employed in resectable disease, to target micrometastases and improve prognosis. Chemotherapy, chemoradiotherapy (chemoRT) and chemoradiotherapy (chemoRT) followed on by chemotherapy have been evaluated in randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 trials clearly established the survival advantage of adjuvant chemotherapy with 5 fluorouracil (5FU) plus folinic acid and gemcitabine respectively over no chemotherapy. The ESPAC-3 (version 2) trial demonstrated equivalence between 5FU plus folinic acid and gemcitabine in terms of survival parameters, though gemcitabine had a better toxicity profile. The results of these key studies, together with smaller ones have been subjected to meta-analyses, with confirmation of improved survival with adjuvant systemic chemotherapy. The EORTC-40891 and ESPAC-1 trials found no survival advantage with adjuvant chemoRT compared to observation, and this has been reflected in a subsequent meta-analysis. The popularisation of chemoRT, with follow on chemotherapy (versus observation) was based on the small underpowered GITSG trial. The ESPAC-1 trial was unable to find a survival benefit for chemoRT, with follow on chemotherapy compared to observation. The RTOG-9704 trial assessed chemoRT with follow on chemotherapy in both arms and found no difference between survival in the gemcitabine and 5FU arms. There has never been a published head-to-head randomised comparison of adjuvant chemotherapy to chemoRT, with follow on chemotherapy. Ongoing randomised trials are looking into adjuvant combination chemotherapy, chemotherapy with follow on chemoRT, and neoadjuvant therapy. Novel agents continue to be assessed in early phase trials with a major emphasis on predictive and prognostic biomarkers. Based on the available evidence, adjuvant chemotherapy with gemcitabine or 5FU/folinic acid is the current recommended gold standard in the management of resected pancreatic cancer.
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New biomarkers and targets in pancreatic cancer and their application to treatment.
Nat Rev Gastroenterol Hepatol
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Late diagnosis of pancreatic ductal adenocarcinoma (pancreatic cancer) and the limited response to current treatments results in an exceptionally poor prognosis. Advances in our understanding of the molecular events underpinning pancreatic cancer development and metastasis offer the hope of tangible benefits for patients. In-depth mutational analyses have shed light on the genetic abnormalities in pancreatic cancer, providing potential treatment targets. New biological studies in patients and in mouse models have advanced our knowledge of the timing of metastasis of pancreatic cancer, highlighting new directions for the way in which patients are treated. Furthermore, our increasing understanding of the molecular events in tumorigenesis is leading to the identification of biomarkers that enable us to predict response to treatment. A major drawback, however, is the general lack of an adequate systematic approach to advancing the use of biomarkers in cancer drug development, highlighted in a Cancer Biomarkers Collaborative consensus report. In this Review, we summarize the latest insights into the biology of pancreatic cancer, and their repercussions for treatment. We provide an overview of current treatments and, finally, we discuss novel therapeutic approaches, including the role of biomarkers in therapy for pancreatic cancer.
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Nanotechnology advances in upper gastrointestinal, liver and pancreatic cancer.
Expert Rev Gastroenterol Hepatol
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Cancers of the upper GI tract, liver and pancreas have some of the poorest prognoses of any malignancies. Advances in diagnosis and treatment are sorely needed to improve the outcomes of patients. Nanotechnology offers the potential for constructing tailor-made therapies capable of targeting specific cancers. The particles themselves may be endowed with multifunctional properties that can be exploited for both diagnosis and treatment. Although development of therapies is still in the early stages, the use of nanoparticles (NPs) is widespread in diagnostic applications and will probably involve all areas of medicine in the future. Research into NPs is ongoing for upper gastrointestinal, liver and pancreatic cancers, and their use is becoming increasingly popular as contrast media for radiological investigations. Although more sophisticated technologies capable of active targeting are still in the early stages of assessment for clinical use, a small number of NP-based therapies are in clinical use.
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Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue.
PLoS ONE
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A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer.
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Understanding metastasis in pancreatic cancer: a call for new clinical approaches.
Cell
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Although metastasis is a major cause of morbidity and mortality in patients with pancreatic cancer, the requisite events are currently unknown. In this issue of Cell, Haeno et al. and Rhim et al. propose that metastasis occurs much earlier than previously anticipated, with clear implications for improving patient care.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.