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Sample records for pancreatic ductal adenocarcinomas

  1. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

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    Cruz-Monserrate, Zobeida; Roland, Christina L.; Deng, Defeng; Arumugam, Thiruvengadam; Moshnikova, Anna; Andreev, Oleg A.; Reshetnyak, Yana K.; Logsdon, Craig D.

    2014-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.

  2. Rational combinations of immunotherapy for pancreatic ductal adenocarcinoma.

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    Blair, Alex B; Zheng, Lei

    2017-06-01

    The complex interaction between the immune system, the tumor and the microenvironment in pancreatic ductal adenocarcinoma (PDA) leads to the resistance of PDA to immunotherapy. To overcome this resistance, combination immunotherapy is being proposed. However, rational combinations that target multiple aspects of the complex anti-tumor immune response are warranted. Novel clinical trials will investigate and optimize the combination immunotherapy for PDA.

  3. Molecular pathogenesis of precursor lesions of pancreatic ductal adenocarcinoma.

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    Biankin, Andrew V; Kench, James G; Dijkman, Floriaan P; Biankin, Sandra A; Henshall, Susan M

    2003-02-01

    Precursor lesions are assuming greater importance in the study of pancreatic ductal adenocarcinoma. As pancreatic cancer is almost universally fatal due to late clinical presentation and biological aggressiveness, characterisation of its precursor lesions may create scope for early diagnosis and improved outcome with conventional therapies as well as the development of novel therapeutic and preventative strategies. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous tumours (IPMTs) are thought to be precursor lesions of ductal adenocarcinoma of the pancreas. Recent work has focused on the molecular aberrations associated with these lesions leading to the formulation of a progression model for pancreatic cancer. Progressive histopathological changes along the progression model are associated with aberrations of cell cycle regulatory and growth factor signalling molecules that occur in pancreatic cancer at high frequency and are common to many cancers. Characterisation of these molecular aberrations provides scope for the development of novel diagnostic and treatment strategies that will ultimately impact on the outcome for people who develop pancreatic cancer.

  4. Aberrant Methylation of Preproenkephalin and p16 Genes in Pancreatic Intraepithelial Neoplasia and Pancreatic Ductal Adenocarcinoma

    OpenAIRE

    Fukushima, Noriyoshi; Sato, Norihiro; Ueki, Takashi; Rosty, Christophe; Walter, Kimberly M.; Wilentz, Robb E.; Yeo, Charles J.; Hruban, Ralph H.; Goggins, Michael

    2002-01-01

    Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3...

  5. Staging of pancreatic ductal adenocarcinoma using dynamic MR imaging

    International Nuclear Information System (INIS)

    Murakami, Kouji; Nawano, Shigeru; Moriyama, Noriyuki; Sekiguchi, Ryuzou; Satake, Mituo; Iwata, Ryouko; Hayashi, Takayuki; Nemoto, Kazuhisa.

    1997-01-01

    Single breath-hold gradient echo images were obtained before and immediately after bolus intravenous administration of Gd-DTPA (dynamic MR imaging) in the study of the pancreas. Of 37 patients with pathologically proved pancreatic ductal adenocarcinoma, seventeen patients who underwent both dynamic MR imaging studies and curative surgery were included in this study. Correlations between histologic findings in the resected specimens and MR images were analyzed as to tumor extension and staging according to the General Rules for the Study of Pancreatic Cancer (4th Edition) published by the Japan Pancreas Society. In comparison with conventional MR images, dynamic MR imaging improved the detectability of pancreatic carcinoma and delineation of the vasculature by clarifying the margin of the tumor and the vessels. Nonenhanced T1-weighted imaging is the best sequence to estimate peripancreatic tumor extension, because the contrast between the tumor and peripancreatic fat deteriorates with the use of contrast material. There is a tendency to overestimate vascular invasion on MR images, the reason for which is considered to be the contractive nature of fibrotic change induced by pancreatic carcinoma. The diagnostic efficacy of lymph node metastasis remains insufficient on MR images because some cases show no enlargement of lymph nodes in spite of the existence of pathological metastasis. Our results suggest that dynamic MR imaging has the advantage of improving the conspicuity of the tumor and the vasculature. (author)

  6. Next generation sequencing of pancreatic ductal adenocarcinoma: right or wrong?

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    Connor, Ashton A; Gallinger, Steven

    2017-07-01

    Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all epithelial malignancies and a paradoxically rising incidence rate. Clinical translation of next generation sequencing (NGS) of tumour and germline samples may ameliorate outcomes by identifying prognostic and predictive genomic and transcriptomic features in appreciable fractions of patients, facilitating enrolment in biomarker-matched trials. Areas covered: The literature on precision oncology is reviewed. It is found that outcomes may be improved across various malignancies, and it is suggested that current issues of adequate tissue acquisition, turnaround times, analytic expertise and clinical trial accessibility may lessen as experience accrues. Also reviewed are PDAC genomic and transcriptomic NGS studies, emphasizing discoveries of promising biomarkers, though these require validation, and the fraction of patients that will benefit from these outside of the research setting is currently unknown. Expert commentary: Clinical use of NGS with PDAC should be used in investigational contexts in centers with multidisciplinary expertise in cancer sequencing and pancreatic cancer management. Biomarker directed studies will improve our understanding of actionable genomic variation in PDAC, and improve outcomes for this challenging disease.

  7. DEK protein overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma.

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    Sun, Jie; Bi, Fangfang; Yang, Yang; Zhang, Yuan; Jin, Aihua; Li, Jinzi; Lin, Zhenhua

    2017-02-01

    DEK, a transcription factor, is involved in mRNA splicing, transcriptional control, cell division and differentiation. Recent studies suggest that DEK overexpression can promote tumorigenesis in a wide range of cancer cell types. However, little is known concerning the status of DEK in pancreatic ductal adenocarcinoma (PDAC). Based on the microarray data from Gene Expression Omnibus (GEO), the expression levels of DEK mRNA in PDAC tissues were significantly higher than levels in the adjacent non-tumor tissues. To explore the clinical features of DEK overexpression in PDAC, 87 PDAC and 52 normal pancreas tissues were selected for immunoenzyme staining of the DEK protein. Localization of the DEK protein was detected in PANC-1 pancreatic cancer cells using immunofluorescence (IF) staining. The correlations between DEK overexpression and the clinical features of PDAC were evaluated using the Chi-squared (χ2) and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. The expression levels of DEK mRNA in PDAC tissues were significantly higher than that in the adjacent non‑tumor tissues. The DEK protein showed a primarily nuclear staining pattern in PDAC. The positive rate of the DEK protein was 52.9% (46/87) in PDAC, which was significantly higher than that in the adjacent normal pancreatic tissues (7.7%, 4/52). DEK overexpression in PDAC was correlated with tumor size, histological grade, tumor‑node‑metastasis (TNM) stage and overall survival (OS) rates. In addition, multivariate analysis demonstrated that DEK overexpression was an independent prognostic factor along with histological grade and TNM stage in patients with PDAC. In conclusion, DEK overexpression is associated with PDAC progression and may be a potential biomarker for poor prognostic evaluation in PDAC.

  8. Circular RNA Signature Predicts Gemcitabine Resistance of Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Feng Shao

    2018-06-01

    Full Text Available Gemcitabine resistance is currently the main problem of chemotherapy for advanced pancreatic cancer patients. The resistance is thought to be caused by altered drug metabolism or reduced apoptosis of cancer cells. However, the underlying mechanism of Gemcitabine resistance in pancreatic cancer remains unclear. In this study, we established Gemcitabine resistant PANC-1 (PANC-1-GR cell lines and compared the circular RNAs (circRNAs profiles between PANC-1 cells and PANC-1-GR cells by RNA sequencing. Differentially expressed circRNAs were demonstrated using scatter plot and cluster heatmap analysis. Gene ontology and pathway analysis were performed to systemically map the genes which are functionally associated to those differentially expressed circRNAs identified from our data. The expression of the differentially expressed circRNAs picked up by RNAseq in PANC-1-GR cells was further validated by qRT-PCR and two circRNAs were eventually identified as the most distinct targets. Consistently, by analyzing plasma samples form pancreatic ductal adenocarcinoma (PDAC patients, the two circRNAs showed more significant expression in the Gemcitabine non-responsive patients than the responsive ones. In addition, we found that silencing of the two circRNAs could restore the sensitivity of PANC-1-GR cells to Gemcitabine treatment, while over-expression of them could increase the resistance of normal PANC-1 and MIA PACA-2 cells, suggesting that they might serve as drug targets for Gemcitabine resistance. Furthermore, the miRNA interaction networks were also explored based on the correlation analysis of the target microRNAs of these two circRNAs. In conclusion, we successfully established new PANC-1-GR cells, systemically characterized the circRNA and miRNA profiles, and identified two circRNAs as novel biomarkers and potential therapeutic targets for Gemcitabine non-responsive PDAC patients.

  9. Comparison of F-18-FDG PET/CT findings between pancreatic solid pseudopapillary tumor and pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Kim, Yong-il; Kim, Seok-ki; Paeng, Jin Chul; Lee, Ho-Young

    2014-01-01

    Objective: Pancreatic solid pseudopapillary tumor (SPT) is a rare benign tumor. Little data are available on positron emission tomographic/computed tomographic (PET/CT) characteristics of this tumor. Therefore, we analyzed the metabolic characteristics of SPT using F-18-FDG PET/CT and compared the results with those of pancreatic ductal adenocarcinoma. Methods: We retrospectively reviewed the records of 11 SPT patients and 46 patients with ductal adenocarcinoma. Ten SPT patients had primary tumors and 1 patient had metastatic SPT. Maximum standardized uptake value (max SUV), mean SUV, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor-to-background ratio (TBR) were evaluated. Mann–Whitney U test between pancreatic SPT and ductal adenocarcinoma was performed. In addition, age, gender and tumor size-adjusted analysis of covariance (ANCOVA) was done between pancreatic SPT and ductal adenocarcinoma. Results: Compared with pancreatic ductal adenocarcinomas, SPTs had significantly higher tumor size-adjusted MTV and TLG. MTV and TLG values were significantly correlated with T-stage of the SPTs. In 1 SPT patient, metastases in the liver and mesentery were revealed by intense uptake of FDG on F-18-FDG PET/CT, and after PET/CT had suggested the presence of pancreatic SPT. Conclusion: We recommend that SPT be considered when a solid pancreatic mass with increased FDG metabolism is encountered on PET/CT. F-18-FDG PET/CT may be useful in detecting subtle metastases of SPT

  10. Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma.

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    Ghassem-Zadeh, Sahar; Gaida, Matthias M; Szanyi, Szilard; Acha-Orbea, Hans; Frossard, Jean-Louis; Hinz, Ulf; Hackert, Thilo; Strobel, Oliver; Felix, Klaus

    2017-06-02

    Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. The cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.

  11. Extended pancreatectomy in pancreatic ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS)

    NARCIS (Netherlands)

    Hartwig, Werner; Vollmer, Charles M.; Fingerhut, Abe; Yeo, Charles J.; Neoptolemos, John P.; Adham, Mustapha; Andrén-Sandberg, Ake; Asbun, Horacio J.; Bassi, Claudio; Bockhorn, Max; Charnley, Richard; Conlon, Kevin C.; Dervenis, Christos; Fernandez-Cruz, Laureano; Friess, Helmut; Gouma, Dirk J.; Imrie, Clem W.; Lillemoe, Keith D.; Milićević, Miroslav N.; Montorsi, Marco; Shrikhande, Shailesh V.; Vashist, Yogesh K.; Izbicki, Jakob R.; Büchler, Markus W.

    2014-01-01

    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

  12. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

    NARCIS (Netherlands)

    Ricci, C.; Mota, C.M.; Moscato, S.; D' Alessandro, D.; Ugel, S.; Sartoris, S.; Bronte, V.; Boggi, U.; Campani, D.; Funel, N.; Moroni, Lorenzo; Danti, S.

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl

  13. BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

    NARCIS (Netherlands)

    Rosati, Alessandra; Basile, Anna; D'Auria, Raffaella; d'Avenia, Morena; de Marco, Margot; Falco, Antonia; Festa, Michelina; Guerriero, Luana; Iorio, Vittoria; Parente, Roberto; Pascale, Maria; Marzullo, Liberato; Franco, Renato; Arra, Claudio; Barbieri, Antonio; Rea, Domenica; Menichini, Giulio; Hahne, Michael; Bijlsma, Maarten; Barcaroli, Daniela; Sala, Gianluca; di Mola, Fabio Francesco; di Sebastiano, Pierluigi; Todoric, Jelena; Antonucci, Laura; Corvest, Vincent; Jawhari, Anass; Firpo, Matthew A.; Tuveson, David A.; Capunzo, Mario; Karin, Michael; de Laurenzi, Vincenzo; Turco, Maria Caterina

    2015-01-01

    The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of

  14. SMAD4 Loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells

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    Chen, Yu-Wen; Hsiao, Pi-Jung; Weng, Ching-Chieh; Kuo, Kung-Kai; Kuo, Tzu-Lei; Wu, Deng-Chyang; Hung, Wen-Chun; Cheng, Kuang-Hung

    2014-01-01

    Background SMAD4 is a gastrointestinal malignancy-specific tumor suppressor gene found mutated in one third of colorectal cancer specimens and half of pancreatic tumors. SMAD4 inactivation by allelic deletion or intragenic mutation mainly occurs in the late stage of human pancreatic ductal adenocarcinoma (PDAC). Various studies have proposed potential SMAD4-mediated anti-tumor effects in human malignancy; however, the relevance of SMAD4 in the PDAC molecular phenotype has not yet been fully c...

  15. Development of a miRNA-based diagnostic assay for pancreatic ductal adenocarcinoma.

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    Szafranska-Schwarzbach, Anna E; Adai, Alex T; Lee, Linda S; Conwell, Darwin L; Andruss, Bernard F

    2011-04-01

    Diagnosis of pancreatic cancer remains a clinical challenge. Both chronic pancreatitis and pancreatic cancer may present with similar symptoms and similar imaging features, often leading to incorrect interpretation. Thus, the use of an objective molecular test that can discriminate between chronic pancreatitis and pancreatic cancer will be a valuable asset in obtaining a definitive diagnosis of pancreatic cancer. Following Clinical Laboratory Improvement Amendments and College of American Pathologists guidelines, Asuragen Clinical Services Laboratory has developed and validated a laboratory-developed test, miRInform(®) Pancreas, to aid in the identification of pancreatic ductal adenocarcinoma. This molecular diagnostic tool uses reverse-transcription quantitative PCR to measure the expression difference between two miRNAs, miR-196a and miR-217, in fixed tissue specimens. This article describes the test validation process as well as determination of performance parameters of miRInform Pancreas.

  16. [Comparison of laparoscopic distal pancreatectomy and open distal pancreatectomy in pancreatic ductal adenocarcinoma].

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    Xu, K; Su, J J; Su, M; Yan, L; Feng, J; Xin, X L; Chen, Y L

    2017-10-23

    Objective: To compare and evaluate the curative effect of laparoscopic distal pancreatectomy(LDP) and traditional open distal pancreatectomy(ODP) in pancreatic ductal adenocarcinoma. Methods: The clinical data of 15 patients treated by LDP and 87 contemporaneous cases treated by ODP from January 2010 to November 2015 was collected, and the curative effect and prognosis of these patients were retrospectively analyzed. Results: The operation time of LDP group was (286.5±48.1) min, significantly longer than that of OPD group(226.6±56.8) min ( P 0.05). In both LDP group and ODP group, none occurred percutaneous drainage, re-admissions, second operation or perioperative death. Conclusions: Compared to ODP, LDP is much safer and more steady in perioperative periodand operation. Patients of pancreatic ductal adenocarcinoma received LDP can acquire more benefit and recovery sooner, and LDP is a safe and effective operative method.

  17. Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: Long-term oncologic outcomes after standard resection.

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    Sahakyan, Mushegh A; Kim, Song Cheol; Kleive, Dyre; Kazaryan, Airazat M; Song, Ki Byung; Ignjatovic, Dejan; Buanes, Trond; Røsok, Bård I; Labori, Knut Jørgen; Edwin, Bjørn

    2017-10-01

    Surgical resection is the only curative option in patients with pancreatic ductal adenocarcinoma. Little is known about the oncologic outcomes of laparoscopic distal pancreatectomy. This bi-institutional study aimed to examine the long-term oncologic results of standard laparoscopic distal pancreatectomy in a large cohort of patients with pancreatic ductal adenocarcinoma. From January 2002 to March 2016, 207 patients underwent standard laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma at Oslo University Hospital-Rikshospitalet (Oslo, Norway) and Asan Medical Centre (Seoul, Republic of Korea). After the exclusion criteria were applied (distant metastases at operation, conversion to an open operation, loss to follow-up), 186 patients were eligible for the analysis. Perioperative and oncologic variables were analyzed for association with recurrence and survival. Median overall and recurrence-free survivals were 32 and 16 months, while 5-year overall and recurrence-free survival rates were estimated to be 38.2% and 35.9%, respectively. Ninety-six (52%) patients developed recurrence: 56 (30%) extrapancreatic, 27 (15%) locoregional, and 13 (7%) combined locoregional and extrapancreatic. Thirty-seven (19.9%) patients had early recurrence (within 6 months of operation). In the multivariable analysis, tumor size >3 cm and no adjuvant chemotherapy were associated with early recurrence (P = .017 and P = .015, respectively). The Cox regression model showed that tumor size >3 cm and lymphovascular invasion were independent predictors of decreased recurrence-free and overall survival. Standard laparoscopic distal pancreatectomy is associated with satisfactory long-term oncologic outcomes in patients with pancreatic ductal adenocarcinoma. Several risk factors, such as tumor size >3 cm, no adjuvant chemotherapy, and lymphovascular invasion, are linked to poor prognosis after standard laparoscopic distal pancreatectomy. Copyright © 2017 Elsevier Inc

  18. Laparoscopic versus open distal pancreatectomy for pancreatic ductal adenocarcinoma: a single-center experience.

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    Zhang, Ai-Bin; Wang, Ye; Hu, Chen; Shen, Yan; Zheng, Shu-Sen

    2017-06-01

    The aim of this study was to compare complications and oncologic outcomes of patients undergoing laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) at a single center. Distal pancreatectomies performed for pancreatic ductal adenocarcinoma during a 4-year period were included in this study. A retrospective analysis of a database of this cohort was conducted. Twenty-two patients underwent LDP for pancreatic ductal adenocarcinoma, in comparison to seventy-six patients with comparable tumor characteristics treated by ODP. No patients with locally advanced lesions were included in this study. Comparing LDP group to ODP group, there were no significant differences in operation time (P=0.06) or blood loss (P=0.24). Complications (pancreatic fistula, P=0.62; intra-abdominal abscess, P=0.44; postpancreatectomy hemorrhage, P=0.34) were similar. There were no significant differences in the number of lymph nodes harvested (11.2±4.6 in LDP group vs. 14.4±5.5 in ODP group, P=0.44) nor the rate of patients with positive lymph nodes (36% in LDP group vs. 41% in ODP group, P=0.71). Incidence of positive margins was similar (9% in LDP group vs. 13% in ODP group, P=0.61). The mean overall survival time was (29.6±3.7) months for the LDP group and (27.6±2.1) months for ODP group. There was no difference in overall survival between the two groups (P=0.34). LDP is a safe and effective treatment for selected patients with pancreatic ductal adenocarcinoma. A slow-compression of pancreas tissue with the GIA stapler is effective in preventing postoperative pancreatic fistula. The oncologic outcome is comparable with the conventional open approach. Laparoscopic radical antegrade modular pancreatosplenectomy contributed to oncological clearance.

  19. Pancreatic ductal adenocarcinoma presenting with acute and chronic pancreatitis as initial presentation: is prognosis better? A comparison study..

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    Thorat, Ashok; Huang, Wen-Hsuan; Yeh, Ta-Sen; Jan, Yi-Yan; Hwang, Tsann-Long

    2014-10-01

    Pancreatic ductal adenocarcinoma (PDAC) may present with acute and /or chronic pancreatitis due to pancreatic ductal obstruction causing diagnostic dilemma. The aim of this retrospective study was to investigate the outcome and prognosis of the patients of PDAC presenting with pancreatitis. From 1991 to 2009, 298 patients with PDAC that underwent surgical treatment were retrospectively studied and divided in two groups depending upon initial symptomatic presentation. Group A (n=254) comprised patients without pancreatitis while group B (n=44) patients presented with acute and/or chronic pancreatitis initially. All the patients in studied cohort were surgically treated. Mean age of group A was 63.1 years & for group B it was 62.9 years. Location of tumor was in head of the pancreas in 66.14% of group A patients (n=168) and 61.36% of group B patients (n=27). Although statistically insignificant, the patients in group B had overall better 5-year survival than the patients in group A (20% vs 15.9%). This retrospective study highlights the overall better survival of PDAC patients presenting with acute and/or chronic pancreatitis than those without as contrary to previous reports which stated the poor prognosis of PDAC patients if associated with underlying pancreatitis.

  20. Comparison of Fasting Human Pancreatic Polypeptide Levels Among Patients With Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Type 2 Diabetes Mellitus.

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    Nagpal, Sajan Jiv Singh; Bamlet, William R; Kudva, Yogish C; Chari, Suresh T

    2018-05-17

    Human pancreatic polypeptide (HPP) is a hormone secreted by the ventral pancreas. While postprandial HPP levels have been studied in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there are limited data on fasting HPP in these diseases. Fasting serum HPP was measured in the following groups of patients: CP with diabetes mellitus (DM) (n = 16), CP without DM (n = 34), PDAC with new-onset DM (n = 50), PDAC without DM (n = 49), new-onset type 2 DM (n = 50), and controls without DM (n = 49). Sixty-six had type 3c DM (CP with DM, n = 16; PDAC with new-onset DM, n = 50). Median fasting HPP levels (in picograms per milliliter) were similar among all groups. Median (interquartile range) HPP levels in new-onset type 2 DM (n = 50; 288.3 [80.1-1072.1]) were similar to those in type 3c DM (n = 66; 242.3 [64.9-890.9]) (P = 0.71). In PDAC (n = 99), HPP values were similar in pancreatic head (n = 75) versus body/tail (n = 24) tumors (245.3 [64.3-1091.3] vs 334.7 [136.1-841.5]; P = 0.95), regardless of DM. Fasting HPP levels are similar in CP, PDAC, and controls regardless of glycemic status.

  1. Clinical significance of MUC13 in pancreatic ductal adenocarcinoma.

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    Khan, Sheema; Zafar, Nadeem; Khan, Shabia S; Setua, Saini; Behrman, Stephen W; Stiles, Zachary E; Yallapu, Murali M; Sahay, Peeyush; Ghimire, Hemendra; Ise, Tomoko; Nagata, Satoshi; Wang, Lei; Wan, Jim Y; Pradhan, Prabhakar; Jaggi, Meena; Chauhan, Subhash C

    2018-01-15

    Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P 0.8; P artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test. Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

  2. Hypoxia inducible BHLHB2 is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Wang, Weibin; Reiser-Erkan, Carolin; Michalski, Christoph W.; Raggi, Matthias C.; Quan, Liao; Yupei, Zhao; Friess, Helmut; Erkan, Mert; Kleeff, Joerg

    2010-01-01

    Research highlights: → The expression and function of BHLHB2 (DEC1/SHARP2) in pancreatic cancer is unknown. → Hypoxia and serum starvation induces BHLHB2 expression in pancreatic ductal adenocarcinoma. → BHLHB2 inhibition in pancreatic cancer cell line SU86.86 increases ED50 of gemcitabine 2.8-fold. → BHLHB2 is an independent prognostic factor in multivariable cox analysis with a hazard ratio of 2:4. -- Abstract: Aims: The cyclic adenosine monophosphate-inducible basic helix-loop-helix (bHLH) domain containing class-B2 transcriptional factor BHLHB2 is differentially expressed in a number of human malignancies. In the present study, the expression, regulation, functions and prognostic impact of BHLHB2 in pancreatic cancer were investigated. Methods: Expression analyses were carried out in tissues of the normal pancreas (n = 10) and pancreatic ductal adenocarcinoma (n = 77) as well as in eight pancreatic cancer cell lines using quantitative RT-PCR, semiquantitative immunohistochemistry, and immunoblot analyses. In vitro functional experiments were conducted using siRNA transfection, hypoxia, serum starvation, apoptosis induction with gemcitabine and actinomycin-D, and invasion assays. Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. Results: BHLHB2 mRNA and protein expressions were strongly induced by hypoxia and by serum starvation in pancreatic cancer cell lines. BHLHB2 silencing with RNAi had no significant effects on growth and invasion but increased apoptosis resistance against gemcitabine by reducing caspace-3 cleavage. In BHLHB2 silenced cells the ED50 of gemcitabine increased from 13.95 ± 1.353 to 38.70 ± 5.262 nM (p < 0.05). Ex vivo, the weak/absent nuclear staining in normal pancreatic ducts and acinar cells was replaced by moderate to strong nuclear/cytoplasmic staining in PanIN lesions and pancreatic cancer cells. Patients with

  3. Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Luigi Laghi

    Full Text Available Pancreatic cancer risk is increased in Lynch syndrome (LS patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI. However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS.MS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27 in 338 consecutive pancreatic ductal adenocarcinoma (PDAC, resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers.Only one PDAC (0.3% showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5% LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one.MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.

  4. CI- and K+ Channels in Pancreatic Ductal Adenocarcinoma (PDAC)

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter

    moderate survival benefits. Therefore, novel targets are urgently needed. Cl- and K+ channels play integral roles in the regulation of critical cellular processes such as proliferation, apoptosis and migration. These processes are commonly perturbed in tumor cells. A phenotypic hallmark of cancer is its......Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers with >95% of the affected dying from it. Despite of intensive efforts to develop new therapeutic strategies, only few drugs (e.g. gemcitabine, erlotinib) are currently approved for treatment, all exhibit only...... pancreatic cancer cell lines (Capan-1, BxPC-3 and AsPC-1) revealed Ca2+-activated Cl- current that showed the biophysical signature of ANO1 (TMEM16A). In line with this, application of ANO1-specific inhibitors and transient gene silencing of ANO1 abrogated this current. Using scratch wound healing assay, we...

  5. Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Janky, Rekin’s; Binda, Maria Mercedes; Allemeersch, Joke; Van den broeck, Anke; Govaere, Olivier; Swinnen, Johannes V.; Roskams, Tania; Aerts, Stein; Topal, Baki

    2016-01-01

    Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC). We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes. We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS. PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer. The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010). The online version of this article (doi:10.1186/s12885-016-2540-6) contains supplementary material, which is available to authorized users

  6. Repeatability and correlations of dynamic contrast enhanced and T2* MRI in patients with advanced pancreatic ductal adenocarcinoma

    NARCIS (Netherlands)

    Klaassen, Remy; Gurney-Champion, Oliver J.; Wilmink, Johanna W.; Besselink, Marc G.; Engelbrecht, Marc R. W.; Stoker, Jaap; Nederveen, Aart J.; van Laarhoven, Hanneke W. M.

    2018-01-01

    In current oncological practice of pancreatic ductal adenocarcinoma (PDAC), there is a great demand for response predictors and markers for early treatment evaluation. In this study, we investigated the repeatability and the interaction of dynamic contrast enhanced (DCE) and T2* MRI in patients with

  7. Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.

    Science.gov (United States)

    Besmer, Dahlia M; Curry, Jennifer M; Roy, Lopamudra D; Tinder, Teresa L; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y; Gendler, Sandra J; Mukherjee, Pinku

    2011-07-01

    MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. ©2011 AACR

  8. PROX1 and β-catenin are prognostic markers in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Saukkonen, Kapo; Hagström, Jaana; Mustonen, Harri; Juuti, Anne; Nordling, Stig; Kallio, Pauliina; Alitalo, Kari; Seppänen, Hanna; Haglund, Caj

    2016-01-01

    The Wnt/β-catenin pathway has a key role in regulating cellular processes and its aberrant signaling can lead to cancer development. The role of β-catenin expression in pancreatic ductal adenocarcinoma is somewhat controversial. Transcription factor PROX1 is a target of Wnt/β-catenin signaling and it is involved in carcinogenesis through alterations in its expression. The actions can be either oncogenic or tumor suppressive depending on the tissue. The aim of this study was to investigate PROX1 and β-catenin expression in pancreatic ductal adenocarcinoma (PDAC). Expression of PROX1 and β-catenin were evaluated in 156 patients by immunohistochemistry of tissue microarrays. Associations between tumor marker expression and clinicopathological parameters were assessed by the Fischer’s exact-test or the linear-by-linear association test. The Kaplan-Meier method and log-rank test were used for survival analysis. Uni- and multivariate survival analyses were carried out by the Cox regression proportional hazard model. High PROX1 expression was seen in 74 (48 %) tumors, and high β-catenin expression in 100 (65 %). High β-catenin expression was associated with lower tumor grade (p = 0.025). High PROX1 and β-catenin expression associated significantly with lower risk of death from PDAC in multivariate analysis (HR = 0.63; 95 % CI 0.42–0.95, p = 0.026; and HR = 0.54; 95 % CI 0.35–0.82, p = 0.004; respectively). The combined high expression of PROX1 and β-catenin also predicted lower risk of death from PDAC (HR = 0.46; 95 % CI 0.28–0.76, p = 0.002). In conclusion, high PROX1 and β-catenin expression were independent factors for better prognosis in pancreatic ductal adenocarcinoma. The online version of this article (doi:10.1186/s12885-016-2497-5) contains supplementary material, which is available to authorized users

  9. Differential expression of aquaporin-3 and aquaporin-5 in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Direito, Inês; Paulino, Jorge; Vigia, Emanuel; Brito, Maria Alexandra; Soveral, Graça

    2017-06-01

    Aquaporin-5 (AQP5) and -3 (AQP3) are protein channels that showed to be up-regulated in a variety of tumors. Our goal was to investigate the expression pattern of AQP5 and AQP3 in pancreatic ductal adenocarcinomas (PDA) and correlate with cell proliferation, tumor stage and progression, and clinical significance. 35 PDA samples in different stages of differentiation and locations were analyzed by immunohistochemistry for expression of AQP5, AQP3 and several markers of cell proliferation and tumorigenesis. In PDA samples AQP5 was overexpressed in the apical membrane of intercalated and intralobular ductal cells while AQP3 was expressed at the plasma membrane of ductal cells. AQP5 was also found in infiltrative cancer cells in duodenum. Simultaneous overexpression of EGFR, Ki-67, and CK7, with decreased E-cad and increased Vim that characterize epithelial mesenchymal transition, tumor formation and invasion, strongly suggest AQP3 and AQP5 involvement in cell proliferation and transformation. AQP3 overexpression is reinforced in late and more aggressive PDA stages whereas AQP5 is related with tumor differentiation, suggesting it may represent a novel marker for PDA aggressiveness and intestinal infiltration. These findings suggest AQP3 and AQP5 involvement in PDA development and the usefulness of AQP5 in early PDA diagnosis. © 2017 Wiley Periodicals, Inc.

  10. Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression

    Directory of Open Access Journals (Sweden)

    Rute M.M. Ferreira

    2017-10-01

    Full Text Available The cell of origin of pancreatic ductal adenocarcinoma (PDAC has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs, duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development.

  11. No miR quirk: dysregulation of microRNAs in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Cheung, Philip Y; Szafranska-Schwarzbach, Anna E; Schlageter, Annette M; Andruss, Bernard F; Weiss, Glen J

    2012-01-01

    MicroRNAs are post-transcriptional regulators of gene expression with tissue-specific expression profiles. Dysregulation of microRNAs has been shown to play a role in carcinogenesis. Although progress has been made in the diagnosis and treatment of many cancers, pancreatic cancer remains an intractable public health problem, causing 6.58% of cancer deaths despite making up less than 3% of cancer diagnoses in the United States. No screening, diagnostic or imaging techniques exist with the sensitivity to detect pancreatic cancer in its early, operable stages. Risk factors include numerous inherited syndromes, diabetes mellitus, and hepatitis C virus infection. Here we review the literature regarding dysregulation of microRNA expression in native pancreas, pancreatic ductal adenocarcinoma (the dominant form of pancreatic cancer), and its risk factors to illuminate the biology and progression of this disease. We explore promising evidence for the use of microRNAs as prognostic and diagnostic tools, and discuss emerging reports on microRNA therapeutics.

  12. BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.

    Science.gov (United States)

    Rosati, Alessandra; Basile, Anna; D'Auria, Raffaella; d'Avenia, Morena; De Marco, Margot; Falco, Antonia; Festa, Michelina; Guerriero, Luana; Iorio, Vittoria; Parente, Roberto; Pascale, Maria; Marzullo, Liberato; Franco, Renato; Arra, Claudio; Barbieri, Antonio; Rea, Domenica; Menichini, Giulio; Hahne, Michael; Bijlsma, Maarten; Barcaroli, Daniela; Sala, Gianluca; di Mola, Fabio Francesco; di Sebastiano, Pierluigi; Todoric, Jelena; Antonucci, Laura; Corvest, Vincent; Jawhari, Anass; Firpo, Matthew A; Tuveson, David A; Capunzo, Mario; Karin, Michael; De Laurenzi, Vincenzo; Turco, Maria Caterina

    2015-11-02

    The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

  13. Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue.

    Directory of Open Access Journals (Sweden)

    Andrea S Bauer

    Full Text Available 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.

  14. Net expression inhibits the growth of pancreatic ductal adenocarcinoma cell PL45 in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Baiwen Li

    Full Text Available Pancreatic ductal adenocarcinoma has a poor prognosis due to late diagnosis and a lack of effective therapeutic options. Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease. The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology. In this study, we found that the majority of pancreatic ductal adenocarcinoma tissues and cell lines had weak or no expression of Net, whereas significantly high level of Net expression occurred in paired adjacent normal tissues we studied. Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway. Our data thus suggested that Net might play an important role in pancreatic carcinogenesis, possibly by acting as a tumor suppressor gene.

  15. An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma.

    Science.gov (United States)

    Dima, Simona O; Tanase, Cristiana; Albulescu, Radu; Herlea, Vlad; Chivu-Economescu, Mihaela; Purnichescu-Purtan, Raluca; Dumitrascu, Traian; Duda, Dan G; Popescu, Irinel

    2012-10-01

    We measured the serum concentration of a panel of inflammatory cytokines and evaluated their association with circulating proangiogenic biomarkers and with outcome in patients with pancreatic ductal adenocarcinoma (PDAC). We collected serum samples from 36 patients with PDAC, 9 patients with chronic pancreatitis, and 22 healthy volunteers as a control. Inflammatory cytokines and proangiogenic biomarkers were measured using the multianalyte xMAP array and carcinoembryonic antigen (CEA) and carbohydrate 19-9 by immunoassay. Patients with PDAC had higher circulating levels of interleukin 6 (IL-6) than those of patients with pancreatitis or healthy individuals and higher levels of IL-10 and tumor necrosis factor α (TNF-α) compared with those of healthy individuals. In patients with PDAC, circulating IL-6, TNF-α, IL-1β, and IL-10 correlated with serum concentrations of vascular endothelial growth factor and basic fibroblast growth factor; circulating IL-6, IL-1β, and TNF-α correlated with carbohydrate 19-9; and IL-8, IL-10, and TNF-α correlated with CEA levels. Circulating IL-8, TNF-α, and CEA; tumor stage; and lymph node metastases were associated with a poor outcome. The results of this exploratory study indicate that inflammatory cytokines should be pursued as potential prognostic biomarkers as well as targets for therapy in larger studies in PDAC.

  16. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice.

    Science.gov (United States)

    Xu, X; Ehdaie, B; Ohara, N; Yoshino, T; Deng, C-X

    2010-02-04

    Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

  17. Missed pancreatic ductal adenocarcinoma: Assessment of early imaging findings on prediagnostic magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Kyung Mi; Kim, Seong Hyun, E-mail: sh6453.kim@samsung.com; Kim, Young Kon; Song, Kyoung Doo; Lee, Soon Jin; Choi, Dongil

    2015-08-15

    Highlights: • MR imaging was superior to CT for the detection of early PDAC. • A focal lesion with no MPD interruption is common MR finding of early PDAC. • A mean volume doubling time of early PDAC was about five months. - Abstract: Objective: To investigate the early imaging findings and growth rate of pancreatic ductal adenocarcinoma (PDAC), and to assess whether MR imaging detects early PDAC better than CT. Materials and methods: The institutional review board approved this retrospective study and waived the requirement for informed consent. Twenty-two patients were included, and two radiologists, by consensus, assessed the presence of focal lesions, interruption of the main pancreatic duct (MPD), MPD dilatation, and pancreatitis, volume doubling time (VDT) of PDAC on prediagnostic MR imaging. Two other observers independently reviewed three image sets (CT images, unenhanced MR images, and unenhanced and contrast-enhanced MR images) for the detection of early PDAC. Paired Wilcoxon signed rank test and receiver operating characteristic (ROC) curve analysis were used for statistical analyses. Results: In 20 (90.9%) patients, prediagnostic MR exams showed abnormality, and all of them showed focal lesions on the first abnormal prediagnostic MR exams. Thirteen lesions (65%) showed no MPD interruption and one lesion (5%) was accompanied by pancreatitis. The mean VDT of PDAC was 151.7 days (range, 18.3–417.8 days). Diagnostic performance of unenhanced MR images (Az, 0.971–0.989) and combined unenhanced and contrast-enhanced MR images (Az, 0.956–0.963) was significantly better than that of CT images (Az, 0.565–0.583; p < 0.01) for both observers, Conclusion: The most common early imaging finding of PDAC on prediagnostic MR exams was a focal lesion with no MPD interruption with a mean volume doubling time of five months. MR imaging was superior to CT for the detection of early PDAC.

  18. Aberrant overexpression of vascular endothelial growth factor in pancreatic ductal adenocarcinoma is associated with aggressive clinical behavior

    Directory of Open Access Journals (Sweden)

    Naomi Y Jiang

    2010-07-01

    Full Text Available Naomi Y Jiang1, Bruce A Woda2, Liping Zhang2, Suyang Hao2, Karen A Dresser2, Di Lu21Massachusetts Institute of Technology, Worcester, MA, USA; 2Department of Pathology, University of Massachusetts Medical Center, Worcester, MA, USAAbstract: Pancreatic adenocarcinoma is a leading cause of cancer-related deaths in the United States. In this study, we studied vascular endothelial growth factor (VEGF expression in ­pancreatic adenocarcinoma by immunohistochemical staining. Clinical follow-up and survival data were analyzed. We determined that VEGF was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. Statistically, VEGF overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.012, and P < 0.005, respectively. Additionally, patients of this subset had a much shorter overall survival than patients without VEGF overexpression, as evidenced by Kaplan–Meier plots and the log-rank test (P = 0.001. The 5-year overall survival rate was 17% in patients with VEGF overexpression compared to 52% in patients without VEGF overexpression. The median survival was only 13 months for patients with VEGF overexpression compared to 65 months for patients without. In conclusion, VEGF is a biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior.Keywords: pancreatic adenocarcinoma, VEGF, cancer

  19. Celecoxib suppresses fibroblast growth factor-2 expression in pancreatic ductal adenocarcinoma PANC-1 cells.

    Science.gov (United States)

    Li, Jing; Luo, Miaosha; Wang, Yan; Shang, Boxin; Dong, Lei

    2016-09-01

    The inhibition of cyclooxygenase (COX)-2 has been reported to suppress growth and induce apoptosis in human pancreatic cancer cells. Nevertheless, the precise biological mechanism of how celecoxib, a selective COX-2 inhibitor, regulates the growth and invasion of pancreatic tumors is not completely understood. It has been shown that fibroblast growth factor-2 (FGF-2) and its receptor levels correlate with the inhibition of cancer cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of the present study was to examine the hypothesis that the antitumor activity of celecoxib in PDAC may be exerted through modulation of FGF-2 function. In the present study, we evaluated the effects of celecoxib on the proliferation, migration, invasion and apoptosis of the PANC-1 cell line. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of FGF-2, FGFR-2, ERK1/2 and MMPs. In the present study, FGF-2 and FGFR-2 were expressed in PANC-1 cells and FGF-2 exerted a stimulatory effect on phosphorylated extracellular signal regulated kinase (p-ERK) expression. Celecoxib treatment suppressed FGF-2 and FGFR-2 expression and decreased MMP-2, MMP-9 and p-ERK expression in the PANC-1 cells. Furthermore, celecoxib treatment caused the resistance of PANC-1 cells to FGF-2 induced proliferation, migration and invasion ability, as well as the increase in their apoptotic rate. Our data provide evidence that targeting FGF-2 with celecoxib may be used as an effective treatment in PDAC.

  20. A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma.

    OpenAIRE

    Jeran K Stratford; David J Bentrem; Judy M Anderson; Cheng Fan; Keith A Volmar; J S Marron; Elizabeth D Routh; Laura S Caskey; Jonathan C Samuel; Channing J Der; Leigh B Thorne; Benjamin F Calvo; Hong Jin Kim; Mark S Talamonti; Christine A Iacobuzio-Donahue

    2010-01-01

    Editors' Summary Background Pancreatic cancer kills nearly a quarter of a million people every year. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin, which controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). Nearly all pancreatic cancers are “pancreatic ductal adenocarcinomas” (PDACs)—tumors that start in the cells that line ...

  1. Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Zou, Qiong; Yang, Zhulin; Li, Daiqiang; Liu, Ziru; Yuan, Yuan

    2016-12-01

    Pancreatic cancer is the fourth most common cause of cancer-related mortality. Novel molecular biomarkers need to be identified for personalized medicine and to improve survival. The aim of this study was to examine chloride intracellular channel 4 (CLIC4) and Indian Hedgehog (Ihh) expression in benign and malignant lesions of the pancreas and to examine the eventual association between CLIC4 and Ihh expression, with clinicopathological features and prognosis of pancreatic cancer. A retrospective study of specimens collected from January 2000 to December 2011 at the Department of Pathology of the Second and Third Xiangya Hospitals, Central South University was undertaken to explore this question. Immunohistochemistry of CLIC4 and Ihh was performed with EnVision ™ in 106 pancreatic ductal adenocarcinoma specimens, 35 paracancer samples (2 cm away from the tumour, when possible or available), 55 benign lesions and 13 normal tissue samples. CLIC4 and Ihh expression in pancreatic ductal adenocarcinoma were significantly higher than in paracancer tissue and benign lesions (CLIC4: P = 0.009 and Ihh: P Ihh: P = 0.0001 respectively). CLIC4 and Ihh expression was negative in normal pancreatic tissues. The expression of CLIC4 and Ihh was associated significantly with tumour grade, lymph node metastasis, tumour invasion and poor overall survival. Thus CLIC4 and Ihh could serve as biological markers for the progression, metastasis and/or invasiveness of pancreatic ductal adenocarcinoma. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

  2. Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size: Positive Implications for Future Targeted Screening.

    Science.gov (United States)

    Hur, Chin; Tramontano, Angela C; Dowling, Emily C; Brooks, Gabriel A; Jeon, Alvin; Brugge, William R; Gazelle, G Scott; Kong, Chung Yin; Pandharipande, Pari V

    2016-08-01

    Pancreatic ductal adenocarcinoma (PDAC) has not experienced a meaningful mortality improvement for the past few decades. Successful screening is difficult to accomplish because most PDACs present late in their natural history, and current interventions have not provided significant benefit. Our goal was to identify determinants of survival for early PDAC to help inform future screening strategies. Early PDACs from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database (2000-2010) were analyzed. We stratified by size and included carcinomas in situ (Tis). Overall cancer-specific survival was calculated. A Cox proportional hazards model was developed and the significance of key covariates for survival prediction was evaluated. A Kaplan-Meier plot demonstrated significant differences in survival by size at diagnosis; these survival benefits persisted after adjustment for key covariates in the Cox proportional hazards analysis. In addition, relatively weaker predictors of worse survival included older age, male sex, black race, nodal involvement, tumor location within the head of the pancreas, and no surgery or radiotherapy. For early PDAC, we found tumor size to be the strongest predictor of survival, even after adjustment for other patient characteristics. Our findings suggest that early PDAC detection can have clinical benefit, which has positive implications for future screening strategies.

  3. Chemotherapy and Radiofrequency-Induced Mild Hyperthermia Combined Treatment of Orthotopic Pancreatic Ductal Adenocarcinoma Xenografts.

    Science.gov (United States)

    Krzykawska-Serda, Martyna; Agha, Mahdi S; Ho, Jason Chak-Shing; Ware, Matthew J; Law, Justin J; Newton, Jared M; Nguyen, Lam; Curley, Steven A; Corr, Stuart J

    2018-04-02

    Patients with pancreatic ductal adenocarcinomas (PDAC) have one of the poorest survival rates of all cancers. The main reason for this is related to the unique tumor stroma and poor vascularization of PDAC. As a consequence, chemotherapeutic drugs, such as nab-paclitaxel and gemcitabine, cannot efficiently penetrate into the tumor tissue. Non-invasive radiofrequency (RF) mild hyperthermia treatment was proposed as a synergistic therapy to enhance drug uptake into the tumor by increasing tumor vascular inflow and perfusion, thus, increasing the effect of chemotherapy. RF-induced hyperthermia is a safer and non-invasive technique of tumor heating compared to conventional contact heating procedures. In this study, we investigated the short- and long-term effects (~20 days and 65 days, respectively) of combination chemotherapy and RF hyperthermia in an orthotopic PDAC model in mice. The benefit of nab-paclitaxel and gemcitabine treatment was confirmed in mice; however, the effect of treatment was statistically insignificant in comparison to saline treated mice during long-term observation. The benefit of RF was minimal in the short-term and completely insignificant during long-term observation. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  4. ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage.

    Science.gov (United States)

    Perkhofer, Lukas; Schmitt, Anna; Romero Carrasco, Maria Carolina; Ihle, Michaela; Hampp, Stephanie; Ruess, Dietrich Alexander; Hessmann, Elisabeth; Russell, Ronan; Lechel, André; Azoitei, Ninel; Lin, Qiong; Liebau, Stefan; Hohwieler, Meike; Bohnenberger, Hanibal; Lesina, Marina; Algül, Hana; Gieldon, Laura; Schröck, Evelin; Gaedcke, Jochen; Wagner, Martin; Wiesmüller, Lisa; Sipos, Bence; Seufferlein, Thomas; Reinhardt, Hans Christian; Frappart, Pierre-Olivier; Kleger, Alexander

    2017-10-15

    Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576-90. ©2017 AACR . ©2017 American Association for Cancer Research.

  5. Second pancreatectomy for recurrent pancreatic ductal adenocarcinoma in the remnant pancreas: A pooled analysis.

    Science.gov (United States)

    Zhou, Yanming; Song, Ailing; Wu, Lupeng; Si, Xiaoying; Li, Yumin

    The aim of this study was to examine the outcomes of second pancreatectomy for the treatment of recurrent pancreatic ductal adenocarcinoma (PDAC) in the remnant pancreas. Search of the PubMed database was undertaken to identify relevant English language studies. Pooled individually data were examined for clinical outcomes after second pancreatectomy for recurrent PDAC. A total of 19 articles involving 55 patients were eligible for inclusion. The median disease-free interval after initial resection was 33 (range 7-143) months. Of the 55 patients reported, 52 (94.5%) patients underwent completion total pancreatectomy in the second operation for recurrences, including 15 patients who developed recurrences more than 5 years after the initial operation. There was no perioperative death. The 1-, 3- and 5-year overall survival rate after the second pancreatectomy was 82.2%, 49.2% and 40.6% respectively. Second pancreatectomy for recurrent PDAC can be performed safely with long-term survival in selected patients. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  6. The adaptor protein CrkII regulates IGF-1-induced biological behaviors of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Liu, Rui; Wang, Qing; Xu, Guangying; Li, Kexin; Zhou, Lingli; Xu, Baofeng

    2016-01-01

    Recently, the adaptor protein CrkII has been proved to function in initiating signals for proliferation and invasion in some malignancies. However, the specific mechanisms underlying insulin-like growth factor 1 (IGF-1)-CrkII signaling-induced proliferation of pancreatic ductal adenocarcinoma (PDAC) were not unraveled. In this work, PDAC tissues and cell lines were subjected to in vitro and in vivo assays. Our findings showed that CrkII was abundantly expressed in PDAC tissues and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When cells were subjected to si-CrkII, si-CrkII inhibited IGF-1-mediated PDAC cell growth. In vitro, we demonstrated the upregulation of CrkII, p-Erk1/2, and p-Akt occurring in IGF-1-treated PDAC cells. Conversely, si-CrkII affected upregulation of CrkII, p-Erk1/2, and p-Akt. In addition, cell cycle and in vivo assay identified that knockdown of CrkII inhibited the entry of G1 into S phase and the increase of PDAC tumor weight. In conclusion, CrkII mediates IGF-1 signaling and further balanced PDAC biological behaviors via Erk1/2 and Akt pathway, which indicates that CrkII gene and protein may act as an effective target for the treatment of PDAC.

  7. Low Expression of TBX4 Predicts Poor Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

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    Meijuan Zong

    2011-08-01

    Full Text Available This study was designed to investigate the expression of the T-box transcription factor 4 (TBX4, a tumor biomarker that was previously identified by proteomics, in pancreatic ductal adenocarcinoma (PDAC and evaluate its clinical utility as a potential prognostic biomarkers for PDAC. The expression of TBX4 was detected in 77 stage II PDAC tumors by immunohistochemistry, and the results were analyzed with regard to clinicopathological characteristics and overall survival. Moreover, Tbx4 promoter methylation status in primary PDAC tumors and normal adjacent pancreas tissues was measured by bisulfite sequencing. Among 77 stage II PDAC tumors, 48 cases (62.3% expressed TBX4 at a high level. No significant correlation between TBX4 expression and other clinicopathological parameters, except tumor grade and liver metastasis recurrence, was found. The survival of patients with TBX4-high expression was significantly longer than those with TBX4-low expression (P = 0.010. In multivariate analysis, low TBX4 expression was an independent prognostic factor for overall survival in patients with stage II PDAC. TBX4 promoter methylation status was frequently observed in both PDAC and normal adjacent pancreas. We conclude that a low level of TBX4 expression suggests a worse prognosis for patients with stage II PDAC. Down-regulation of the TBX4 gene in pancreas is less likely to be regulated by DNA methylation.

  8. Use of imaging during symptomatic follow-up after resection of pancreatic ductal adenocarcinoma.

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    Groot, Vincent P; Daamen, Lois A; Hagendoorn, Jeroen; Borel Rinkes, Inne H M; van Santvoort, Hjalmar C; Molenaar, I Quintus

    2018-01-01

    Controversy exists whether follow-up after resection of pancreatic ductal adenocarcinoma (PDAC) should include standardized imaging for the detection of disease recurrence. The purpose of this study was to evaluate how often patients undergo imaging in a setting where routine imaging is not performed. Secondly, the pattern, timing, and treatment of recurrent PDAC were assessed. This was a post hoc analysis of a prospective database of all consecutive patients undergoing pancreatic resection of PDAC between January 2011 and January 2015. Data on imaging procedures during follow-up, recurrence location, and treatment for recurrence were extracted and analyzed. Associations between clinical characteristics and post-recurrence survival were assessed with the log-rank test and Cox univariable and multivariable proportional hazards models. A total of 85 patients were included. Seventy-four patients (87%) underwent imaging procedures during follow-up at least once, with a mean amount of 3.1 ± 1.9 imaging procedures during the entire follow-up period. Sixty-eight patients (80%) were diagnosed with recurrence, 58 (85%) of whom after the manifestation of clinical symptoms. Additional tumor-specific treatment was administered in 17 of 68 patients (25%) with recurrence. Patients with isolated local recurrence, treatment after recurrence, and a recurrence-free survival >10 mo had longer post-recurrence survival. Even though a symptomatic follow-up strategy does not include routine imaging, the majority of patients with resected PDAC underwent additional imaging procedures during their follow-up period. Further prospective studies are needed to determine the actual clinical value, psychosocial implications, and cost-effectiveness of different forms of follow-up after resection of PDAC. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Survival Prediction in Pancreatic Ductal Adenocarcinoma by Quantitative Computed Tomography Image Analysis.

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    Attiyeh, Marc A; Chakraborty, Jayasree; Doussot, Alexandre; Langdon-Embry, Liana; Mainarich, Shiana; Gönen, Mithat; Balachandran, Vinod P; D'Angelica, Michael I; DeMatteo, Ronald P; Jarnagin, William R; Kingham, T Peter; Allen, Peter J; Simpson, Amber L; Do, Richard K

    2018-04-01

    Pancreatic cancer is a highly lethal cancer with no established a priori markers of survival. Existing nomograms rely mainly on post-resection data and are of limited utility in directing surgical management. This study investigated the use of quantitative computed tomography (CT) features to preoperatively assess survival for pancreatic ductal adenocarcinoma (PDAC) patients. A prospectively maintained database identified consecutive chemotherapy-naive patients with CT angiography and resected PDAC between 2009 and 2012. Variation in CT enhancement patterns was extracted from the tumor region using texture analysis, a quantitative image analysis tool previously described in the literature. Two continuous survival models were constructed, with 70% of the data (training set) using Cox regression, first based only on preoperative serum cancer antigen (CA) 19-9 levels and image features (model A), and then on CA19-9, image features, and the Brennan score (composite pathology score; model B). The remaining 30% of the data (test set) were reserved for independent validation. A total of 161 patients were included in the analysis. Training and test sets contained 113 and 48 patients, respectively. Quantitative image features combined with CA19-9 achieved a c-index of 0.69 [integrated Brier score (IBS) 0.224] on the test data, while combining CA19-9, imaging, and the Brennan score achieved a c-index of 0.74 (IBS 0.200) on the test data. We present two continuous survival prediction models for resected PDAC patients. Quantitative analysis of CT texture features is associated with overall survival. Further work includes applying the model to an external dataset to increase the sample size for training and to determine its applicability.

  10. Associations between ABO blood groups and pancreatic ductal adenocarcinoma: influence on resection status and survival.

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    El Jellas, Khadija; Hoem, Dag; Hagen, Kristin G; Kalvenes, May Britt; Aziz, Sura; Steine, Solrun J; Immervoll, Heike; Johansson, Stefan; Molven, Anders

    2017-07-01

    Both serology-based and genetic studies have reported an association between pancreatic cancer risk and ABO blood groups. We have investigated this relationship in a cohort of pancreatic cancer patients from Western Norway (n = 237) and two control materials (healthy blood donors, n = 379; unselected hospitalized patients, n = 6149). When comparing patient and blood donor ABO allele frequencies, we found only the A 1 allele to be associated with significantly higher risk for pancreatic ductal adenocarcinoma (PDAC) (23.8% vs. 17.9%; OR = 1.43, P = 0.018). Analyzing phenotypes, blood group A was more frequent among PDAC cases than blood donors (50.8% vs. 40.6%; OR = 1.51, P = 0.021), an enrichment fully explained by the A 1 subgroup. Blood group O frequency was lower in cases than in blood donors (33.8% vs. 42.7%; OR = 0.69, P = 0.039). This lower frequency was confirmed when cases were compared to hospitalized patients (33.8% vs. 42.9%; OR = 0.68, P = 0.012). Results for blood group B varied according to which control cohort was used for comparison. When patients were classified according to surgical treatment, the enrichment of blood group A was most prominent among unresected cases (54.0%), who also had the lowest prevalence of O (28.7%). There was a statistically significant better survival (P = 0.04) for blood group O cases than non-O cases among unresected but not among resected patients. Secretor status did not show an association with PDAC or survival. Our study demonstrates that pancreatic cancer risk is influenced by ABO status, in particular blood groups O and A 1 , and that this association may reflect also in tumor resectability and survival. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  11. Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.

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    He, Ping; Yang, Jong Won; Yang, Vincent W; Bialkowska, Agnieszka B

    2018-04-01

    Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs. We performed studies in adult mice with conditional disruption of Klf5 (Klf5 fl/fl ) and/or expression of Kras G12D (LSL-Kras G12D ) via Cre ERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of Kras G12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-Kras G12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed. Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre ERTM ;LSL-Kras G12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-Cre ERTM ;LSL-Kras G12D ;Klf5 fl

  12. Texture analysis for survival prediction of pancreatic ductal adenocarcinoma patients with neoadjuvant chemotherapy

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    Chakraborty, Jayasree; Langdon-Embry, Liana; Escalon, Joanna G.; Allen, Peter J.; Lowery, Maeve A.; O'Reilly, Eileen M.; Do, Richard K. G.; Simpson, Amber L.

    2016-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States. The five-year survival rate for all stages is approximately 6%, and approximately 2% when presenting with distant disease.1 Only 10-20% of all patients present with resectable disease, but recurrence rates are high with only 5 to 15% remaining free of disease at 5 years. At this time, we are unable to distinguish between resectable PDAC patients with occult metastatic disease from those with potentially curable disease. Early classification of these tumor types may eventually lead to changes in initial management including the use of neoadjuvant chemotherapy or radiation, or in the choice of postoperative adjuvant treatments. Texture analysis is an emerging methodology in oncologic imaging for quantitatively assessing tumor heterogeneity that could potentially aid in the stratification of these patients. The present study derives several texture-based features from CT images of PDAC patients, acquired prior to neoadjuvant chemotherapy, and analyzes their performance, individually as well as in combination, as prognostic markers. A fuzzy minimum redundancy maximum relevance method with leave-one-image-out technique is included to select discriminating features from the set of extracted features. With a naive Bayes classifier, the proposed method predicts the 5-year overall survival of PDAC patients prior to neoadjuvant therapy and achieves the best results in terms of the area under the receiver operating characteristic curve of 0:858 and accuracy of 83:0% with four-fold cross-validation techniques.

  13. Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    DuFort, Christopher C; DelGiorno, Kathleen E; Hingorani, Sunil R

    2016-06-01

    The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  14. Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges.

    Science.gov (United States)

    Root, Alex; Allen, Peter; Tempst, Paul; Yu, Kenneth

    2018-03-07

    Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary

  15. Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges

    Directory of Open Access Journals (Sweden)

    Alex Root

    2018-03-01

    Full Text Available Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but

  16. SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression.

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    Chuntao Gao

    Full Text Available Stem cell factor (SCF and hypoxia-inducible factor-1α (HIF-1α both have important functions in pancreatic ductal adenocarcinoma (PDAC. This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05. Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

  17. Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma: A retrospective cohort study.

    Science.gov (United States)

    Ninomiya, Go; Fujii, Tsutomu; Yamada, Suguru; Yabusaki, Norimitsu; Suzuki, Kojiro; Iwata, Naoki; Kanda, Mitsuro; Hayashi, Masamichi; Tanaka, Chie; Nakayama, Goro; Sugimoto, Hiroyuki; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

    2017-03-01

    To investigate the impact of the body composition such as skeletal muscle, visceral fat and body mass index (BMI) on patients with resected pancreatic ductal adenocarcinoma (PDAC). A total of 265 patients who underwent curative surgery for PDAC were examined in this study. The total skeletal muscle and fat tissue areas were evaluated in a single image obtained at the third lumber vertebra during a preoperative computed tomography (CT) scan. The patients were assigned to either the sarcopenia or non-sarcopenia group based on their skeletal muscle index (SMI) and classified into high visceral fat area (H-VFA) or low VFA (L-VFA) groups. The association of clinicopathological features and prognosis with the body composition were statistically analyzed. There were 170 patients (64.2%) with sarcopenia. The median survival time (MST) was 23.7 months for sarcopenia patients and 25.8 months for patients without sarcopenia. The MST was 24.4 months for H-VFA patients and 25.8 months for L-VFA patients. However, sarcopenia patients with BMI ≥22 exhibited significantly poorer survival than patients without sarcopenia (MST: 19.2 vs. 35.4 months, P = 0.025). There was a significant difference between patients with and without sarcopenia who did not receive chemotherapy (5-year survival rate: 0% vs. 68.3%, P = 0.003). The multivariate analysis revealed that tumor size, positive dissected peripancreatic tissue margin, and sarcopenia were independent prognostic factors. Sarcopenia is an independent prognostic factor in PDAC patients with a BMI ≥22. Therefore, evaluating skeletal muscle mass may be a simple and useful approach for predicting patient prognosis. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  18. Intratumoral heterogeneity of 18F-FDG uptake predicts survival in patients with pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Hyun, Seung Hyup; Kim, Ho Seong; Lee, Kyung-Han; Kim, Byung-Tae; Choi, Joon Young; Choi, Seong Ho; Choi, Dong Wook; Lee, Jong Kyun; Lee, Kwang Hyuck; Park, Joon Oh

    2016-01-01

    To assess whether intratumoral heterogeneity measured by 18 F-FDG PET texture analysis has potential as a prognostic imaging biomarker in patients with pancreatic ductal adenocarcinoma (PDAC). We evaluated a cohort of 137 patients with newly diagnosed PDAC who underwent pretreatment 18 F-FDG PET/CT from January 2008 to December 2010. First-order (histogram indices) and higher-order (grey-level run length, difference, size zone matrices) textural features of primary tumours were extracted by PET texture analysis. Conventional PET parameters including metabolic tumour volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) were also measured. To assess and compare the predictive performance of imaging biomarkers, time-dependent receiver operating characteristic (ROC) curves for censored survival data and areas under the ROC curve (AUC) at 2 years after diagnosis were used. Associations between imaging biomarkers and overall survival were assessed using Cox proportional hazards regression models. The best imaging biomarker for overall survival prediction was first-order entropy (AUC = 0.720), followed by TLG (AUC = 0.697), MTV (AUC = 0.692), and maximum SUV (AUC = 0.625). After adjusting for age, sex, clinical stage, tumour size and serum CA19-9 level, multivariable Cox analysis demonstrated that higher entropy (hazard ratio, HR, 5.59; P = 0.028) was independently associated with worse survival, whereas TLG (HR 0.98; P = 0.875) was not an independent prognostic factor. Intratumoral heterogeneity of 18 F-FDG uptake measured by PET texture analysis is an independent predictor of survival along with tumour stage and serum CA19-9 level in patients with PDAC. In addition, first-order entropy as a measure of intratumoral metabolic heterogeneity is a better quantitative imaging biomarker of prognosis than conventional PET parameters. (orig.)

  19. A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma.

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    Jeran K Stratford

    2010-07-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7-10.0. Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets. Please see later in the article for the Editors' Summary.

  20. Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

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    Kapo Saukkonen

    Full Text Available Podocalyxin-like 1 is a transmembrane glyco-protein whose overexpression associates in many cancers with poor prognosis and unfavorable clinicopathological characteristics. Until now, its prognostic value has never been studied in pancreatic ductal adenocarcinoma (PDAC. The aim of this study was to investigate podocalyxin expression in PDAC by a novel monoclonal antibody and a commercially available polyclonal antibody.With tissue microarrays and immuno-histochemistry, podocalyxin expression evaluation involved 168 PDAC patients. The associations of the podocalyxin tumor expression with clinicopathological variables were explored by Fisher's exact test and the linear-by-linear test. Survival analyses were by Kaplan-Meier analysis and the Cox proportional hazard model.The polyclonal antibody revealed membranous podocalyxin expression in 73 (44.0% specimens and the monoclonal antibody was highly expressed in 36 (21.8% cases. Membranous expression by the polyclonal antibody was associated with T classification (p=0.045 and perineural invasion (p=0.005, and high expression by the mono-clonal antibody with poor differentiation (p=0.033. High podocalyxin expression associated significantly with higher risk of death from PDAC by both the polyclonal antibody (hazard ratio (HR = 1.62; 95% confidence interval (CI 1.12-2.33; p=0.01 and the monoclonal antibody (HR = 2.10, 95% CI 1.38-3.20; p<0.001. The results remained significant in multivariate analysis, adjusted for age, gender, stage, lymph node ratio (≥/< 20%, and perivascular invasion (respectively as HR = 2.03; 95% CI 1.32-3.13, p=0.001; and as HR = 2.36; 95% CI 1.47-3.80, p<0.001.We found podocalyxin to be an independent factor for poor prognosis in PDAC. To our knowledge, this is the first such report of its prognostic value.

  1. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017.

    Science.gov (United States)

    Isaji, Shuji; Mizuno, Shugo; Windsor, John A; Bassi, Claudio; Fernández-Del Castillo, Carlos; Hackert, Thilo; Hayasaki, Aoi; Katz, Matthew H G; Kim, Sun-Whe; Kishiwada, Masashi; Kitagawa, Hirohisa; Michalski, Christoph W; Wolfgang, Christopher L

    2018-01-01

    This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight

  2. X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

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    Arne Tapfer

    Full Text Available To explore the potential of grating-based x-ray phase-contrast computed tomography (CT for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i high-resolution synchrotron radiation (SR imaging and ii dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i high-performance imaging for virtual microscopy applications and ii biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR of selected regions of interest (ROI in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

  3. SMAD4 Loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells

    International Nuclear Information System (INIS)

    Chen, Yu-Wen; Hsiao, Pi-Jung; Weng, Ching-Chieh; Kuo, Kung-Kai; Kuo, Tzu-Lei; Wu, Deng-Chyang; Hung, Wen-Chun; Cheng, Kuang-Hung

    2014-01-01

    SMAD4 is a gastrointestinal malignancy-specific tumor suppressor gene found mutated in one third of colorectal cancer specimens and half of pancreatic tumors. SMAD4 inactivation by allelic deletion or intragenic mutation mainly occurs in the late stage of human pancreatic ductal adenocarcinoma (PDAC). Various studies have proposed potential SMAD4-mediated anti-tumor effects in human malignancy; however, the relevance of SMAD4 in the PDAC molecular phenotype has not yet been fully characterized. The AsPC-1, CFPAC-1 and PANC-1 human PDAC cell lines were used. The restoration or knockdown of SMAD4 expression in PDAC cells were confirmed by western blotting, luciferase reporter and immunofluorescence assays. In vitro cell proliferation, xenograft, wound healing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry analysis were conducted using PDAC cells in which SMAD4 was either overexpressed or knocked down. Here, we report that re-expression of SMAD4 in SMAD4-null PDAC cells does not affect tumor cell growth in vitro or in vivo, but significantly enhances cells migration in vitro. SMAD4 restoration transcriptionally activates the TGF-β1/Nestin pathway and induces expression of several transcriptional factors. In contrast, SMAD4 loss in PDAC leads to increased expression of E-cadherin, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and CD133. Furthermore, SMAD4 loss causes alterations to multiple kinase pathways (particularly the phosphorylated ERK/p38/Akt pathways), and increases chemoresistance in vitro. Finally, PDAC cells with intact SMAD4 are more sensitive to TGF-β1 inhibitor treatment to reduced cell migration; PDAC cells lacking SMAD4 showed decreased cell motility in response to EGFR inhibitor treatment. This study revealed the molecular basis for SMAD4-dependent differences in PDAC with the aim of identifying the subset of patients likely to respond to

  4. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells.

    Science.gov (United States)

    Chen, Yu-Wen; Hsiao, Pi-Jung; Weng, Ching-Chieh; Kuo, Kung-Kai; Kuo, Tzu-Lei; Wu, Deng-Chyang; Hung, Wen-Chun; Cheng, Kuang-Hung

    2014-03-14

    SMAD4 is a gastrointestinal malignancy-specific tumor suppressor gene found mutated in one third of colorectal cancer specimens and half of pancreatic tumors. SMAD4 inactivation by allelic deletion or intragenic mutation mainly occurs in the late stage of human pancreatic ductal adenocarcinoma (PDAC). Various studies have proposed potential SMAD4-mediated anti-tumor effects in human malignancy; however, the relevance of SMAD4 in the PDAC molecular phenotype has not yet been fully characterized. The AsPC-1, CFPAC-1 and PANC-1 human PDAC cell lines were used. The restoration or knockdown of SMAD4 expression in PDAC cells were confirmed by western blotting, luciferase reporter and immunofluorescence assays. In vitro cell proliferation, xenograft, wound healing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry analysis were conducted using PDAC cells in which SMAD4 was either overexpressed or knocked down. Here, we report that re-expression of SMAD4 in SMAD4-null PDAC cells does not affect tumor cell growth in vitro or in vivo, but significantly enhances cells migration in vitro. SMAD4 restoration transcriptionally activates the TGF-β1/Nestin pathway and induces expression of several transcriptional factors. In contrast, SMAD4 loss in PDAC leads to increased expression of E-cadherin, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and CD133. Furthermore, SMAD4 loss causes alterations to multiple kinase pathways (particularly the phosphorylated ERK/p38/Akt pathways), and increases chemoresistance in vitro. Finally, PDAC cells with intact SMAD4 are more sensitive to TGF-β1 inhibitor treatment to reduced cell migration; PDAC cells lacking SMAD4 showed decreased cell motility in response to EGFR inhibitor treatment. This study revealed the molecular basis for SMAD4-dependent differences in PDAC with the aim of identifying the subset of patients likely to respond to

  5. Coexpression of EGFR and CXCR4 predicts poor prognosis in resected pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Huanwen Wu

    Full Text Available Epidermal growth factor receptor (EGFR is highly expressed in pancreatic ductal adenocarcinoma (PDAC and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.In the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.In total, 64 (48.9% patients expressed EGFR, 68 (51.9% expressed CXCR4, and 33 (25.2% coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938. EGFR expression significantly correlated with tumor differentiation (P = 0.031, whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001. EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026, TNM stage (P = 0.048, and poor tumor differentiation (P = 0.004. By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS and overall survival (OS. Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001 and OS (HR = 2.48, P = 0.001.In conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse

  6. Long-term survival with repeat resection for lung oligometastasis from pancreatic ductal adenocarcinoma: a case report.

    Science.gov (United States)

    Matsuki, Ryota; Sugiyama, Masanori; Takei, Hidefumi; Kondo, Haruhiko; Fujiwara, Masachika; Shibahara, Junji; Furuse, Junji

    2018-03-27

    Long-term survival after resection of metastases from pancreatic ductal adenocarcinoma is rare. A 54-year-old man underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) with UICC staging pT3N1M0 followed by adjuvant chemotherapy with gemcitabine (GEM). Three years after radical resection of the primary tumor, a tiny nodule was found in the lower lobe of the left lung. Despite treatment with GEM, it increased gradually, but no other metastases were found. Eighteen months after the first indication of the nodule, wedge resection was performed. Pathological examination of the nodule indicated a metastatic tumor from PDAC. Pulmonary metastasectomy was again performed for lung oligometastases at 77 and 101 months after PD. The patient has been asymptomatic without tumor recurrence for 4 years since the last pulmonary resection. In PDAC, the treatment strategy for oligometastasis is controversial. However, a few cases of long-term survival after pulmonary metastasectomy for oligometastasis of PDAC have been reported. More such cases need to be studied to address this issue effectively.

  7. Imaging study of pancreatic ductal adenocarcinomas in Syrian hamsters using X-ray micro-computed tomography (CT)

    International Nuclear Information System (INIS)

    Kitahashi, Tsukasa; Mutoh, Michihiro; Tsurusaki, Masakatsu

    2010-01-01

    X-ray computed tomography (CT) has been used for diagnoses of human pancreatic cancer. Although micro-CT is a useful approach to evaluate macromorphology of organs/tissue also in animal models, reports on pancreatic tumors are limited. In this study, the utility of micro-CT was assessed in characterizing chemically induced pancreatic tumors in Syrian hamsters. Hamsters treated with or without N-nitrosobis(2-oxopropyl)amine (BOP) were injected with the antispasmodic agent, scopolamine butylbromide, and contrast agents, 5 or 10 mL/kg body weight of iopamidol or Fenestra VC at 18-38 weeks, then examined by micro-CT scanning with a respiratory gating system. Both peristaltic and respiratory movements were substantially suppressed by the combination of scopolamine butylbromide treatment and the respiratory gating system, resulting in improvements of image qualities. Iopamidol clearly visualized the pancreatic parenchyma and contrasted the margins among the pancreas and other abdominal organs/tissue. Meanwhile Fenestra VC predominantly contrasted abdominal vascular systems, but the margins among pancreas and other organs/tissue remained obscure. Six pancreatic tumors of 4-13 mm in diameter were detected in four of 15 animals, but not the five tumors of 1-4 mm in diameter. The inner tumor images were heterogeneously or uniformly visualized by iopamidol and Fenestra VC. Overall, iopamidol could clearly contrast between pancreatic parenchyma and the tumors as compared with Fenestra VC. All tumors confirmed were histopathologically diagnosed as pancreatic ductal adenocarcinomas. Thus, micro-CT could be useful to evaluate the carcinogenic processes and preventive methods of pancreatic cancer in hamsters and to assess the novel contrast agents for detection of small pancreatic cancer in humans. (author)

  8. Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 have a profound defect in tumor growth and metastasis

    Science.gov (United States)

    Besmer, Dahlia M.; Curry, Jennifer M.; Roy, Lopamudra D.; Tinder, Teresa L.; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y.; Gendler, Sandra J.; Mukherjee, Pinku

    2011-01-01

    MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared to both KC and KCM. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9). Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

  9. Diagnostic value of curved multiplanar reformatted images in multislice CT for the detection of resectable pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Fukushima, Hiromichi; Takada, Akira; Mori, Yoshimi; Suzuki, Kojiro; Sawaki, Akiko; Iwano, Shingo; Satake, Hiroko; Ota, Toyohiro; Ishigaki, Takeo; Itoh, Shigeki; Ikeda, Mitsuru

    2006-01-01

    The purpose of this study was to assess the usefulness of curved multiplanar reformatted (MPR) images obtained by multislice CT for the depiction of the main pancreatic duct (MPD) and detection of resectable pancreatic ductal adenocarcinoma. This study included 28 patients with pancreatic carcinoma (size range 12-40 mm) and 22 without. Curved MPR images with 0.5-mm continuous slices were generated along the long axis of the pancreas from pancreatic-phase images with a 0.5- or 1-mm slice thickness. Seven blinded readers independently interpreted three sets of images (axial images, curved MPR images, and both axial and curved MPR images) in scrolling mode. The depiction of the MPD and the diagnostic performance for the detection of carcinoma were statistically compared among these images. MPR images were significantly superior to axial images in depicting the MPD, and the use of both axial and MPR images resulted in further significant improvements. For the detection of carcinoma, MPR images were equivalent to axial images, and the diagnostic performance was significantly improved by the use of both axial and MPR images. High-resolution curved MPR images can improve the depiction of the MPD and the diagnostic performance for the detection of carcinoma compared with axial images alone. (orig.)

  10. Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells

    DEFF Research Database (Denmark)

    Kong, Su Chii; Nøhr-Nielsen, Asbjørn; Zeeberg, Katrine

    2016-01-01

    , localization, activity, and function were explored in human PDAC cells (MIAPaCa-2, Panc-1, BxPC-3, AsPC-1) and normal human pancreatic ductal epithelial (HPDE) cells, by quantitative polymerase chain reaction, immunoblotting, immunocytochemistry, lactate flux, migration, and invasion assays. RESULTS: MCT1......, or knockdown of MCT1 or MCT4. PDAC cell migration was largely unaffected by MCT1/MCT2 inhibition or MCT1 knockdown but was reduced by 4-CIN and by MCT4 knockdown (BxPC-3). Invasion measured in Boyden chamber (BxPC-3, Panc-1) and spheroid outgrowth (BxPC-3) assays was attenuated by 4-CIN and AR-C155858...

  11. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    DEFF Research Database (Denmark)

    Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.

    2016-01-01

    by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were......Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop...... stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression...

  12. Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Zhang, Meng; Fan, Hai-Yan; Li, Sheng-Chao

    2015-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a formidable medical challenge due to its malignancies and the absence of effective treatment. c-Myc, as an important transcription factor, plays crucial roles in cell cycle progression, apoptosis and cellular transformation. The c-Myc inhibitor, 10058-F4, has been reported act as a tumor suppressor in several different tumors. In current study, the tumor-suppressive roles of 10058-F4 was observed in human pancreatic cancer cells in vitro as demonstrated by decreased cell viability, cell cycle arrest at the G1/S transition and increased caspase3/7 activity. And tumor responses to gemcitabine were also significantly enhanced by 10058-F4 in PANC-1 and SW1990 cells. In a subcutaneous xenograft model, however, 10058-F4 showed no significant influence on pancreatic tumorigenesis. When combined with gemcitabine, tumorigenesis was drastically attenuated compared with gemcitabine group or 10058-F4 group; this synergistic effect was accompanied with decreased PCNA-positive cells and reduced TUNEL-positive cells in the combined treated group. Subsequent studies revealed that decreased glycolysis may be involved in the inhibitory effect of 10058-F4 on PDAC. Taken together, this study demonstrates the roles of 10058-F4 in PDAC and provides evidence that 10058-F4 in combination with gemcitabine showed significant clinical benefit over the usage of gemcitabine alone. Copyright © 2015. Published by Elsevier Masson SAS.

  13. Overexpression of SOX18 correlates with accelerated cell growth and poor prognosis in human pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Wang, Yazhou; Guo, Huahu; Zhang, Dafang; Yu, Xin; Leng, Xisheng; Li, Shu; Zhu, Weihua

    2016-01-01

    Transcription factor SOX18 has been proved to play a significant role in carcinogenesis. However, no investigation was performed about the expression of SOX18 in pancreatic ductal adenocarcinoma (PDAC). In our work, we found that the PDAC tissues had higher level of SOX18 mRNA and protein expression than matched non-tumor pancreatic tissues and high level of SOX18 protein indicated poor prognosis for PDAC patients. After knockdown of SOX18 gene in PANC-1 and SW1990 cell lines, which showed higher expression level of SOX18 among five PDAC cell lines, the abilities of proliferation, migration and invasion were inhibited and the tumor growth was suppressed in vivo. In addition, the flow cytometry results indicated that down-regulation of SOX18 induced G1/S phase arrest. Furthermore, we found that the expression of cyclin D1, c-myc and MMP-7, three tumorigenesis promoters, was inhabited with downregulation of SOX18. In conclusion, our study reveals that SOX18 plays a significant role in promoting the growth of PDAC, and might serve as a promising target for PDAC therapy. - Highlights: • Overexpression of SOX18 correlates with poor prognosis for pancreatic cancer. • SOX18 promotes pancreatic cancer cell growth in vitro and in vivo. • SOX18 promotes pancreatic cancer cell migration and invasion. • Knockdown of SOX18 induces G1/S phase arrest. • Knockdown of SOX18 induces decrease of cyclin D1, c-myc and MMP-7.

  14. Silver nanoparticles of different sizes induce a mixed type of programmed cell death in human pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Zielinska, Ewelina; Zauszkiewicz-Pawlak, Agata; Wojcik, Michal; Inkielewicz-Stepniak, Iwona

    2018-01-01

    Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison. Our results indicated that AgNPs with size of 2.6 and 18 nm decreased viability, proliferation and caused death of pancreatic cancer cells in a size- and concentration-dependent manner. Ultrastructural analysis identified that cellular uptake of AgNPs resulted in apoptosis, autophagy, necroptosis and mitotic catastrophe. These alterations were associated with increased pro-apoptotic protein Bax and decreased level of anti-apoptotic protein Bcl-2. Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively. In addition, we found that PANC-1 cells were more vulnerable to AgNPs-induced cytotoxicity compared to pancreatic non-tumor cells. In conclusion, AgNPs by inducing mixed type of programmed cell death in PANC-1 cells, could provide a new therapeutic strategy to overcome chemoresistance in one of the deadliest human cancer. PMID:29435134

  15. Role of epithelial mesenchymal transition (EMT in pancreatic ductal adenocarcinoma (PDAC: is tumor budding the missing link?

    Directory of Open Access Journals (Sweden)

    Eva eKaramitopoulou

    2013-09-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is <5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of epithelial-mesenchymal transition (EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

  16. Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Klett, Hagen; Fuellgraf, Hannah; Levit-Zerdoun, Ella; Hussung, Saskia; Kowar, Silke; Küsters, Simon; Bronsert, Peter; Werner, Martin; Wittel, Uwe; Fritsch, Ralph; Busch, Hauke; Boerries, Melanie

    2018-01-01

    Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1) using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5) using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.

  17. Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia

    2016-12-06

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

  18. Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Hagen Klett

    2018-04-01

    Full Text Available Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC. Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1 using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5 using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.

  19. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice.

    Science.gov (United States)

    Philip, Bincy; Roland, Christina L; Daniluk, Jaroslaw; Liu, Yan; Chatterjee, Deyali; Gomez, Sobeyda B; Ji, Baoan; Huang, Haojie; Wang, Huamin; Fleming, Jason B; Logsdon, Craig D; Cruz-Monserrate, Zobeida

    2013-12-01

    Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but it is not clear how obesity contributes to pancreatic carcinogenesis. The oncogenic form of KRAS is expressed during early stages of PDAC development and is detected in almost all of these tumors. However, there is evidence that mutant KRAS requires an additional stimulus to activate its full oncogenic activity and that this stimulus involves the inflammatory response. We investigated whether the inflammation induced by a high-fat diet, and the accompanying up-regulation of cyclooxygenase-2 (COX2), increases Kras activity during pancreatic carcinogenesis in mice. We studied mice with acinar cell-specific expression of KrasG12D (LSL-Kras/Ela-CreERT mice) alone or crossed with COX2 conditional knockout mice (COXKO/LSL-Kras/Ela-CreERT). We also studied LSL-Kras/PDX1-Cre mice. All mice were fed isocaloric diets with different amounts of fat, and a COX2 inhibitor was administered to some LSL-Kras/Ela-CreERT mice. Pancreata were collected from mice and analyzed for Kras activity, levels of phosphorylated extracellular-regulated kinase, inflammation, fibrosis, pancreatic intraepithelial neoplasia (PanIN), and PDACs. Pancreatic tissues from LSL-Kras/Ela-CreERT mice fed high-fat diets (HFDs) had increased Kras activity, fibrotic stroma, and numbers of PanINs and PDACs than LSL-Kras/Ela-CreERT mice fed control diets; the mice fed the HFDs also had shorter survival times than mice fed control diets. Administration of a COX2 inhibitor to LSL-Kras/Ela-CreERT mice prevented these effects of HFDs. We also observed a significant reduction in survival times of mice fed HFDs. COXKO/LSL-Kras/Ela-CreERT mice fed HFDs had no evidence for increased numbers of PanIN lesions, inflammation, or fibrosis, as opposed to the increases observed in LSL-Kras/Ela-CreERT mice fed HFDs. In mice, an HFD can activate oncogenic Kras via COX2, leading to pancreatic inflammation and fibrosis and development of PanINs and PDAC. This

  20. Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients

    International Nuclear Information System (INIS)

    Tian, Mei; Cui, Ya-Zhou; Song, Guan-Hua; Zong, Mei-Juan; Zhou, Xiao-Yan; Chen, Yu; Han, Jin-Xiang

    2008-01-01

    There is an urgent need to discover more sensitive and specific biomarkers to improve early diagnosis and screen high-risk patients for pancreatic ductal adenocarcinoma (PDAC). Pancreatic juice is an ideal specimen for PDAC biomarkers discovery, because it is an exceptionally rich source of proteins released from pancreatic cancer cells. To identify novel potential biomarkers for PDAC from pancreatic juice, we carried out difference gel electrophoresis (DIGE) and tandem mass spectrometry (MS/MS) to compare the pancreatic juice profiling from 9 PDAC patients and 9 cancer-free controls. Of the identified differently expressed proteins, three up-regulated proteins in pancreatic cancer juice, matrix metalloproteinase-9 (MMP-9), oncogene DJ1 (DJ-1) and alpha-1B-glycoprotein precursor (A1BG), were selected for validation by Western blot and immunohistochemistry. Serum MMP-9 levels were also detected by enzyme linked immunosorbent assay (ELISA). Fourteen proteins were up-regulated and ten proteins were down-regulated in cancerous pancreatic juice compared with cancer-free controls. Increased MMP-9, DJ-1 and A1BG expression in cancerous pancreatic juice were confirmed by Western blot. Immunohistochemical study showed MMP-9, DJ-1 and A1BG positively expressed in 82.4%, 72.5% and 86.3% of pancreatic cancer tissues, significantly higher than that in normal pancreas tissues. Up-regulation of DJ-1 was associated with better differentiation (p < 0.05). Serum MMP-9 levels were significantly higher in PDAC (255.14 ng/ml) than those in chronic pancreatitis (210.22 ng/ml, p = 0.009) and healthy control (203.77 ng/ml, p = 0.027). The present proteome analysis revealed MMP-9, DJ-1 and A1BG proteins as elevated in pancreatic juice from PDAC, which suggest their further utility in PDAC diagnosis and screening. This is the first time A1BG was identified as a potential biomarker in pancreatic cancer associated samples. The measurement of serum MMP-9 might be clinically useful for PDAC

  1. Contrast-enhanced CT and diffusion-weighted MR imaging: Performance as a prognostic factor in patients with pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Fukukura, Yoshihiko; Takumi, Koji; Higashi, Michiyo; Shinchi, Hiroyuki; Kamimura, Kiyohisa; Yoneyama, Tomohide; Tateyama, Akihiro

    2014-01-01

    Objective: To determine whether contrast enhancement of CT and apparent diffusion coefficient on diffusion-weighted MR imaging are important parameters that can predict outcomes for patients with pancreatic ductal adenocarcinoma. Materials and methods: Ninety-two patients with histologically confirmed pancreatic ductal adenocarcinoma who underwent quadriphasic CT (including unenhanced, pancreatic parenchymal, portal venous and delayed phases) and fat-suppressed single-shot echo-planar diffusion-weighted MR imaging at 3.0 T were retrospectively analyzed to investigate prognostic factors. Overall survival curves were drawn using the Kaplan–Meier method. Effects on survival of variables including age, sex, tumor location, tumor size, TNM stage, carbohydrate antigen 19-9, carcinoembryonic antigen, treatment, tumor contrast enhancement and apparent diffusion coefficient values were analyzed in univariate analysis using the log-rank test. Variables were analyzed in multivariate analyses using the Cox proportional hazards regression model. Results: Median survival for the entire patient population was 18.2 months. Higher contrast enhancement during all phases was associated with significantly longer overall survival (P < 0.001 for all phases). The difference in overall survival between groups divided by median apparent diffusion coefficient value was not significant (P = 0.672). TNM stage (P = 0.026) and tumor contrast enhancement on CT (P = 0.027) were significantly related to survival in multivariate analysis. Conclusions: Poor enhancement of pancreatic adenocarcinomas on enhanced CT is associated with reduced patient survival

  2. Contrast-enhanced CT and diffusion-weighted MR imaging: Performance as a prognostic factor in patients with pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fukukura, Yoshihiko, E-mail: fukukura@m.kufm.kagoshima-u.ac.jp [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Takumi, Koji [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Higashi, Michiyo [Department of Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Shinchi, Hiroyuki [Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Kamimura, Kiyohisa; Yoneyama, Tomohide; Tateyama, Akihiro [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan)

    2014-04-15

    Objective: To determine whether contrast enhancement of CT and apparent diffusion coefficient on diffusion-weighted MR imaging are important parameters that can predict outcomes for patients with pancreatic ductal adenocarcinoma. Materials and methods: Ninety-two patients with histologically confirmed pancreatic ductal adenocarcinoma who underwent quadriphasic CT (including unenhanced, pancreatic parenchymal, portal venous and delayed phases) and fat-suppressed single-shot echo-planar diffusion-weighted MR imaging at 3.0 T were retrospectively analyzed to investigate prognostic factors. Overall survival curves were drawn using the Kaplan–Meier method. Effects on survival of variables including age, sex, tumor location, tumor size, TNM stage, carbohydrate antigen 19-9, carcinoembryonic antigen, treatment, tumor contrast enhancement and apparent diffusion coefficient values were analyzed in univariate analysis using the log-rank test. Variables were analyzed in multivariate analyses using the Cox proportional hazards regression model. Results: Median survival for the entire patient population was 18.2 months. Higher contrast enhancement during all phases was associated with significantly longer overall survival (P < 0.001 for all phases). The difference in overall survival between groups divided by median apparent diffusion coefficient value was not significant (P = 0.672). TNM stage (P = 0.026) and tumor contrast enhancement on CT (P = 0.027) were significantly related to survival in multivariate analysis. Conclusions: Poor enhancement of pancreatic adenocarcinomas on enhanced CT is associated with reduced patient survival.

  3. The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Asma Begum

    Full Text Available Cancer stem cells (CSCs play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC. A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.

  4. Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality

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    Loizou, L.; Leidner, B.; Axelsson, E.; Fischer, M.A.; Grigoriadis, A.; Kartalis, N. [Karolinska Institutet, Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); C1-46 Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Albiin, N. [Karolinska Institutet, Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Ersta Hospital, Department of Radiology, Stockholm (Sweden); Del Chiaro, M.; Segersvaerd, R. [Karolinska University Hospital Huddinge, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Center for Digestive Diseases, Stockholm (Sweden); Verbeke, C. [Karolinska Institutet and Karolinska University Hospital Huddinge, Division of Pathology, Department of Laboratory Medicine, Stockholm (Sweden); Sundin, A. [Uppsala University Hospital, Department of Surgical Sciences, Division of Radiology, Uppsala University and Department of Radiology, Uppsala (Sweden)

    2016-11-15

    To compare a low-tube-voltage with or without high-iodine-load multidetector CT (MDCT) protocol with a normal-tube-voltage, normal-iodine-load (standard) protocol in patients with pancreatic ductal adenocarcinoma (PDAC) with respect to tumour conspicuity and image quality. Thirty consecutive patients (mean age: 66 years, men/women: 14/16) preoperatively underwent triple-phase 64-channel MDCT examinations twice according to: (i) 120-kV standard protocol (PS; 0.75 g iodine (I)/kg body weight, n = 30) and (ii) 80-kV protocol A (PA; 0.75 g I/kg, n = 14) or protocol B (PB; 1 g I/kg, n = 16). Two independent readers evaluated tumour delineation and image quality blindly for all protocols. A third reader estimated the pancreas-to-tumour contrast-to-noise ratio (CNR). Statistical analysis was performed with the Chi-square test. Tumour delineation was significantly better in PB and PA compared with PS (P = 0.02). The evaluation of image quality was similar for the three protocols (all, P > 0.05). The highest CNR was observed with PB and was significantly better compared to PA (P = 0.02) and PS (P = 0.0002). In patients with PDAC, a low-tube-voltage, high-iodine-load protocol improves tumour delineation and CNR leading to higher tumour conspicuity compared to standard protocol MDCT. (orig.)

  5. Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality

    International Nuclear Information System (INIS)

    Loizou, L.; Leidner, B.; Axelsson, E.; Fischer, M.A.; Grigoriadis, A.; Kartalis, N.; Albiin, N.; Del Chiaro, M.; Segersvaerd, R.; Verbeke, C.; Sundin, A.

    2016-01-01

    To compare a low-tube-voltage with or without high-iodine-load multidetector CT (MDCT) protocol with a normal-tube-voltage, normal-iodine-load (standard) protocol in patients with pancreatic ductal adenocarcinoma (PDAC) with respect to tumour conspicuity and image quality. Thirty consecutive patients (mean age: 66 years, men/women: 14/16) preoperatively underwent triple-phase 64-channel MDCT examinations twice according to: (i) 120-kV standard protocol (PS; 0.75 g iodine (I)/kg body weight, n = 30) and (ii) 80-kV protocol A (PA; 0.75 g I/kg, n = 14) or protocol B (PB; 1 g I/kg, n = 16). Two independent readers evaluated tumour delineation and image quality blindly for all protocols. A third reader estimated the pancreas-to-tumour contrast-to-noise ratio (CNR). Statistical analysis was performed with the Chi-square test. Tumour delineation was significantly better in PB and PA compared with PS (P = 0.02). The evaluation of image quality was similar for the three protocols (all, P > 0.05). The highest CNR was observed with PB and was significantly better compared to PA (P = 0.02) and PS (P = 0.0002). In patients with PDAC, a low-tube-voltage, high-iodine-load protocol improves tumour delineation and CNR leading to higher tumour conspicuity compared to standard protocol MDCT. (orig.)

  6. Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

    LENUS (Irish Health Repository)

    Teo, Minyuen

    2013-03-01

    A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes.

  7. Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Qingqing Liu

    Full Text Available Argininosuccinate synthetase 1 (ASS1, the rate-limiting enzyme for arginine biosynthesis, is expressed in many types of human malignancies. Recent studies showed that ASS1 may have tumor suppressor function and that ASS1 deficiency is associated with clinical aggressiveness in nasopharyngeal carcinoma, myxofibrosarcomas and bladder cancer. The goal of this study was to evaluate the prognostic impact of ASS1 expression in patients with pancreatic ductal adenocarcinoma (PDAC. Our study included two independent cohorts: untreated cohort, which was comprised of 135 patients with PDAC who underwent pancreatoduodenectomy (PD without pre-operative neoadjuvant therapy, and treated cohort, which was comprised of 122 patients with PDAC who have completed neoadjuvant therapy and PD. The expression level of ASS1 was evaluated by immunohistochemistry and the results were correlated with clinicopathologic parameters and survival using SPSS statistics. Our study showed that 12% of PDAC in untreated cohort and 15% of PDAC in treated cohort has low expression of ASS1 (ASS1-low. ASS1-low was associated with higher recurrence (p = 0.045, shorter disease-free survival (DFS, 4.8 ± 1.6 months vs 15.3 ± 2.2 months, p = 0.001 and shorter overall survival (OS, 14.6 ± 6.4 months vs 26.5 ± 3.5 months, p = 0.005 in untreated cohort and shorter OS in treated cohort compared to ASS1-high tumors. In multivariate analysis, ASS1-low (HR: 0.45, 95% CI: 0.26-0.79, p = 0.005 was an independent prognostic factor for DFS in untreated cohort and an independent prognostic factor for OS (HR: 0.56, 95% CI: 0.32-0.97, p = 0.04 in treated cohort. Our results provide supporting evidence for future clinical trial using arginine deprivation agents either alone or in combination with conventional chemotherapy in treating pancreatic cancer.

  8. Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Kumar, Vidhya; Boucher, Yves; Liu, Hao; Ferreira, Diego; Hooker, Jacob; Catana, Ciprian; Hoover, Andrew J; Ritter, Tobias; Jain, Rakesh K; Guimaraes, Alexander R

    2016-10-01

    Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI) of magnetic iron oxide nanoparticles (MNPs) and micro-positron emission tomography (PET) measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan. All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg) or saline (control vehicle) for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.). Dynamic PET images were also acquired for 60 minutes using an 18 F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test. In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean±SEM) [12.1±1.7 (n=19) vs 6.7±1.1 (n=20); P<.02] and vessel size index (128.2±35.6 vs 57.5±18; P<.05). Losartan also induced a significant increase in the intratumoral uptake of 18 F-5FU by 53% (P<.0001). MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18 F-5FU. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia.

    Science.gov (United States)

    Badea, Liviu; Herlea, Vlad; Dima, Simona Olimpia; Dumitrascu, Traian; Popescu, Irinel

    2008-01-01

    The precise details of pancreatic ductal adenocarcinoma (PDAC) pathogenesis are still insufficiently known, requiring the use of high-throughput methods. However, PDAC is especially difficult to study using microarrays due to its strong desmoplastic reaction, which involves a hyperproliferating stroma that effectively "masks" the contribution of the minoritary neoplastic epithelial cells. Thus it is not clear which of the genes that have been found differentially expressed between normal and whole tumor tissues are due to the tumor epithelia and which simply reflect the differences in cellular composition. To address this problem, laser microdissection studies have been performed, but these have to deal with much smaller tissue sample quantities and therefore have significantly higher experimental noise. In this paper we combine our own large sample whole-tissue study with a previously published smaller sample microdissection study by Grützmann et al. to identify the genes that are specifically overexpressed in PDAC tumor epithelia. The overlap of this list of genes with other microarray studies of pancreatic cancer as well as with the published literature is impressive. Moreover, we find a number of genes whose over-expression appears to be inversely correlated with patient survival: keratin 7, laminin gamma 2, stratifin, platelet phosphofructokinase, annexin A2, MAP4K4 and OACT2 (MBOAT2), which are all specifically upregulated in the neoplastic epithelia, rather than the tumor stroma. We improve on other microarray studies of PDAC by putting together the higher statistical power due to a larger number of samples with information about cell-type specific expression and patient survival.

  10. Multicenter Phase II Study of Intravenous and Intraperitoneal Paclitaxel With S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis.

    Science.gov (United States)

    Satoi, Sohei; Fujii, Tsutomu; Yanagimoto, Hiroaki; Motoi, Fuyuhiko; Kurata, Masanao; Takahara, Naminatsu; Yamada, Suguru; Yamamoto, Tomohisa; Mizuma, Masamichi; Honda, Goro; Isayama, Hiroyuki; Unno, Michiaki; Kodera, Yasuhiro; Ishigami, Hironori; Kon, Masanori

    2017-02-01

    To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, "an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium" in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis. PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive. Paclitaxel was administered i.v. at 50 mg/m and i.p. at 20 mg/m on days 1 and 8. S-1 was administered at 80 mg/m/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446). Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47-22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery. This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.

  11. Elevated urinary levels of urokinase-type plasminogen activator receptor (uPAR) in pancreatic ductal adenocarcinoma identify a clinically high-risk group

    International Nuclear Information System (INIS)

    Sorio, Claudio; Scarpa, Aldo; Mafficini, Andrea; Furlan, Federico; Barbi, Stefano; Bonora, Antonio; Brocco, Giorgio; Blasi, Francesco; Talamini, Giorgio; Bassi, Claudio

    2011-01-01

    The urokinase plasminogen activator receptor is highly expressed and its gene is amplified in about 50% of pancreatic ductal adenocarcinomas; this last feature is associated with worse prognosis. It is unknown whether the level of its soluble form (suPAR) in urine may be a diagnostic-prognostic marker in these patients. The urinary level of suPAR was measured in 146 patients, 94 pancreatic ductal adenocarcinoma and 52 chronic pancreatitis. Urine from 104 healthy subjects with similar age and gender distribution served as controls. suPAR levels were normalized with creatinine levels (suPAR/creatinine, ng/mg) to remove urine dilution effect. Urinary suPAR/creatinine values of pancreatic ductal adenocarcinoma patients were significantly higher (median 9.8; 25 th -75 th percentiles 5.3-20.7) than those of either healthy donors (median 0; 0-0.5) or chronic pancreatitis patients (median 2.7; 0.9-4.7). The distribution of values among cancer patients was widespread and asymmetric, 53% subjects having values beyond the 95 th percentile of healthy donors. The values of suPAR/creatinine did not correlate with tumour stage, Ca19-9 or CEA levels. Higher values correlated with poor prognosis among non-resected patients at univariate analysis; multivariate Cox regression identified high urinary suPAR/creatinine as an independent predictor of poor survival among all cancer patients (odds ratio 2.10, p = 0.0023), together with tumour stage (stage III odds ratio 2.65, p = 0.0017; stage IV odds ratio 4.61, p < 0.0001) and female gender (odds ratio 1.85, p = 0.01). A high urinary suPAR/creatinine ratio represents a useful marker for the identification of a subset of patients with poorer outcome

  12. “Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Circulating tumor cells (CTCs) appear to be involved in early dissemination of many cancers, although which characteristics are important in metastatic spread are not clear. Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal a...

  13. Immunohistochemical Markers Distinguishing Cholangiocellular Carcinoma (CCC) from Pancreatic Ductal Adenocarcinoma (PDAC) Discovered by Proteomic Analysis of Microdissected Cells.

    Science.gov (United States)

    Padden, Juliet; Ahrens, Maike; Kälsch, Julia; Bertram, Stefanie; Megger, Dominik A; Bracht, Thilo; Eisenacher, Martin; Kocabayoglu, Peri; Meyer, Helmut E; Sipos, Bence; Baba, Hideo A; Sitek, Barbara

    2016-03-01

    Cholangiocellular carcinoma (CCC) and pancreatic ductal adenocarcinoma (PDAC) are two highly aggressive cancer types that arise from epithelial cells of the pancreatobiliary system. Owing to their histological and morphological similarity, differential diagnosis between CCC and metastasis of PDAC located in the liver frequently proves an unsolvable issue for pathologists. The detection of biomarkers with high specificity and sensitivity for the differentiation of these tumor types would therefore be a valuable tool. Here, we address this problem by comparing microdissected CCC and PDAC tumor cells from nine and eleven cancer patients, respectively, in a label-free proteomics approach. The novel biomarker candidates were subsequently verified by immunohistochemical staining of 73 CCC, 78 primary, and 18 metastatic PDAC tissue sections. In the proteome analysis, we found 180 proteins with a significantly differential expression between CCC and PDAC cells (p value 2). Nine candidate proteins were chosen for an immunohistochemical verification out of which three showed very promising results. These were the annexins ANXA1, ANXA10, and ANXA13. For the correct classification of PDAC, ANXA1 showed a sensitivity of 84% and a specificity of 85% and ANXA10 a sensitivity of 90% at a specificity of 66%. ANXA13 was higher abundant in CCC. It presented a sensitivity of 84% at a specificity of 55%. In metastatic PDAC tissue ANXA1 and ANXA10 showed similar staining behavior as in the primary PDAC tumors (13/18 and 17/18 positive, respectively). ANXA13, however, presented positive staining in eight out of eighteen secondary PDAC tumors and was therefore not suitable for the differentiation of these from CCC. We conclude that ANXA1 and ANXA10 are promising biomarker candidates with high diagnostic values for the differential diagnosis of intrahepatic CCC and metastatic liver tumors deriving from PDAC. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Liu, Hung-Yi; Korc, Murray; Lin, Chien-Chi

    2018-04-01

    The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT). Copyright © 2018 Elsevier Ltd. All rights

  15. Repeatability and correlations of dynamic contrast enhanced and T2* MRI in patients with advanced pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Klaassen, Remy; Gurney-Champion, Oliver J; Wilmink, Johanna W; Besselink, Marc G; Engelbrecht, Marc R W; Stoker, Jaap; Nederveen, Aart J; van Laarhoven, Hanneke W M

    2018-07-01

    In current oncological practice of pancreatic ductal adenocarcinoma (PDAC), there is a great demand for response predictors and markers for early treatment evaluation. In this study, we investigated the repeatability and the interaction of dynamic contrast enhanced (DCE) and T2* MRI in patients with advanced PDAC to enable for such evaluation using these techniques. 15 PDAC patients underwent two DCE, T2* and anatomical 3 T MRI sessions before start of treatment. Parametric maps were calculated for the transfer constant (K trans ), rate constant (k ep ), extracellular extravascular space (v e ) and perfusion fraction (v p ). Quantitative R2* (1/T2*) maps were obtained from the multi-echo T2* images. Differences between normal and cancerous pancreas were determined using a Wilcoxon matched pairs test. Repeatability was obtained using Bland-Altman analysis and relations between DCE and T2*/R2* were observed by Spearman correlation and voxel-wise binned plots of tumor voxels. PDAC K trans (p = 0.007), k ep (p T2*. Voxel wise analysis showed a steep increase in R2* for tumor voxels with lower K trans and v e . We showed good repeatability of DCE and T2* related MRI parameters in advanced PDAC patients. Furthermore, we have illustrated the relation of DCE K trans and v e with tissue T2* and R2* indicating substantial value of these parameters for detecting tumor hypoxia in future studies. The results from our study pave the way for further response evaluation studies and patient selection based on DCE and T2* parameters. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis

    International Nuclear Information System (INIS)

    Chile, Thais; Bacchella, Telésforo; Giorgi, Ricardo Rodrigues; Fortes, Maria Angela Henriques Zanella; Corrêa-Giannella, Maria Lúcia Cardillo; Brentani, Helena Paula; Maria, Durvanei Augusto; Puga, Renato David; Paula, Vanessa de Jesus R de; Kubrusly, Marcia Saldanha; Novak, Estela Maria

    2013-01-01

    Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression of HOXB7 homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated. Real time quantitative PCR (qRT-PCR) (Taqman) was employed to assess HOXB7 mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdown HOXB7 mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively. Overexpression of HOXB7 mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1. HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle. The present study confirms the overexpression of HOXB7 mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes. HOXB7 might be a promising target for future therapies

  17. Solid pseudopapillary tumor of the pancreas: A population-based comparison with pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    G. Paul Wright

    2016-09-01

    Conclusion: SPTP is a rare pancreatic neoplasm found more commonly in young women in the tail of the pancreas and is associated with a significantly more favorable prognosis than PDAC. [Arch Clin Exp Surg 2016; 5(3.000: 148-153

  18. Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Vidhya Kumar

    2016-10-01

    Full Text Available PURPOSE: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI of magnetic iron oxide nanoparticles (MNPs and micro–positron emission tomography (PET measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan. METHOD AND MATERIALS: All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg or saline (control vehicle for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.. Dynamic PET images were also acquired for 60 minutes using an 18F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test. RESULTS: In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean ± SEM [12.1 ± 1.7 (n = 19 vs 6.7 ± 1.1 (n = 20; P < .02] and vessel size index (128.2 ± 35.6 vs 57.5 ± 18; P < .05. Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53% (P < .0001. CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

  19. Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase

    Directory of Open Access Journals (Sweden)

    Thomas Große-Steffen

    2012-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN and the tumor cell transition, biopsies of patients with PDAC (n=115 were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.

  20. Association between genetic subgroups of pancreatic ductal adenocarcinoma defined by high density 500 K SNP-arrays and tumor histopathology.

    Directory of Open Access Journals (Sweden)

    María Laura Gutiérrez

    Full Text Available The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP-arrays to define those chromosomal regions which most commonly harbour copy number (CN alterations and loss of heterozygozity (LOH in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70% extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9 versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11. From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterozygozity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC.

  1. "Ductal adenocarcinoma in anular pancreas".

    Science.gov (United States)

    Benassai, Giacomo; Perrotta, Stefano; Furino, Ermenegildo; De Werra, Carlo; Aloia, Sergio; Del Giudice, Roberto; Amato, Bruno; Vigliotti, Gabriele; Limite, Gennaro; Quarto, Gennaro

    2015-09-01

    The annular pancreas is a congenital anomaly in which pancreatic tissue partially or completely surrounds the second portion of the duodenum. Its often located above of papilla of Vater (85%), rarely below (15%). This pancreatic tissue is often easily dissociable to the duodenum but there is same cases where it the tissue is into the muscolaris wall of the duodenum. We describe three case of annular pancreas hospitalized in our facility between January 2004 and January 2009. There were 2 male 65 and 69 years old respectively and 1 female of 60 years old, presented complaining of repeated episodes of mild epigastric pain. Laboratory tests (including tumor markers), a direct abdomen X-ray with enema, EGDS and total body CT scan were performed to study to better define the diagnosis. EUS showed the presence of tissue infiltrating the muscle layer all around the first part of duodenum. Biopsies performed found the presence of pancreatic tissue with focal areas of adenocarcinoma. Subtotal gastrectomy with Roux was performed. The histological examinations shows an annular pancreas of D1 with multiple focal area of adenocarcinoma. (T1aN0M0). We performed a follow up at 5 years. One patients died after 36 months for cardiovascular hit. Two patients, one male and one female, was 5-years disease-free. Annular pancreas is an uncommon congenital anomaly which usually presents itself in infants and newborn. Rarely it can present in late adult life with wide range of clinical severities thereby making its diagnosis difficult. Pre-operative diagnosis is often difficult. CT scan can illustrate the pancreatic tissue encircling the duodenum. ERCP and MRCP are useful in outlining the annular pancreatic duct. Surgery still remains necessary to confirm diagnosis and bypassing the obstructed segment. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  2. Hypoxia-inducible factor-1α regulates chemotactic migration of pancreatic ductal adenocarcinoma cells through directly transactivating the CX3CR1 gene.

    Directory of Open Access Journals (Sweden)

    Tiansuo Zhao

    Full Text Available CX3CR1 is an important chemokine receptor and regulates the chemotactic migration of pancreatic ductal adenocarcinoma (PDAC cells. Up to now, its regulatory mechanism remains largely undefined. Here, we report that hypoxia upregulates the expression of CX3CR1 in pancreatic cancer cells. When hypoxia-inducible factor (HIF-1α expression was knocked down in vitro and in vivo, the expression of CX3CR1 was significantly decreased. Chromatin immunoprecipitation assay demonstrated that HIF-1α bound to the hypoxia-response element (HRE; 5'-A/GCGTG-3' of CX3CR1 promoter under normoxia, and this binding was significantly enhanced under hypoxia. Overexpression of HIF-1α significantly upregulated the expression of luciferase reporter gene under the control of the CX3CR1 promoter in pancreatic cancer cells. Importantly, we demonstrated that HIF-1α may regulate cancer cell migration through CX3CR1. The HIF-1α/CX3CR1 pathway might represent a valuable therapeutic target to prevent invasion and distant metastasis in PDAC.

  3. Endogenous n-3 Polyunsaturated Fatty Acids Delay Progression of Pancreatic Ductal Adenocarcinoma in Fat-1-p48Cre/+-LSL-KrasG12D/+ Mice

    Directory of Open Access Journals (Sweden)

    Altaf Mohammed

    2012-12-01

    Full Text Available Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1 transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs and their progression to pancreatic ductal adenocarcinoma (PDAC. Six-weekold female p48Cre/+-LSL-KrasG12D/+ andcompoundFat-1-p48Cre/+-LSL-KrasG12D/+ mice were fed (AIN-76A diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P 85%; P < .05–0.01 in pancreas of compound transgenic mice than in those of p48Cre/+-LSL-KrasG12D/+ mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX, 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals.

  4. Heterogeneity index evaluated by slope of linear regression on 18F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Kim, Yong-il; Kim, Yong Joong; Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo; Chung, June-Key; Kang, Keon Wook

    2017-01-01

    18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18 F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18 F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative 18 F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18 F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18 F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the 18 F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0.001, respectively) demonstrated significant results

  5. Differentiation of mass-forming focal pancreatitis from pancreatic ductal adenocarcinoma: value of characterizing dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity color mapping

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mimi [Hanyang University College of Medicine, Department of Radiology, Hanyang Medical Center, Seoul (Korea, Republic of); Jang, Kyung Mi [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jae-Hun; Jeong, Woo Kyoung; Kim, Seong Hyun; Kang, Tae Wook; Kim, Young Kon; Cha, Dong Ik [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Kyunga [Samsung Medical Center, Biostatics and Clinical Epidemiology Center, Research Institute for Future Medicine, Seoul (Korea, Republic of)

    2017-04-15

    To evaluate the value of dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity colour mapping (SICM) to differentiate mass-forming focal pancreatitis (MFFP) from pancreatic ductal adenocarcinoma (PDAC). Forty-one clinicopathologically proven MFFPs and 144 surgically confirmed PDACs were enrolled. Laboratory and MR imaging parameters were used to differentiate MFFP from PDAC. In particular, enhancement patterns on MR images adding SICM were evaluated. By using classification tree analysis (CTA), we determined the predictors for the differentiation of MFFP from PDAC. In the CTA, with all parameters except enhancement pattern on SICM images, ductal obstruction grade and T1 hypointensity grade of the pancreatic lesion were the first and second splitting predictor for differentiation of MFFP from PDAC, in order. By adding an enhancement pattern on the SICM images to CTA, the enhancement pattern was the only splitting predictor to differentiate MFFP from PDAC. The CTA model including enhancement pattern on SICM images has sensitivity of 78.0 %, specificity of 99.3 %, and accuracy of 94.6 % for differentiating MFFP from PDAC. The characterization of enhancement pattern for pancreatic lesions on contrast-enhanced MR images adding SICM would be helpful to differentiate MFFP from PDAC. (orig.)

  6. PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF-κB pathway

    Science.gov (United States)

    Tang, Dong; Zhang, Jingqiu; Yuan, Zhongxu; Zhang, Hongpeng; Chong, Yang; Huang, Yuqin; Wang, Jie; Xiong, Qingquan; Wang, Sen; Wu, Qi; Tian, Ying; Lu, Yongdie; Ge, Xiao; Shen, Wenjing; Wang, Daorong

    2017-01-01

    Galectin-1 has previously been shown to be strongly expressed in activated pancreatic stellate cells (PSCs) and promote the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms by which Galectin-1 promotes the malignant behavior of pancreatic cancer cells remain unclear. In this study, we examined the effects of Galectin-1 knockdown or overexpression in PSCs co-cultured with pancreatic cancer (PANC-1) cells. Immunohistochemical analysis showed expression of epithelial-mesenchymal transition (EMT) markers and MMP9 were positively associated with the expression of Galectin-1 in 66 human PDAC tissues. In addition, our in vitro studies showed PSC-derived Galectin-1 promoted the proliferation, invasion, and survival (anti-apoptotic effects) of PANC-1 cells. We also showed PSC-derived Galectin-1 induced EMT of PANC-1 cells and activated the NF-кB pathway in vitro. Our mixed (PSCs and PANC-1 cells) mouse orthotopic xenograft model indicated that overexpression of Galectin-1 in PSCs significantly promoted the proliferation, growth, invasion, and liver metastasis of the transplanted tumor. Moreover, Galectin-1 overexpression in PSCs was strongly associated with increased expression of EMT markers in both the orthotopic xenograft tumor in the pancreas and in metastatic lesions of naked mice. We conclude that PSC-derived Galectin-1 promotes the malignant behavior of PDAC by inducing EMT via activation of the NF-κB pathway. Our results suggest that targeting Galectin-1 in PSCs could represent a promising therapeutic strategy for PDAC progression and metastasis. PMID:29156810

  7. Does a family history of pancreatic ductal adenocarcinoma and cyst size influence the follow-up strategy for intraductal papillary mucinous neoplasms of the pancreas?

    Science.gov (United States)

    Mandai, Koichiro; Uno, Koji; Yasuda, Kenjiro

    2014-08-01

    This study aimed to evaluate the relationship between pancreatic ductal adenocarcinoma (PDAC) family history and PDAC development in patients followed up for intraductal papillary mucinous neoplasms (IPMNs) and to assess the cyst size relevance in determining follow-up strategies. We analyzed 300 patients with branch duct and mixed-type IPMN who were followed up at our facility. Among the patients aged 70 years or older, the frequency of PDAC did not differ significantly between those with 1 first-degree relative with PDAC and those without a family history. Although patients with IPMNs of greater than or equal to 30 mm were followed up for a significantly shorter duration than those patients with IPMNs of less than 30 mm, the frequency of IPMN progression and malignant IPMN was significantly greater in the former. The frequency of IPMN progression and pancreatic cancer did not differ significantly according to IPMN size (family history. Special attention should be paid to IPMN progression and malignant transformation in patients with IPMNs of greater than or equal to 30 mm, but cyst size need not be considered when determining follow-up strategies for patients with IPMNs of less than 30 mm without mural nodules.

  8. High Volume Washing of the Abdomen in Increasing Survival After Surgery in Patients With Pancreatic Cancer That Can Be Removed by Surgery

    Science.gov (United States)

    2017-10-25

    Acinar Cell Carcinoma; Ampulla of Vater Adenocarcinoma; Cholangiocarcinoma; Duodenal Adenocarcinoma; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraductal Papillary Mucinous Neoplasm, Pancreatobiliary-Type; Periampullary Adenocarcinoma

  9. MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

    DEFF Research Database (Denmark)

    Schultz, Nicolai A; Werner, Jens; Willenbrock, Hanni

    2012-01-01

    MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-di...

  10. Lower maximum standardized uptake value of fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography imaging in pancreatic ductal adenocarcinoma patients with diabetes.

    Science.gov (United States)

    Chung, Kwang Hyun; Park, Joo Kyung; Lee, Sang Hyub; Hwang, Dae Wook; Cho, Jai Young; Yoon, Yoo-Seok; Han, Ho-Seong; Hwang, Jin-Hyeok

    2015-04-01

    The effects of diabetes mellitus (DM) on sensitivity of fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography ((18)F-FDG PET/CT) for diagnosing pancreatic ductal adenocarcinomas (PDACs) is not well known. This study was aimed to evaluate the effects of DM on the validity of (18)F-FDG PET/CT in PDAC. A total of 173 patients with PDACs who underwent (18)F-FDG PET/CT were enrolled (75 in the DM group and 98 in the non-DM group). The maximum standardized uptake values (SUVsmax) were compared. The mean SUVmax was significantly lower in the DM group than in the non-DM group (4.403 vs 5.998, P = .001). The sensitivity of SUVmax (cut-off value 4.0) was significantly lower in the DM group than in the non-DM group (49.3% vs 75.5%, P < .001) and also lower in normoglycemic DM patients (n = 24) than in non-DM patients (54.2% vs 75.5%, P = .038). DM contributes to a lower SUVmax of (18)F-FDG PET/CT in patients with PDACs. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. High Expression of FAM83B Predicts Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma and Correlates with Cell Cycle and Cell Proliferation.

    Science.gov (United States)

    Shen, Chao-Qin; Yan, Ting-Ting; Liu, Wei; Zhu, Xiao-Qiang; Tian, Xiang-Long; Fu, Xue-Liang; Hua, Rong; Zhang, Jun-Feng; Huo, Yan-Miao; Liu, De-Jun; Yang, Jian-Yu; Sun, Yong-Wei; Fang, Jing-Yuan; Chen, Hao-Yan; Hong, Jie

    2017-01-01

    FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. What's more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo . Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. It's of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.

  12. OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo.

    Science.gov (United States)

    Zhi, Xiao; Chen, Wei; Xue, Fei; Liang, Chao; Chen, Bryan Wei; Zhou, Yue; Wen, Liang; Hu, Liqiang; Shen, Jian; Bai, Xueli; Liang, Tingbo

    2015-09-22

    Despite its relative rarity, pancreatic ductal adenocarcinoma (PDAC) accounts for a large percentage of cancer deaths. In this study, we investigated the in vitro efficacy of OSI-027, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, to treat PDAC cell lines alone, and in combination with gemcitabine (GEM). Similarly, we tested the efficacy of these two compounds in a xenograft mouse model of PDAC. OSI-027 significantly arrested cell cycle in G0/G1 phase, inhibited the proliferation of Panc-1, BxPC-3, and CFPAC-1 cells, and downregulated mTORC1, mTORC2, phospho-Akt, phospho-p70S6K, phospho-4E-BP1, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in these cells. Moreover, OSI-027 also downregulated multidrug resistance (MDR)-1, which has been implicated in chemotherapy resistance in PDAC cells and enhanced apoptosis induced by GEM in the three PDAC cell lines. When combined, OSI-027 with GEM showed synergistic cytotoxic effects both in vitro and in vivo. This is the first evidence of the efficacy of OSI-027 in PDAC and may provide the groundwork for a new clinical PDAC therapy.

  13. Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Matthew H. Wong

    2016-07-01

    Full Text Available BACKGROUND: Extensive cross talk exists between PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK pathways, and both are upregulated in pancreatic ductal adenocarcinoma (PDAC. Our previous study suggested that epidermal growth factor receptor inhibitor erlotinib which acts upstream of these pathways acts synergistically with PI3K inhibitors in PDAC. Horizontal combined blockade upstream and downstream of these two pathways is therefore explored. METHODS: Erlotinib paired with PI3K inhibitor (BYL719 was tested against erlotinib plus dual PI3K/mTOR inhibitor BEZ-235, and MEK inhibitor (PD98059 plus BEZ235, on five primary PDAC cell lines and on two pairs of parent and erlotinib-resistant (ER cell lines. A range of in vitro assays including cell proliferation, Western blotting, migration, clonogenic, cell cycle, and apopotic assays was used to test for the efficacy of combined blockade. RESULTS: Dual downstream blockade of the MAPK and PAM pathways was more effective in attenuating downstream molecular signals. Synergy was demonstrated for erlotinib and BEZ235 and for PD-98059 and BEZ-235. This resulted in a trend of increased growth cell cycle arrest, apoptosis, cell proliferation, and colony and migration suppression. This combination showed more efficacy in cell lines with acquired resistance to erlotinib. CONCLUSIONS: The additional mTOR blockade provided by BEZ235 in combined blockade resulted in increased anticancer effect. The hypersensitivity of ER cell lines to additional mTOR blockade suggested PAM pathway oncogenic dependence via mTOR. Dual downstream combined blockade of MAPK and PAM pathways with MEK and PI3K/mTOR inhibitor appeared most effective and represents an attractive therapeutic strategy against pancreatic cancer and its associated drug resistance.

  14. Differential diagnosis between intraductal papillary mucinous neoplasm with an associated invasive carcinoma and pancreatic ductal adenocarcinoma on ultrasonography: the utility of echo intensity and contrast enhancement

    Energy Technology Data Exchange (ETDEWEB)

    Saito, Masato [Dept. of Radiology, Sapporo Teishinkai Hospital, Sapporo (Japan); Hirokawa, Naoki; Usami, Yoko; Someya, Masanori; Sakata, Kohichi [Dept. of Radiology, Sapporo Medical University School of Medicine, Sapporo (Japan)

    2017-07-15

    The aim of this study was to investigate the utility of echo intensity and contrast enhancement in the differential diagnosis between intraductal papillary mucinous neoplasm with an associated invasive carcinoma (IPMN-IC) and pancreatic ductal adenocarcinoma (PDAC) on ultrasonography. This study included eight and 37 patients who had pathologically confirmed IPMN-IC and PDAC, respectively, and were enrolled for a comparative analysis of the sonographic features of the tumors. In the quantitative echo intensity evaluation, the two groups were compared with respect to the difference between the tumor intensity and the pancreatic intensity (TI-PI) and between the tumor intensity and the vascular intensity (TI-VI). In the quantitative contrast enhancement evaluation, the increase in echo intensity (ΔTI) and increase in echo intensity per unit of time (slope) were compared between the groups. The echo intensity and contrast enhancement were also compared between the two groups in patients with T3-T4 disease. In addition, the correlations of the histological type, tumor size, stromal type, and T factor with echogenicity and contrast enhancement were analyzed. IPMN-IC had significantly greater echo intensity and contrast enhancement than PDAC (TI-PI, P=0.004; TI-VI, P=0.001; ΔTI, P=0.012; slope, P=0.002). In T3-T4 disease, IPMN-IC also showed greater echo intensity and faster enhancement than PDAC. Echo intensity and contrast enhancement were correlated with histological type (TI-PI, P=0.003; TI-VI, P<0.001; ΔTI, P=0.007; slope, P<0.001). IPMN-IC and PDAC can be differentiated by the quantitative evaluation of echo intensity and contrast enhancement.

  15. Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers.

    Science.gov (United States)

    Irigoyen, Antonio; Jimenez-Luna, Cristina; Benavides, Manuel; Caba, Octavio; Gallego, Javier; Ortuño, Francisco Manuel; Guillen-Ponce, Carmen; Rojas, Ignacio; Aranda, Enrique; Torres, Carolina; Prados, Jose

    2018-01-01

    Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses ('gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease.

  16. Annexin A10 optimally differentiates between intrahepatic cholangiocarcinoma and hepatic metastases of pancreatic ductal adenocarcinoma: a comparative study of immunohistochemical markers and panels.

    Science.gov (United States)

    Kälsch, Julia; Padden, Juliet; Bertram, Stefanie; Pott, Leona L; Reis, Henning; Westerwick, Daniela; Schaefer, Christoph M; Sowa, Jan-P; Möllmann, Dorothe; Fingas, Christian; Dechȇne, Alexander; Sitek, Barbara; Eisenacher, Martin; Canbay, Ali; Ahrens, Maike; Baba, Hideo A

    2017-05-01

    Discriminating intrahepatic cholangiocarcinoma (ICC) from hepatic metastases of pancreatic ductal adenocarcinoma (mPDAC) can be challenging. While pathologists might depend on clinical information regarding a primary tumor, their diagnosis will lead the patient either to potentially curative surgery (for ICC) or to palliation (for mPDAC). Beyond the validation of recently published potential biomarkers for PDAC (primary or metastatic) in a large cohort, we assessed diagnostic performance of the most promising candidates in the challenging task of discriminating metastatic PDAC (mPDAC) from ICC. In a training set of 87 ICC and 88 pPDAC, our previously identified biomarkers Annexin A1 (ANXA1), ANXA10, and ANXA13 were tested and compared with 11 published biomarkers or panels (MUCIN 1, Agrin, S100P, MUC5 AC, Laminin, VHL, CK 17, N-Cadherin, ELAC2, PODXL and HSPG2). Biomarkers with best results were further tested in an independent series of biopsies of 27 ICC and 36 mPDAC. Highest AUC values (between 0.72 and 0.84) for the discrimination between ICC and pPDAC were found in the training set for Annexin A1, Annexin A10, MUC5 AC, CK17, and N-Cadherin. These markers were further tested on an independent series of liver biopsies containing ICC or mPDAC. Diagnostic characteristics were evaluated for individual markers as well as for 3× panels. ANXA 10 showed the highest diagnostic potential of all single markers, correctly classifying 75% of mPDAC and 85% of ICC. Our results suggest that ANXA10 may be useful to differentiate between ICC and mPDAC, when only a tissue specimen is available.

  17. A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma

    International Nuclear Information System (INIS)

    Hong, Theodore S.; Ryan, David P.; Borger, Darrell R.; Blaszkowsky, Lawrence S.; Yeap, Beow Y.; Ancukiewicz, Marek; Deshpande, Vikram; Shinagare, Shweta; Wo, Jennifer Y.; Boucher, Yves; Wadlow, Raymond C.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Zhu, Andrew X.; Ferrone, Cristina R.; Mamon, Harvey J.; Adams, Judith; Winrich, Barbara; Grillo, Tarin

    2014-01-01

    Purpose: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. Methods and Materials: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. Results: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). Conclusions: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS G12D status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival

  18. TH-EF-BRA-04: Individually Optimized Contrast-Enhanced 4D-CT for Radiotherapy Simulation in Pancreatic Ductal Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Choi, W; Xue, M; Lane, B; Patel, K; Regine, W; Wang, J; Chen, S; D’souza, W; Lu, W [University of Maryland School of Medicine, Baltimore, MD (United States); Kang, M [Kyungpook National University School of Medicine, Daegu (Korea, Republic of); Klahr, P [Philips Healthcare, Highland Heights, OH (United States)

    2016-06-15

    Purpose: To develop an individually optimized contrast-enhanced (CE) 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). Methods: Ten PDA patients were enrolled. Each underwent 3 CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. We compared image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) in the 3 CTs. We also evaluated interobserver variations in contouring the tumor using simultaneous truth and performance level estimation (STAPLE). Results: Average image quality scores for CE 3DCT and CE 4D-CT were comparable (4.0 and 3.8, respectively; P=0.47), and both were significantly better than that for 4D-CT (2.6, P<0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 HU, respectively; P=0.71), and the latter was significantly higher than in 4D-CT (9.2 HU, P=0.03). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P<0.001) and 4D-CT (19.4 HU, P=0.005). CNRs were comparable in CE 3D-CT and CE 4DCT (1.4 and 0.8, respectively; P=0.23), and the former was significantly better than in 4D-CT (0.6, P = 0.04). Mean tumor volumes were smaller in CE 3D-CT (29.8 cm{sup 3}) and CE 4D-CT (22.8 cm{sup 3}) than in 4D-CT (42.0 cm{sup 3}), although these differences were not statistically significant. Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P=0.23). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. Conclusion: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan. Supported in part by Philips Healthcare.

  19. Linc00511 acts as a competing endogenous RNA to regulate VEGFA expression through sponging hsa-miR-29b-3p in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Zhao, Xiaohui; Liu, Yimin; Li, Zhihua; Zheng, Shangyou; Wang, Zairui; Li, Wenzhu; Bi, Zhuofei; Li, Liting; Jiang, Yanhui; Luo, Yuming; Lin, Qing; Fu, Zhiqiang; Rufu, Chen

    2018-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in PDAC are poorly understood. Here, we identify a fundamental role for a novel lincRNA, linc00511, in the progression of PDAC. Linc00511 levels in PDAC tissue specimens and cell lines were examined by quantitative real-time PCR. Corresponding adjacent non-neoplastic tissues were used as controls. The function of linc00511 in PDAC cell lines was determined by RNA interference approach in vitro and in vivo. Fluorescence in situ hybridization (FISH) was used to characterize linc00511 expression in PDAC cells. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were obtained from bioinformatic analysis, luciferase assays and RIP assays. The association between the linc00511/hsa-miR29b-3p axis and VEGFA was verified by Western blotting assay. Immunohistochemistry was performed to evaluate the expression of VEGFA in PDAC samples. The aberrant up-regulation of linc00511 was detected in PDAC cell lines and patient specimens compared with controls. An increase in linc00511 expression indicates the adverse clinical pathological characteristics and poor prognosis. Functionally, linc00511 depletion in PDAC cells decreased proliferation, migration, invasion and endothelial tube formation. Mechanistically, linc00511 could up-regulate VEGFA via its competing endogenous RNA (ceRNA) activity on hsa-miR-29b-3p. In summary, our results define an important axis controlling proliferation, invasion and tumour angiogenesis in PDAC. Linc00511 is a novel lncRNA that plays a significant regulatory role in the pathogenesis and progression of PDAC. Thus, Linc00511 represents a new prognostic biomarker to predict clinical outcome of PDAC patients after surgery and may serve as a potential therapeutic target for PDAC treatment. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by

  20. Survival Analysis in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Chemoradiotherapy Followed by Surgery According to the International Consensus on the 2017 Definition of Borderline Resectable Cancer

    Directory of Open Access Journals (Sweden)

    Aoi Hayasaki

    2018-03-01

    Full Text Available Background: The aim of this study was to validate a new definition of borderline resectable pancreatic ductal adenocarcinoma (PDAC provided by the 2017 international consensus on the basis of three dimensions of anatomical (A, biological (B, and conditional (C factors, using the data of the patients who had been registered for our institutional protocol of chemoradiotherapy followed by surgery (CRTS for localized patients with PDAC. Methods: Among 307 consecutive patients pathologically diagnosed with localized PDAC who were enrolled in our CRTS protocol from February 2005 to December 2016, we selected 285 patients who could be re-evaluated after CRT. These 285 patients were classified according to international consensus A definitions as follows: R (resectable; n = 62, BR-PV (borderline resectable, superior mesenteric vein (SMV/portal vein (PV involvement alone; n = 27, BR-A (borderline resectable, arterial involvement; n = 50, LA (locally advanced; n = 146. Disease-specific survival (DSS was analyzed according to A, B (serum CA 19-9 levels and lymph node metastasis diagnosed by computed tomography findings before CRT, and C factors (performance status (PS factors. Results: The rates of resection and R0 resection were similar between R (83.9 and 98.0% and BR-PV (85.2 and 95.5%, but much lower in BR-A (70.0 and 84.8% and LA (46.6 and 62.5%. DSS evaluated by median survival time (months showed a similar trend to surgical outcomes: 33.7 in R, 27.3 in BR-PV, 18.9 in BR-A and 19.3 in LA, respectively. DSS in R patients with CA 19-9 levels > 500 U/mL was significantly poorer than in patients with CA 19-9 levels ≤ 500 U/mL, but there were no differences in DSS among BR-PV, BR-A, and LA patients according to CA 19-9 levels. Regarding lymph node metastasis, there was no significant difference in DSS according to each resectability group. DSS in R patients with PS ≥ 2 was significantly worse than in patients with PS 0-1. Conclusions: The

  1. Synthesis and evaluation of a radioiodinated peptide probe targeting αvβ6 integrin for the detection of pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Ueda, Masashi; Fukushima, Takahiro; Ogawa, Kei; Kimura, Hiroyuki; Ono, Masahiro; Yamaguchi, Takashi; Ikehara, Yuzuru; Saji, Hideo

    2014-01-01

    Highlights: • We developed a radioiodinated peptide probe targeting αvβ6 integrin ( 123 I-IFMDV2). • 123 I-IFMDV2 had a high affinity and selectivity for αvβ6 integrin. • 123 I-IFMDV2 showed a specific binding to αvβ6 integrin in vivo. • 123 I-IFMDV2 enabled clear visualization of the αvβ6-integrin-positive tumor. - Abstract: Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related death. Since significant upregulation of αvβ6 integrin has been reported in PDAC, this integrin is a promising target for PDAC detection. In this study, we aimed to develop a radioiodinated probe for the imaging of αvβ6 integrin-positive PDAC with single-photon emission computed tomography (SPECT). Methods: Four peptide probes were synthesized and screened by competitive and saturation binding assays using 2 PDAC cell lines (AsPC-1, αvβ6 integrin-positive; MIA PaCa-2, αvβ6 integrin-negative). The probe showing the best affinity was used to study the biodistribution assay, an in vivo blocking study, and SPECT imaging using tumor bearing mice. Autoradiography and immunohistochemical analysis were also performed. Results: Among the 4 probes examined in this study, 125 I-IFMDV2 showed the highest affinity for αvβ6 integrin expressed in AsPC-1 cells and no affinity for MIA PaCa-2 cells. The accumulation of 125 I-IFMDV2 in the AsPC-1 xenograft was 3–5 times greater than that in the MIA PaCa-2 xenograft, consistent with the expression of αvβ6 integrin in each xenograft, and confirmed by immunohistochemistry. Pretreatment with excess amounts of A20FMDV2 significantly blocked the accumulation of 125 I-IFMDV2 in the AsPC-1 xenograft, but not in the MIA PaCa-2 xenograft. Furthermore, 123 I-IFMDV2 enabled clear visualization of the AsPC-1 xenograft. Conclusion: 123 I-IFMDV2 is a potential SPECT probe for the imaging of αvβ6 integrin in PDAC

  2. A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Theodore S., E-mail: tshong1@partners.org [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ryan, David P.; Borger, Darrell R.; Blaszkowsky, Lawrence S.; Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ancukiewicz, Marek [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Deshpande, Vikram; Shinagare, Shweta [Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Wo, Jennifer Y.; Boucher, Yves [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Wadlow, Raymond C.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Zhu, Andrew X. [Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ferrone, Cristina R. [Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Mamon, Harvey J. [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Adams, Judith; Winrich, Barbara; Grillo, Tarin [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); and others

    2014-07-15

    Purpose: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. Methods and Materials: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. Results: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). Conclusions: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS{sup G12D} status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

  3. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    O'Reilly, Eileen M; Lee, Jonathan W; Lowery, Maeve A; Capanu, Marinela; Stadler, Zsofia K; Moore, Malcolm J; Dhani, Neesha; Kindler, Hedy L; Estrella, Hayley; Maynard, Hannah; Golan, Talia; Segal, Amiel; Salo-Mullen, Erin E; Yu, Kenneth H; Epstein, Andrew S; Segal, Michal; Brenner, Robin; Do, Richard K; Chen, Alice P; Tang, Laura H; Kelsen, David P

    2018-04-01

    A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Gemcitabine and cisplatin were dosed at 600 and 25 mg/m 2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society. © 2018 American Cancer Society.

  4. Poorly differentiated ductal adenocarcinoma of the pancreas with rapid progression in a young man.

    Science.gov (United States)

    Tezuka, Koji; Ishiyama, Tomoharu; Takeshita, Akiko; Matsumoto, Hidekazu; Jingu, Akira; Kikuchi, Jiro; Yamaya, Hideyuki; Ohe, Rintaro; Ishizawa, Tetsuya

    2018-04-16

    Pancreatic cancer in young adults is very rare. We report a case of young-onset poorly differentiated pancreatic ductal adenocarcinoma with rapid progression and poor prognosis in a 31-year-old Japanese man with no obvious family history of malignancy. Preoperative examinations revealed a mass lesion in the body of the pancreas, accompanied by a slightly dilated main pancreatic duct distal to the mass lesion. Pancreatic cancer with acute pancreatitis was suspected because of an elevation of serum pancreatic enzyme and tumor marker, along with imaging findings. Distal pancreatectomy with resection of the common hepatic artery and splenectomy along with lymph node dissection was performed. Microscopically, the tumor was mainly composed of poorly differentiated ductal adenocarcinoma. The postoperative course was uneventful, but the patient had multiple liver metastases 2 months postoperatively, in spite of adjuvant chemotherapy, and died 8 months postoperatively. This case may represent a rare instance of young-onset poorly differentiated ductal adenocarcinoma with rapid progression and may indicate potential risk factors of pancreatic cancer in young adults.

  5. Multidetector computer tomography in the pancreatic adenocarcinoma assessment: an update

    Directory of Open Access Journals (Sweden)

    Vincenza Granata

    2016-11-01

    Full Text Available Abstract Ductal adenocarcinoma of the pancreas is one of the most aggressive forms of cancer, with only a minority of cases being resectable at the moment of their diagnosis. The accurate detection and characterization of pancreatic carcinoma is very important for patient management. Multidetector-row computed tomography (MDCT has become the cross-sectional modality of choice in the diagnosis, staging, treatment planning, and follow-up of patients with pancreatic tumors. However, approximately 11% of ductal adenocarcinomas still remain undetected at MDCT because of the lack of attenuation gradient between the lesion and the adjacent pancreatic parenchyma. In this systematic literature review we investigate the current evolution of the CT technique, limitations, and perspectives in the evaluation of pancreatic carcinoma.

  6. Heterogeneity index evaluated by slope of linear regression on {sup 18}F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yong-il [CHA University, Department of Nuclear Medicine, CHA Bundang Medical Center, Seongnam (Korea, Republic of); Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Yong Joong [Veterans Health Service Medical Center, Seoul (Korea, Republic of); Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Chung, June-Key [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of)

    2017-11-15

    {sup 18}F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of {sup 18}F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and {sup 18}F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative {sup 18}F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each {sup 18}F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and {sup 18}F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the {sup 18}F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0

  7. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Marina Pasca di Magliano

    2007-11-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma.

  8. Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study

    NARCIS (Netherlands)

    van Hilst, Jony; de Rooij, Thijs; Klompmaker, Sjors; Rawashdeh, Majd; Aleotti, Francesca; Al-Sarireh, Bilal; Alseidi, Adnan; Ateeb, Zeeshan; Balzano, Gianpaolo; Berrevoet, Frederik; Björnsson, Bergthor; Boggi, Ugo; Busch, Olivier R.; Butturini, Giovanni; Casadei, Riccardo; del Chiaro, Marco; Chikhladze, Sophia; Cipriani, Federica; van Dam, Ronald; Damoli, Isacco; van Dieren, Susan; Dokmak, Safi; Edwin, Bjørn; van Eijck, Casper; Fabre, Jean-Marie; Falconi, Massimo; Farges, Olivier; Fernández-Cruz, Laureano; Forgione, Antonello; Frigerio, Isabella; Fuks, David; Gavazzi, Francesca; Gayet, Brice; Giardino, Alessandro; Bas Groot, Koerkamp; Hackert, Thilo; Hassenpflug, Matthias; Kabir, Irfan; Keck, Tobias; Khatkov, Igor; Kusar, Masa; Lombardo, Carlo; Marchegiani, Giovanni; Marshall, Ryne; Menon, Krish V.; Montorsi, Marco; Orville, Marion; de Pastena, Matteo; Pietrabissa, Andrea; Poves, Ignaci; Primrose, John; Pugliese, Raffaele; Ricci, Claudio; Roberts, Keith; Røsok, Bård; Sahakyan, Mushegh A.; Sánchez-Cabús, Santiago; Sandström, Per; Scovel, Lauren; Solaini, Leonardo; Soonawalla, Zahir; Souche, F. Régis; Sutcliffe, Robert P.; Tiberio, Guido A.; Tomazic, Aleš; Troisi, Roberto; Wellner, Ulrich; White, Steven; Wittel, Uwe A.; Zerbi, Alessandro; Bassi, Claudio; Besselink, Marc G.; Abu Hilal, Mohammed

    2017-01-01

    The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent

  9. Biomarkers in pancreatic adenocarcinoma: current perspectives.

    Science.gov (United States)

    Swords, Douglas S; Firpo, Matthew A; Scaife, Courtney L; Mulvihill, Sean J

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

  10. What is the origin of pancreatic adenocarcinoma?

    Directory of Open Access Journals (Sweden)

    Pandey Krishan K

    2003-01-01

    Full Text Available Abstract The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed. Based on the world literature and recent observations, pancreatic cells seem to have potential for phenotypical transdifferentiation, i.e ductal-islet, ductal-acinar, acinar-ductal, acinar-islet, islet-acinar and islet-ductal cells. Although the possibility is discussed that cancer may arise from either islet, ductal or acinar cells, the circumstances favoring the islet cells as the tumor cell origin include their greater transdifferentiation potency into both pancreatic and extrapancreatic cells, the presence of a variety of carcinogen-metabolizing enzymes, some of which are present exclusively in islet cells and the growth factor-rich environment of islets.

  11. Ductal adenocarcinoma of the prostate: immunohistochemical findings and clinical significance

    Directory of Open Access Journals (Sweden)

    Sha JJ

    2013-10-01

    Full Text Available Jianjun Sha,1,2 Juanjie Bo,1 Jiahua Pan,1 Lianhua Zhang,1 Hanqing Xuan,1 Wei Chen,1 Dong Li,1 Zhaoliang Wang,1 Dongming Liu,1 Yiran Huang1,2 1Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 2School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, People's Republic of China Introduction: To investigate the clinical features, diagnosis, treatment, and prognosis of ductal adenocarcinoma of the prostate. Methods: The clinicopathological and immunohistochemical data of seven patients with ductal adenocarcinoma of the prostate were retrospectively analyzed. All patients underwent physical examination, magnetic resonance imaging (MRI, bone scan, cystoscopy, and computed tomography (CT scan. The level of prostate-specific antigen (PSA before and after surgery was assessed. Different prostate cancer markers were used for immunohistochemical staining. Results: The mean age of the seven patients diagnosed with prostatic ductal adenocarcinoma in this study was 76.2 years (range 57–88. Five patients presented with intermittent and painless gross hematuria, one patient with progressive dysuria, and one patient with elevated serum PSA on routine health examination. The level of PSA before surgery ranged from 1.3 to 45.0 ng/mL. Immunohistochemical staining results of the prostatic ductal adenocarcinoma confirmed positivity for PSA, prostatic acid phosphatase, androgen receptor, and alpha-methyacyl co-enzyme A (CoA-reductase markers. Two of the patients underwent bilateral orchiectomy combined with anti-androgen therapy, three underwent transurethral resection of prostate, one received radical prostatectomy, and one received medical castration therapy. The clinical outcomes of all patients were satisfactory, based on follow-up data. The symptoms of hematuria and dysuria were ameliorated well, and the postoperative PSA level decreased below 4.0 ng/mL. Recurrence or metastasis of disease was

  12. Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans.

    Science.gov (United States)

    Pour, P. M.; Weide, L.; Liu, G.; Kazakoff, K.; Scheetz, M.; Toshkov, I.; Ikematsu, Y.; Fienhold, M. A.; Sanger, W.

    1997-01-01

    To investigate the role of the islets of Langerhans in pancreatic carcinogenesis, freshly isolated islets from male Syrian hamsters were transplanted into the right submandibular glands of 50 female hamsters that were or were not pre-treated with streptozotocin. Thyroid gland fragments, cellulose powder, and immortal hamster pancreatic ductal cells were injected into the left submandibular gland of the same hamsters. All recipient hamsters were then treated with the potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine weekly at a dose of 40 mg/kg of body weight for 3 weeks. Between 3 and 8 weeks later, 18 of 75 (24%) hamsters developed large ductal-type adenocarcinomas in the submandibular gland region, where islets were transplanted, but none developed tumors in the left submandibular gland. In 9 of 18 hamsters, tumors were multiple so that a total of 31 cancers were found. Eleven of these carcinomas were in the vicinity of transplanted islets, eight of which showed intra-insular ductular or cyst formation as seen in the pancreas of hamsters during pancreatic carcinogenesis. The formation of ductular structures within islets was also demonstrated in vitro. Some tumor cells in the vicinity of these islets were reactive with anti-insulin. Y chromosome message was found by polymerase chain reaction analysis in one of the three tumors examined. Also, like the induced pancreatic tumors, all three submandibular gland tumors that were examined had the mutation of the c-Ki-ras oncogene at codon 12 and all tumors expressed blood group A antigen. These and other findings strongly suggest that some components of islets, most probably stem cells, are the origin of ductal-type adenocarcinomas in this model. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:9176407

  13. Number of evaluated lymph nodes and positive lymph nodes, lymph node ratio, and log odds evaluation in early-stage pancreatic ductal adenocarcinoma: numerology or valid indicators of patient outcome?

    Science.gov (United States)

    Lahat, G; Lubezky, N; Gerstenhaber, F; Nizri, E; Gysi, M; Rozenek, M; Goichman, Y; Nachmany, I; Nakache, R; Wolf, I; Klausner, J M

    2016-09-29

    We evaluated the prognostic significance and universal validity of the total number of evaluated lymph nodes (ELN), number of positive lymph nodes (PLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in a relatively large and homogenous cohort of surgically treated pancreatic ductal adenocarcinoma (PDAC) patients. Prospectively accrued data were retrospectively analyzed for 282 PDAC patients who had pancreaticoduodenectomy (PD) at our institution. Long-term survival was analyzed according to the ELN, PLN, LNR, and LODDS. Of these patients, 168 patients (59.5 %) had LN metastasis (N1). Mean ELN and PLN were 13.5 and 1.6, respectively. LN positivity correlated with a greater number of evaluated lymph nodes; positive lymph nodes were identified in 61.4 % of the patients with ELN ≥ 13 compared with 44.9 % of the patients with ELN < 13 (p = 0.014). Median overall survival (OS) and 5-year OS rate were higher in N0 than in N1 patients, 22.4 vs. 18.7 months and 35 vs. 11 %, respectively (p = 0.008). Mean LNR was 0.12; 91 patients (54.1 %) had LNR < 0.3. Among the N1 patients, median OS was comparable in those with LNR ≥ 0.3 vs. LNR < 0.3 (16.7 vs. 14.1 months, p = 0.950). Neither LODDS nor various ELN and PLN cutoff values provided more discriminative information within the group of N1 patients. Our data confirms that lymph node positivity strongly reflects PDAC biology and thus patient outcome. While a higher number of evaluated lymph nodes may provide a more accurate nodal staging, it does not have any prognostic value among N1 patients. Similarly, PLN, LNR, and LODDS had limited prognostic relevance.

  14. TMPRSS2-ERG gene fusions are infrequent in prostatic ductal adenocarcinomas.

    Science.gov (United States)

    Lotan, Tamara L; Toubaji, Antoun; Albadine, Roula; Latour, Mathieu; Herawi, Mehsati; Meeker, Alan K; DeMarzo, Angelo M; Platz, Elizabeth A; Epstein, Jonathan I; Netto, George J

    2009-03-01

    Ductal adenocarcinoma of the prostate is an unusual subtype that may be associated with a more aggressive clinical course, and is less responsive to conventional therapies than the more common prostatic acinar adenocarcinoma. However, given its frequent association with an acinar component at prostatectomy, some have challenged the concept of prostatic ductal adenocarcinoma as a distinct clinicopathologic entity. We studied the occurrence of the TMPRSS2-ERG gene fusion, in 40 surgically resected ductal adenocarcinoma cases, and in their associated acinar component using fluorescence in situ hybridization. A group of 38 'pure' acinar adenocarcinoma cases matched with the ductal adenocarcinoma group for pathological grade and stage was studied as a control. Compared with the matched acinar adenocarcinoma cases, the TMPRSS2-ERG gene fusion was significantly less frequently observed in ductal adenocarcinoma (45 vs 11% of cases, P=0.002, Fisher's exact test). Here, of the ductal adenocarcinoma cases with the gene fusion, 75% were fused through deletion, and the remaining case was fused through translocation. The TMPRSS2-ERG gene fusion was also rare in the acinar component of mixed ductal-acinar tumors when compared with the pure acinar adenocarcinoma controls (5 vs 45%, P=0.001, Fisher's exact test). In 95% of the ductal adenocarcinoma cases in which a concurrent acinar component was analyzed, there was concordance for presence/absence of the TMPRSS2-ERG gene fusion between the different histologic subtypes. In the control group of pure acinar adenocarcinoma cases, 59% were fused through deletion and 41% were fused through translocation. The presence of the TMPRSS2-ERG gene fusion in some cases of prostatic ductal adenocarcinoma supports the concept that ductal adenocarcinoma and acinar adenocarcinoma may be related genetically. However, the significantly lower rate of the gene fusion in pure ductal adenocarcinoma cases underscores the fact that genetic and biologic

  15. Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Funamizu, Naotake; Hu, Chaoxin; Lacy, Curtis; Schetter, Aaron; Zhang, Geng; He, Peijun; Gaedcke, Jochen; Ghadimi, Michael B; Ried, Thomas; Yfantis, Harris G; Lee, Dong H; Subleski, Jeffrey; Chan, Tim; Weiss, Jonathan M; Back, Timothy C; Yanaga, Katsuhiko; Hanna, Nader; Alexander, H Richard; Maitra, Anirban; Hussain, S Perwez

    2013-02-15

    MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer. Copyright © 2012 UICC.

  16. Biomarkers in pancreatic adenocarcinoma: current perspectives

    Directory of Open Access Journals (Sweden)

    Swords DS

    2016-12-01

    Full Text Available Douglas S Swords, Matthew A Firpo, Courtney L Scaife, Sean J Mulvihill Department of Surgery, University of Utah Health Sciences, Salt Lake City, UT, USA Abstract: Pancreatic ductal adenocarcinoma (PDAC has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9, which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA, CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC. Keywords: pancreatic cancer, biomarkers, screening, CA 19-9, CEA

  17. Model organoids provide new research opportunities for ductal pancreatic cancer

    NARCIS (Netherlands)

    Boj, Sylvia F; Hwang, Chang-Il; Baker, Lindsey A; Engle, Dannielle D; Tuveson, David A; Clevers, Hans

    We recently established organoid models from normal and neoplastic murine and human pancreas tissues. These organoids exhibit ductal- and disease stage-specific characteristics and, after orthotopic transplantation, recapitulate the full spectrum of tumor progression. Pancreatic organoid technology

  18. Pancreatic ductal bicarbonate secretion: challenge of the acinar acid load

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    Peter eHegyi

    2011-07-01

    Full Text Available Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel, however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.

  19. Solitary main pancreatic ductal calculus of possible biliary origin causing acute pancreatitis.

    Science.gov (United States)

    Chaparala, Ramakrishna Prasad Chowdary; Patel, Rafiuddin; Guthrie, James Ahsley; Davies, Mervyn Huw; Guillou, Pierre J; Menon, Krishna V

    2005-09-10

    Pancreatic ductal calculi are most often associated with chronic pancreatitis. Radiological features of chronic pancreatitis are readily evident in the presence of these calculi. However, acute pancreatitis due to a solitary main pancreatic ductal calculus of biliary origin is rare. A 59-year-old man presented with a first episode of acute pancreatitis. Contrast enhanced computerized tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP) revealed a calculus in the main pancreatic duct in the head of the pancreas causing acute pancreatitis. There were no features suggestive of chronic pancreatitis on CT scanning. The episode acute pancreatitis was managed conservatively. ERCP extraction of the calculus failed as the stone was impacted in the main pancreatic duct resulting in severe acute pancreatitis. Once this resolved, a transduodenal exploration and extraction of the pancreatic ductal calculus was performed successfully. Crystallographic analysis revealed the composition of the calculus was different to that seen in chronic pancreatitis, but more in keeping with a calculus of biliary origin. This could be explained by migration of the biliary calculus via the common channel into the main pancreatic duct. Following the operation the patient made an uneventful recovery and was well at two-year follow up. Acute pancreatitis due to a solitary main pancreatic ductal calculus of biliary origin is rare. Failing endoscopic extraction, transduodenal exploration and extraction is a safe option after resolution of acute pancreatitis.

  20. Lateral Pancreaticojejunostomy for Chronic Pancreatitis and Pancreatic Ductal Dilation in Children.

    Science.gov (United States)

    Shah, Adil A; Petrosyan, Mikael; Kane, Timothy D

    2018-06-06

    Pancreatic ductal obstruction leading to ductal dilation and recurrent pancreatitis is uncommon in children. Treatment is dependent upon etiology but consists of decompression of the pancreatic duct (PD) proximally, if possible, by endoscopic retrograde cholangiopancreatography (ERCP) intervention or surgical decompression with pancreaticojejunal anastomosis. After institutional review board approval, we retrospectively reviewed the records for 2 children who underwent lateral pancreaticojejunostomy for pancreatic ductal dilation. Data, including demographics, diagnostic studies, operative details, complications, outcomes, and follow-up, were analyzed. Case 1 was a 4-year-old female with pancreatic ductal obstruction with multiple episodes of recurrent pancreatitis and failure of ERCP to clear her PD of stones. She underwent a laparoscopic cholecystectomy with a lateral pancreaticojejunostomy (Puestow procedure). She recovered well with no further episodes of pancreatitis and normal pancreatic function 4 years later. Case 2 was a 2-year-old female who developed recurrent pancreatitis and was found to have papillary stenosis and long common bile-PD channel. Despite multiple sphincterotomies, laparoscopic cholecystectomy, and laparoscopic hepaticoduodenostomy, she continued to experience episodes of pancreatitis. She underwent a laparoscopy converted to open lateral pancreaticojejunostomy. Her recovery was also smooth having had no episodes of pancreatitis or hospital admissions for over 2 years following the Puestow. Indication for lateral pancreaticojejunostomy or Puestow procedure is rare in children and even less often performed using laparoscopy. In our small experience, both patients with pancreatic ductal obstruction managed with Puestow's procedure enjoy durable symptom and pain relief in the long term.

  1. [Management of localized, locally advanced and metastatic pancreatic adenocarcinoma].

    Science.gov (United States)

    Delpero, Jean-Robert; Turrini, Olivier; Raoul, Jean-Luc

    2015-03-01

    Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy. The prognosis is extremely poor because PDAC is usually a systemic disease at diagnosis. All stages, the survival does not exceed 5% at 5 years. However 15% of PDAC can be resected and today a margin-negative resection followed by adjuvant chemotherapy remains the only potential for a prolonged survival. Postoperative mortality had significantly decreased and the benefit of postoperative adjuvant chemotherapy has been clearly shown. Substantial progress has been made in the field of palliative chemotherapy by introducing new chemotherapy regimens (FOLFIRINOX [folinic acid, 5-fluorouracil, irinotecan and oxaliplatin] and gemcitabine/nab-paclitaxel), when the patient's performance status allows the use of these drugs. The role of radiation therapy remains controversial.

  2. Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine Neoplasia pancreática intraepithelial e adenocarcinoma ductal induzidos pelo DMBA em camundongos: efeitos do álcool e da cafeína

    Directory of Open Access Journals (Sweden)

    Luiz Roberto Wendt

    2007-06-01

    Full Text Available PURPOSE: To evaluate the effects of alcohol and caffeine in a pancreatic carcinogenesis mouse model induced by 7,12-dimethylbenzantracene (DMBA, according to the PanIN classification system. METHODS: 120 male, Mus musculus, CF-1 mice were divided into four groups. Animals received either water or caffeine or alcohol or alcohol + caffeine in their drinking water. In all animals, 1 mg of DMBA was implanted into the head of the pancreas. After 30 days, euthanasia was performed; excised pancreata were then fixed in formalin, stained with hematoxylin-eosin and categorized as follows: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 or adenocarcinoma. RESULTS: PanIN lesions were verified in all groups. Adenocarcinoma was detected in 15% of animals in the caffeine group, 16.6% in the water group, 23.8% in the alcohol + caffeine group and 52.9% in the alcohol group (POBJETIVO: Avaliar os efeitos do álcool e da cafeína na carcinogênese pancreática induzida pelo 7,12-dimetilbenzantraceno (DMBA em camundongos, descrevendo as lesões de acordo com a classificação das neoplasias pacreáticas intraepiteliais (PanIN. MÉTODOS: 120 camundogos machos, Mus musculus, CF-1 foram divididos em quatro grupos. Animais receberam água ou cafeína ou álcool ou álcool + cafeína para beber. Em todos animais, 1 mg de DMBA foi implantado na cabeça do pâncreas. Após 30 dias, eutanásia foi realizada, o pâncreas foi removido, fixado em formalina e corado com hematoxilina e eosina sendo classificado em: ductos normais, hiperplasia reativa, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 ou adenocarcinoma. RESULTADOS: Neoplasias pancreáticas intraepiteliais foram encontradas em todos grupos. Adenocarcinoma foi detectado em 15% dos animais do grupo cafeína, 16,6% do grupo água, 23,8% do grupo álcool + cafeína e 52,9% do grupo álcool (P<0,05. CONCLUSÕES: O modelo experimental de carcinogênese pancreática em camundongos utilizando DMBA induz

  3. Focal pancreatic enlargement: differentiation between pancreatic adenocarcinoma and focal pancreatitis on CT and ERCP

    International Nuclear Information System (INIS)

    Kim, Eun Kyung; Kim, Ki Whang; Lee, Jong Tae; Kim, Hee Soo; Yoo, Hyung Sik; Yu, Jeong Sik; Yoon, Sang Wook

    1995-01-01

    To differentiate the pancreatic adenocarcinoma from focal pancreatitis on CT and ERCP in cases of focal pancreatic enlargement. We analysed CT findings of 66 patients of pancreatic adenocarcinoma (n = 45) or focal pancreatitis (n = 21) with respect to size, density, calcification, pancreatic or biliary duct dilatation, fat plane obliteration around the vessels, direction of retroperitoneal extension, lymphadenopathy, pseudocyst formation and atrophy of pancreas. ERCP available in 48 patients were analysed in respect to morphologic appearance of CBD and pancreatic duct, and distance between the two ducts. The patients in focal pancreatitis were younger with more common history of alcohol drinking. There was no statistical difference in calcifications of the mass (18% in the adenocarcinoma, 33% in the focal pancreatitis), but a tendency of denser, larger number of calcifications was noted in focal pancreatitis. The finding of fat plane obliteration around the vessels were more common in pancreatic adenocarcinoma, and fascial thickenings were more prominent in focal pancreatitis, although not statistically significant. On ERCP, there were no differential points of CBD, pancreatic duct morphology, but distance between the two ducts at the lesion center was more wider in focal pancreatitis. Differentiating focal pancreatitis from pancreatic adenocarcinoma is difficult. However, we should consider the possibility of focal pancreatitis in cases of patients with young age, having alcoholic history in association with CT findings of large numbers of and dense calcifications, and ERCP findings of prominent separation of two duct at the lesion center

  4. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

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    Thilo Welsch

    Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold

  5. Ductal adenocarcinoma and unusual differential diagnosis; Duktales Adenokarzinom und ungewoehnliche Differenzialdiagnosen

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    Haage, P.; Schwartz, C.A.; Scharwaechter, C. [Universitaet Witten/Herdecke, Zentrum fuer Radiologie HELIOS Universitaetsklinikum Wuppertal, Wuppertal (Germany)

    2016-04-15

    Ductal pancreatic adenocarcinoma is by far the most common solid tumor of the pancreas. It has a very poor prognosis, especially in the more advanced stages which are no longer locally confined. Due to mostly unspecific symptoms, imaging is key in the diagnostic process. Because of the widespread use of imaging techniques, incidental findings are to a greater extent discovered in the pancreas, which subsequently entail further work-up. Ductal pancreatic adenocarcinoma can be mimicked by a large number of different lesions, such as anatomical variants, peripancreatic structures and tumors, rarer primary solid pancreatic tumors, cystic tumors, metastases or different variants of pancreatitis. Additionally, a number of precursor lesions can be differentiated. The correct classification is thus important as an early diagnosis of ductal pancreatic adenocarcinoma is relevant for the prognosis and because the possibly avoidable treatment is very invasive. All major imaging techniques are principally suitable for pancreatic imaging. In addition to sonography of the abdomen, usually the baseline diagnostic tool, computed tomography (CT) with its superior spatial resolution, magnetic resonance imaging (MRI) with its good soft tissue differentiation capabilities, possibly in combination with MR cholangiopancreatography (MRCP), endosonography with its extraordinary spatial resolution, conceivably with additional endoscopic retrograde CP or the option of direct biopsy and finally positron emission tomography CT (PET-CT) as a molecular imaging tool are all particularly useful modalities. The various techniques all have its advantages and disadvantages; depending on the individual situation they may need to be combined. (orig.) [German] Das duktale Adenokarzinom ist der weitaus haeufigste solide Tumor des Pankreas. Die Prognose ist sehr schlecht, insbesondere bei fortgeschrittenen, nicht mehr lokal begrenzten Tumoren. Bei meist unspezifischen geringen Beschwerden kommt der

  6. Pancreatic adenocarcinoma and diabetes mellitus

    International Nuclear Information System (INIS)

    Novotna, T.

    2015-01-01

    Impaired glucose tolerance or frank diabetes mellitus is known to occur more frequently in patients with pancreatic cancer than in the general population. At the time of the diagnosis of pancreatic cancer, more than 70% of patients taking the glucose tolerance test show diabetes or impaired glucose tolerance (1). Relationship among diabetes mellitus and pancreatic cancer is vague but sure, although neither the nature nor the sequence of the possible cause – effect relationship has been established. The reason for the high frequency of glucose intolerance in patients with pancreatic cancer remains controversial. (author)

  7. Antimicrobial Peptide Human Neutrophil Peptide 1 as a Potential Link Between Chronic Inflammation and Ductal Adenocarcinoma of the Pancreas.

    Science.gov (United States)

    Pausch, Thomas; Adolph, Sarah; Felix, Klaus; Bauer, Andrea S; Bergmann, Frank; Werner, Jens; Hartwig, Werner

    Defensins are antimicrobial peptides playing a role in innate immunity, in epithelial cell regeneration, and in carcinogenesis of inflammation-triggered malignancies. We analyzed this role in pancreatic ductal adenocarcinoma (PDAC) in the context of its association with chronic pancreatitis (CP). Human tissue of healthy pancreas, CP, and PDAC was screened for defensins by immunohistochemistry. Defensin α 1 (human neutrophil peptide 1 [HNP-1]) expression was validated using mass spectrometry and microarray analysis. Human neutrophil peptide 1 expression and influences of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, and interferon γ) were studied in human pancreatic cancer cells (Colo 357, T3M4, PANC-1) and normal human pancreatic duct epithelial cells (HPDE). Accumulation of HNP-1 in malignant pancreatic ductal epithelia was seen. Spectrometry showed increased expression of HNP-1 in CP and even more in PDAC. At RNA level, no significant regulation was found. In cancer cells, HNP-1 expression was significantly higher than in HPDE. Proinflammatory cytokines significantly led to increased HNP-1 levels in culture supernatants and decreased levels in lysates of cancer cells. In HPDE cytokines significantly decreased HNP-1 levels. Inflammatory regulation of HNP-1 in PDAC tissue and cells indicates that HNP-1 may be a link between chronic inflammation and malignant transformation in the pancreas.

  8. Organoid Models of Human and Mouse Ductal Pancreatic Cancer

    Science.gov (United States)

    Boj, Sylvia F.; Hwang, Chang-Il; Baker, Lindsey A.; Chio, Iok In Christine; Engle, Dannielle D.; Corbo, Vincenzo; Jager, Myrthe; Ponz-Sarvise, Mariano; Tiriac, Hervé; Spector, Mona S.; Gracanin, Ana; Oni, Tobiloba; Yu, Kenneth H.; van Boxtel, Ruben; Huch, Meritxell; Rivera, Keith D.; Wilson, John P.; Feigin, Michael E.; Öhlund, Daniel; Handly-Santana, Abram; Ardito-Abraham, Christine M.; Ludwig, Michael; Elyada, Ela; Alagesan, Brinda; Biffi, Giulia; Yordanov, Georgi N.; Delcuze, Bethany; Creighton, Brianna; Wright, Kevin; Park, Youngkyu; Morsink, Folkert H.M.; Molenaar, I. Quintus; Borel Rinkes, Inne H.; Cuppen, Edwin; Hao, Yuan; Jin, Ying; Nijman, Isaac J.; Iacobuzio-Donahue, Christine; Leach, Steven D.; Pappin, Darryl J.; Hammell, Molly; Klimstra, David S.; Basturk, Olca; Hruban, Ralph H.; Offerhaus, George Johan; Vries, Robert G.J.; Clevers, Hans; Tuveson, David A.

    2015-01-01

    SUMMARY Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation and exhibit ductal- and disease stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy. PMID:25557080

  9. ERP in chronic pancreatitis - ductal morphology, relation to exocrine function and pain - clinical value

    International Nuclear Information System (INIS)

    Norup Lauridsen, K.; Raahede, J.; Kruse, A.; Thommesen, P.; Aarhus Univ.

    1985-01-01

    ERP was analyzed in 87 patients with chronic pancreatitis with special reference to its clinical value in management of pain, the dominating symptom in uncomplicated chronic pancreatitis. A significant correlation was found between ductal changes due to pancreatitis and decrease in pancreatic function. However, no association was found between severe pancreatic pain and pancreatic function or pancreatic morphology. The significance of ERP in management of patients with persistent severe pancreatic pain is discussed. (orig.) [de

  10. A unifying concept: pancreatic ductal anatomy both predicts and determines the major complications resulting from pancreatitis.

    Science.gov (United States)

    Nealon, William H; Bhutani, Manoop; Riall, Taylor S; Raju, Gottumukkala; Ozkan, Orhan; Neilan, Ryan

    2009-05-01

    Precepts about acute pancreatitis, necrotizing pancreatitis, and pancreatic fluid collections or pseudocyst rarely include the impact of pancreatic ductal injuries on their natural course and outcomes. We previously examined and established a system to categorize ductal changes. We sought a unifying concept that may predict course and direct therapies in these complex patients. We use our system categorizing ductal changes in pseudocyst of the pancreas and severe necrotizing pancreatitis (type I, normal duct; type II, duct stricture; type III, duct occlusion or "disconnected duct"; and type IV, chronic pancreatitis). From 1985 to 2006, a policy was implemented of routine imaging (cross-sectional, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography). Clinical outcomes were measured. Among 563 patients with pseudocyst, 142 resolved spontaneously (87% of type I, 5% of type II, and no type III, and 3% of type IV). Percutaneous drainage was successful in 83% of type I, 49% of type II, and no type III or type IV. Among 174 patients with severe acute pancreatitis percutaneous drainage was successful in 64% of type I, 38% of type II, and no type III. Operative debridement was required in 39% of type I and 83% and 85% of types II and III, respectively. Persistent fistula after debridement occurred in 27%, 54%, and 85% of types I, II, and III ducts, respectively. Late complications correlated with duct injury. Pancreatic ductal changes predict spontaneous resolution, success of nonoperative measures, and direct therapies in pseudocyst. Ductal changes also predict patients with necrotizing pancreatitis who are most likely to have immediate and delayed complications.

  11. Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.

    Science.gov (United States)

    Wauters, Elke; Sanchez-Arévalo Lobo, Victor J; Pinho, Andreia V; Mawson, Amanda; Herranz, Daniel; Wu, Jianmin; Cowley, Mark J; Colvin, Emily K; Njicop, Erna Ngwayi; Sutherland, Rob L; Liu, Tao; Serrano, Manuel; Bouwens, Luc; Real, Francisco X; Biankin, Andrew V; Rooman, Ilse

    2013-04-01

    The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. ©2012 AACR.

  12. Clinical predictors of resectability of pancreatic adenocarcinoma.

    Science.gov (United States)

    Almadi, Majid A; Alharbi, Othman; Azzam, Nahla; Altayeb, Mohannad; Javed, Moammed; Alsaif, Faisal; Hassanain, Mazen; Alsharabi, Abdulsalam; Al-Saleh, Khalid; Aljebreen, Abdulrahman M

    2013-01-01

    Identifying patient-related factors as well as symptoms and signs that can predict pancreatic cancer at a resectable stage, which could be used in an attempt to identify patients at an early stage of pancreatic cancer that would be appropriate for surgical resection and those at an unresectable stage be sparred unnecessary surgery. A retrospective chart review was conducted at a major tertiary care, university hospital in Riyadh, Saudi Arabia. The study population included individuals who underwent a computed tomography and a pancreatic mass was reported as well as the endoscopic reporting database of endoscopic procedures where the indication was a pancreatic mass, between April 1996 and April 2012. Any patient with a histologically confirmed diagnosis of adenocarcinoma of the pancreas was included in the analysis. We included patients' demographic information (age, gender), height, weight, body mass index, historical data (smoking, comorbidities), symptoms (abdominal pain and its duration, anorexia and its duration, weight loss and its amount, and over what duration, vomiting, abdominal distention, itching and its duration, change in bowel movements, change in urine color), jaundice and its duration. Other variables were also collected including laboratory values, location of the mass, the investigation undertaken, and the stage of the tumor. A total of 61 patients were included, the mean age was 61.2 ± 1.51 years, 25 (41%) were females. The tumors were located in the head (83.6%), body (10.9%), tail (1.8%), and in multiple locations (3.6%) of the pancreas. Half of the patients (50%) had Stage IV, 16.7% stages IIB and III, and only 8.3% were stages IB and IIA. On univariable analysis a lower hemoglobin level predicted resectability odds ratio 0.65 (95% confidence interval, 0.42-0.98), whereas on multivariable regression none of the variables included in the model could predict resectability of pancreatic cancer. A CA 19-9 cutoff level of 166 ng/mL had a

  13. Prostatic intraepithelial neoplasia-like ductal prostatic adenocarcinoma: A case suitable for active surveillance?

    Directory of Open Access Journals (Sweden)

    Soroush Rais-Bahrami

    2017-01-01

    Full Text Available In contrast to typical prostatic ductal adenocarcinoma, prostatic intraepithelial neoplasia (PIN-like ductal adenocarcinoma is a rare variant of prostate cancer with low-grade clinical behavior. We report a case of a 66-year-old African-American male with an elevated serum prostate-specific antigen who underwent multiparametric prostate magnetic resonance imaging (MRI and MRI/ultrasound fusion-guided biopsies. Pathology demonstrated low-volume Gleason score 3 + 3 = 6 (Grade Group 1, acinar adenocarcinoma involving one core and PIN-like ductal adenocarcinoma on a separate core. Herein, we discuss the potential role of active surveillance for patients with this rare variant of prostate cancer found in the era of advanced imaging with multiparametric MRI for prostate cancer.

  14. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient

    Directory of Open Access Journals (Sweden)

    Sarah Pfrommer

    2013-09-01

    Full Text Available Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life.

  15. Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology.

    Science.gov (United States)

    Ferri, María José; Saez, Marc; Figueras, Joan; Fort, Esther; Sabat, Miriam; López-Ben, Santiago; de Llorens, Rafael; Aleixandre, Rosa Núria; Peracaula, Rosa

    2016-01-01

    There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19-9 (CA 19-9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies. CA 19-9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls. The combination of CA 19-9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19-9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients. Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.

  16. Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology.

    Directory of Open Access Journals (Sweden)

    María José Ferri

    Full Text Available There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19-9 (CA 19-9 is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies.CA 19-9, carcinoembryonic antigen (CEA, C-reactive protein, albumin, insulin growth factor-1 (IGF-1 and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls.The combination of CA 19-9, IGF-1 and albumin resulted in a combined area under the curve (AUC of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19-9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients.Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.

  17. Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans.

    OpenAIRE

    Pour, P. M.; Weide, L.; Liu, G.; Kazakoff, K.; Scheetz, M.; Toshkov, I.; Ikematsu, Y.; Fienhold, M. A.; Sanger, W.

    1997-01-01

    To investigate the role of the islets of Langerhans in pancreatic carcinogenesis, freshly isolated islets from male Syrian hamsters were transplanted into the right submandibular glands of 50 female hamsters that were or were not pre-treated with streptozotocin. Thyroid gland fragments, cellulose powder, and immortal hamster pancreatic ductal cells were injected into the left submandibular gland of the same hamsters. All recipient hamsters were then treated with the potent pancreatic carcinog...

  18. Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.

    Science.gov (United States)

    Ding, Li; Liou, Geou-Yarh; Schmitt, Daniel M; Storz, Peter; Zhang, Jin-San; Billadeau, Daniel D

    2017-09-01

    Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras G12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. Soft-tissue metastasis revealing a pancreatic adenocarcinoma: One ...

    African Journals Online (AJOL)

    Soft tissue metastases from pancreatic adenocarcinoma are rare lesions and can be the source of diagnostic confusion both clinically and pathologically. To our knowledge, one patient has been reported on with soft tissue lesions that ultimately disclose a pancreatic adenocarcinoma. We report here on a patient who ...

  20. Algenpantucel-L immunotherapy in pancreatic adenocarcinoma.

    Science.gov (United States)

    Coveler, Andrew L; Rossi, Gabriela R; Vahanian, Nicholas N; Link, Charles; Chiorean, E Gabriela

    2016-02-01

    Pancreatic adenocarcinoma is the 4th leading cause of cancer death in the USA and the EU. A minority of patients presents with surgically resectable and potentially curable disease, but among these, 80% are destined to relapse and overall survival rates with adjuvant chemotherapy average 24 months. Immunotherapy is a promising therapeutic option and a potential paradigm shift in the treatment of patients with pancreatic cancer, and may be particularly effective when used early in the disease course to prevent metastatic spread. Algenpantucel-L (HyperAcute Pancreas, NewLink Genetics, Ames, IA, USA) is a whole-cell immunotherapy consisting of irradiated allogeneic pancreatic cancer cells genetically engineered to express the murine enzyme α-GT, which results in hyperacute rejection of the tumor cells with complement- and antibody-dependent cytotoxicity. Phase II clinical trial data has been encouraging, particularly for patients who demonstrated humoral immunologic responses. Here, we report preliminary results and biomarkers correlations with clinical activity of algenpantucel-L in pancreatic cancer.

  1. Obstructive jaundice secondary to pancreatic head adenocarcinoma in a young teenage boy: a case report

    Directory of Open Access Journals (Sweden)

    Khattab Mohammed

    2011-09-01

    Full Text Available Abstract Introduction Pancreatic adenocarcinoma is extremely rare in childhood. We report a case of metastatic pancreatic adenocarcinoma in a 13-year-old boy, revealed by jaundice. Case presentation A 13-year-old Moroccan boy was admitted with obstructive jaundice to the children's Hospital of Rabat, Department of Pediatric Oncology. Laboratory study results showed a high level of total and conjugated bilirubin. Computerized tomography of the abdomen showed a dilatation of the intra-hepatic and extra-hepatic bile ducts with a tissular heterogeneous tumor of the head of the pancreas and five hepatic lesions. Biopsy of a liver lesion was performed, and a histopathological examination of the sample confirmed the diagnosis of metastatic ductal adenocarcinoma of the pancreas. Our patient underwent a palliative biliary derivation. After that, chemotherapy was administered (5-fluorouracil and epirubicin, however no significant response to treatment was noted and our patient died six months after diagnosis. Conclusion Malignant pancreatic tumors, especially ductal carcinomas, are exceedingly rare in the pediatric age group and their clinical features and treatment usually go unappreciated by most pediatric oncologists and surgeons.

  2. BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-induced Apoptosis

    Directory of Open Access Journals (Sweden)

    Christina A. Wicker

    2009-01-01

    Full Text Available Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12, which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC. BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways.

  3. Syk Tyrosine Kinase Acts as a Pancreatic Adenocarcinoma Tumor Suppressor by Regulating Cellular Growth and Invasion

    OpenAIRE

    Layton, Tracy; Stalens, Cristel; Gunderson, Felizza; Goodison, Steve; Silletti, Steve

    2009-01-01

    We have identified the nonreceptor tyrosine kinase syk as a marker of differentiation/tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Syk expression is lost in poorly differentiated PDAC cells in vitro and in situ, and stable reexpression of syk in endogenously syk-negative Panc1 (Panc1/syk) cells retarded their growth in vitro and in vivo and reduced anchorage-independent growth in vitro. Panc1/syk cells exhibited a more differentiated morphology and down-regulated cyclin D1, ak...

  4. Expression of the Antiapoptotic Protein BAG3 Is a Feature of Pancreatic Adenocarcinoma and Its Overexpression Is Associated With Poorer Survival

    NARCIS (Netherlands)

    Rosati, Alessandra; Bersani, Samantha; Tavano, Francesca; Dalla Pozza, Elisa; de Marco, Margot; Palmieri, Marta; de Laurenzi, Vincenzo; Franco, Renato; Scognamiglio, Giosuè; Palaia, Raffaele; Fontana, Andrea; di Sebastiano, Pierluigi; Donadelli, Massimo; Dando, Ilaria; Medema, Jan Paul; Dijk, Frederike; Welling, Lieke; di Mola, Fabio Francesco; Pezzilli, Raffaele; Turco, Maria Caterina; Scarpa, Aldo

    2012-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A

  5. Chronic Pancreatitis.

    Science.gov (United States)

    Stram, Michelle; Liu, Shu; Singhi, Aatur D

    2016-12-01

    Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. SMAD4 loss enables EGF, TGF?1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

    OpenAIRE

    Moz, Stefania; Basso, Daniela; Bozzato, Dania; Galozzi, Paola; Navaglia, Filippo; Negm, Ola H.; Arrigoni, Giorgio; Zambon, Carlo-Federico; Padoan, Andrea; Tighe, Paddy; Todd, Ian; Franchin, Cinzia; Pedrazzoli, Sergio; Punzi, Leonardo; Plebani, Mario

    2016-01-01

    Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor ?1 (TGF?1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGF?1 and S100A8/A...

  7. Management of unresectable, locally advanced pancreatic adenocarcinoma.

    Science.gov (United States)

    Salgado, M; Arévalo, S; Hernando, O; Martínez, A; Yaya, R; Hidalgo, M

    2018-02-01

    The diagnosis of unresectable locally advanced pancreatic adenocarcinoma (LAPC) requires confirmation, through imaging tests, of the unfeasibility of achieving a complete surgical resection, in the absence of metastatic spread. The increase in overall survival (OS), together with an appropriate symptom management is the therapeutic target in LAPC, maintaining an acceptable quality of life and, if possible, increasing the time until the appearance of metastasis. Chemoradiation (CRT) improves OS compared to best support treatment or radiotherapy (RT) but with greater toxicity. No significant increase in OS has been achieved with CRT when compared to chemotherapy (QT) alone in patients without disease progression after four months of treatment with QT. However, a significantly better local control, that is, a significant increase in the time to disease progression was associated with this approach. The greater effectiveness of the schemes FOLFIRINOX and gemcitabine (Gem) + Nab-paclitaxel compared to gemcitabine alone, has been extrapolated from metastatic disease to LAPC, representing a possible alternative for patients with good performance status (ECOG 0-1). In the absence of randomized clinical trials, Gem is the standard treatment in LAPC. If disease control is achieved after 4-6 cycles of QT, the use of CRT for consolidation can be considered an option vs QT treatment maintenance. Capecitabine has a better toxicity profile and effectiveness compared to gemcitabine as a radiosensitizer. After local progression, and without evidence of metastases, treatment with RT or CRT, in selected patients, can support to maintain the regional disease control.

  8. Radiofrequency assisted pancreaticoduodenectomy for palliative surgical resection of locally advanced pancreatic adenocarcinoma.

    Science.gov (United States)

    Kumar, Jayant; Reccia, Isabella; Sodergren, Mikael H; Kusano, Tomokazu; Zanellato, Artur; Pai, Madhava; Spalding, Duncan; Zacharoulis, Dimitris; Habib, Nagy

    2018-03-20

    Despite careful patient selection and preoperative investigations curative resection rate (R0) in pancreaticoduodenectomy ranges from 15% to 87%. Here we describe a new palliative approach for pancreaticoduodenectomy using a radiofrequency energy device to ablate tumor in situ in patients undergoing R1/R2 resections for locally advanced pancreatic ductal adenocarcinoma where vascular reconstruction was not feasible. There was neither postoperative mortality nor significant morbidity. Each time the ablation lasted less than 15 minutes. Following radiofrequency ablation it was observed that the tumor remnant attached to the vessel had shrunk significantly. In four patients this allowed easier separation and dissection of the ablated tumor from the adherent vessel leading to R1 resection. In the other two patients, the ablated tumor did not separate from vessel due to true tumor invasion and patients had an R2 resection. The ablated remnant part of the tumor was left in situ. Whenever pancreaticoduodenectomy with R0 resection cannot be achieved, this new palliative procedure could be considered in order to facilitate resection and enable maximum destruction in remnant tumors. Six patients with suspected tumor infiltration and where vascular reconstruction was not warranted underwent radiofrequency-assisted pancreaticoduodenectomy for locally advanced pancreatic ductal adenocarcinoma. Radiofrequency was applied across the tumor vertically 5-10 mm from the edge of the mesenteric and portal veins. Following ablation, the duodenum and the head of pancreas were removed after knife excision along the ablated line. The remaining ablated tissue was left in situ attached to the vessel.

  9. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.

    Science.gov (United States)

    Hu, Zishuo I; Shia, Jinru; Stadler, Zsofia K; Varghese, Anna M; Capanu, Marinela; Salo-Mullen, Erin; Lowery, Maeve A; Diaz, Luis A; Mandelker, Diana; Yu, Kenneth H; Zervoudakis, Alice; Kelsen, David P; Iacobuzio-Donahue, Christine A; Klimstra, David S; Saltz, Leonard B; Sahin, Ibrahim H; O'Reilly, Eileen M

    2018-03-15

    Purpose: Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC. Experimental Design: Archival and prospectively acquired samples and matched normal DNA from N = 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status. Results: MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease). Conclusions: An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients. Clin Cancer Res; 24(6); 1326-36. ©2018 AACR . ©2018 American Association for Cancer Research.

  10. Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice.

    Science.gov (United States)

    Quirin, Kayla A; Kwon, Jason J; Alioufi, Arafat; Factora, Tricia; Temm, Constance J; Jacobsen, Max; Sandusky, George E; Shontz, Kim; Chicoine, Louis G; Clark, K Reed; Mendell, Joshua T; Korc, Murray; Kota, Janaiah

    2018-03-16

    Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 10 12 viral genomes (vg). Intraductal delivery of 1 × 10 11 vg scAAV6.GFP transduced acini, ductal cells, and islet cells with >50%, ∼48%, and >80% efficiency, respectively, and >80% pancreatic transduction was achieved with 5 × 10 11 vg. In a Kras G12D -driven pancreatic cancer mouse model, intraductal delivery of scAAV6.GFP targeted acini, epithelial, and stromal cells and exhibited persistent gene expression 5 months post-delivery. In normal mice, intraductal delivery induced a transient increase in serum amylase/lipase that resolved within a day of infusion with no sustained pancreatic inflammation or fibrosis. Similarly, in PDAC mice, intraductal delivery did not increase pancreatic intraepithelial neoplasia progression/fibrosis. Our study demonstrates that scAAV6 targets the pancreas/neoplasm efficiently and safely via retrograde pancreatic intraductal delivery.

  11. Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice

    Directory of Open Access Journals (Sweden)

    Kayla A. Quirin

    2018-03-01

    Full Text Available Recombinant adeno-associated virus (rAAV-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9 expressing GFP in a self-complementary (sc AAV vector under an EF1α promoter (scAAV.GFP following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg. Intraductal delivery of 1 × 1011 vg scAAV6.GFP transduced acini, ductal cells, and islet cells with >50%, ∼48%, and >80% efficiency, respectively, and >80% pancreatic transduction was achieved with 5 × 1011 vg. In a KrasG12D-driven pancreatic cancer mouse model, intraductal delivery of scAAV6.GFP targeted acini, epithelial, and stromal cells and exhibited persistent gene expression 5 months post-delivery. In normal mice, intraductal delivery induced a transient increase in serum amylase/lipase that resolved within a day of infusion with no sustained pancreatic inflammation or fibrosis. Similarly, in PDAC mice, intraductal delivery did not increase pancreatic intraepithelial neoplasia progression/fibrosis. Our study demonstrates that scAAV6 targets the pancreas/neoplasm efficiently and safely via retrograde pancreatic intraductal delivery.

  12. Paratesticular adenocarcinoma. Unusual presentation of metastasis of pancreatic cancer

    International Nuclear Information System (INIS)

    Ocvirk, J.; Seruga, B.

    2007-01-01

    Metastatic paratesticular adenocarcinoma from the pancreatic cancer is very rare. To our knowledge, there are less than 20 cases published in the literature. We experienced a case of paratesticular adenocarcinoma from the primary pancreatic cancer. A 42-year-old man was presented with locoregionally advanced carcinoma of the tail of the pancreas with intraoperatively found liver metastases and with a tumour in the right hemi-scrotum. Ultrasound of the scrotum revealed a paratesticular tumour. A fine needle aspiration biopsy (FNAB) confirmed a poorly differentiated adenocarcinoma and it was in concordance with the diagnosis of the primary tumour. The patient started treatment with chemotherapy with gemcitabine. Unfortunately, he progressed one month later and the treatment was discontinued. Outcome in the adenocarcinoma of the pancreas is dismal. The only possible treatment option for metastatic disease is systemic therapy but the results are disappointing, as in the present case. (author)

  13. Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Anita Balázs

    2018-05-01

    Full Text Available Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP, therefore we aimed to (i investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii to correlate the mucus phenotype with epithelial ion transport function.Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.

  14. Ansa Pancreatica: A Case Report of a Type of Ductal Variation in a Patient with Idiopathic Acute Recurrent Pancreatitis

    International Nuclear Information System (INIS)

    Kim, Hye Mi; Park, Jung Yup; Kim, Myeong Jin

    2010-01-01

    Ansa pancreatica is a rare type of pancreatic ductal variation. Recently, ansa pancreatic has been considered as a predisposing factor in patients with idiopathic acute pancreatitis. To the best of our knowledge, no previously published report in Korea has described ansa pancreatica. We report a case of acute recurrent pancreatitis with ansa pancreatica, which was revealed on magnetic resonance cholangiopancreatography (MRCP)

  15. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    Science.gov (United States)

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

  16. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    Science.gov (United States)

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  17. Nanoparticle albumin-bound (nab)-paclitaxel for the treatment of pancreas ductal adenocarcinoma

    OpenAIRE

    Weekes, Colin; Narayanan,Vignesh

    2015-01-01

    Vignesh Narayanan,1 Colin D Weekes1,2 1Division of Medical Oncology, Department of Medicine, 2Developmental Therapeutics Program, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA Abstract: Pancreatic adenocarcinoma is a leading cause of cancer-related mortality worldwide, and surgical resection offers the only chance of cure. Since the majority of patients have unresectable disease at presentation, the emphasis has been on identifying effective...

  18. Two cases of chronic pancreatitis associated with anomalous pancreaticobiliary ductal union and SPINK1 mutation

    Directory of Open Access Journals (Sweden)

    Eun Sam Rho

    2013-05-01

    Full Text Available Chronic pancreatitis is a progressive inflammatory disease resulting from repeated episodes of acute pancreatitis that impair exocrine function and eventually produce endocrine insufficiency. Some causes of chronic pancreatitis appear to be associated with alterations in the serine&#8211;protease inhibitor, Kazal type 1 (SPINK1 , cationic trypsinogen (PRSS1 , and cystic fibrosis&#8211;transmembrane conductance regulator (CFTR genes, or with structural disorders in the pancreaticobiliary ductal system, such as pancreatic divisum or anomalous pancreaticobiliary ductal union (APBDU. However, it is unusual to observe both genetic alteration and structural anomaly. Here, we report 2 cases with both APBDU and a mutation in the SPINK1 genes, and we discuss the implications of these findings in clinical practice.

  19. Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

    Directory of Open Access Journals (Sweden)

    Green Richard M

    2010-03-01

    Full Text Available Abstract Background BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP. BSEP disease is associated with an increased risk of hepatobiliary cancer. Case Presentation A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat. Conclusions Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.

  20. ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC)

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter; Novak, Ivana; Pedersen, Stine Helene Falsig

    2015-01-01

    function has only been poorly understood. The aim of the present study is to establish the significance of ANO1 in PDAC behavior and demarcate its roles in PDAC from those of the volume-regulated anion channel (VRAC). We performed qPCR and Western blot measurements on different PDAC cell lines (Panc-1, Mia...

  1. pH Regulatory Transporters in Pancreatic Ductal Adenocarcinoma

    DEFF Research Database (Denmark)

    Kong, Su Chii

    The abnormal features of hypoxia and altered metabolisms in solid tumours lead to an increased glycolysis that is uncoupled from oxidative phosphorylation in the TCA cycle. Tumoural cells often exhibit dysregulated expressions and activities of various membrane pH regulatory transporters to cope...... with the elevated acid production from this glycolysis, as well as from cellular ATP hydrolysis, sequentially creating a favourable intracellular pH and hostile acidic tumour microenvironment, fortify the tumour cells with highly invasive, metastatic and drug resistant phenotype. In current work, we study...... proliferation was found to be decreased while apoptosis was increased with concanamycin A treatment, indicative of V-ATPases being involved in PDAC cell survival mechanisms as well. Comprehending pH regulation in tumour cells might provide insights in preventing tumourigenesis by pH disruptions. Data presented...

  2. A rare case of thyroid metastasis from pancreatic adenocarcinoma.

    LENUS (Irish Health Repository)

    Kelly, Michael E

    2012-02-01

    CONTEXT: Thyroid metastasis from pancreatic adenocarcinoma is extremely rare, with only two previous cases in the literature. We report a case of pancreatic adenocarcinoma metastasising to the thyroid. We review the incidence, diagnosis, and management of this rare occurrence. CASE REPORT: A 38-year-old man with a synchronous 6-month history of thyroid swelling, presented with epigastric pain and signs of obstructive jaundice. He was investigated by abdominal computerised tomography and endoscopic retrograde cholangiopancreatography. The diagnosis of pancreatic neoplasm was made. His thyroid neoplasm was investigated at another tertiary centre and thought to be a papillary neoplasm. He underwent a pancreaticoduodenectomy and recovered well post-operatively. Eight weeks later he had a total thyroidectomy. Histology confirmed that the thyroid mass was both morphologically and immunophenotypically similar to the pancreatic neoplasm. CONCLUSION: This case demonstrates the importance of a full investigation when a patient with suspected neoplastic history presents with a thyroid nodule. We outline the crucial role that immunohistochemistry plays in detecting and classifying primary and secondary thyroid neoplasms. The detection of a solitary thyroid metastasis from pancreatic adenocarcinoma may indicate a poor prognosis, and it is debatable whether resection of the primary should be undertaken when it presents with a solitary metastasis.

  3. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D; Tinder, Teresa L; Subramani, Durai B; Bradley, Judy M; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2009-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

  4. Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma.

    Science.gov (United States)

    Fritz, Stefan; Fernandez-del Castillo, Carlos; Mino-Kenudson, Mari; Crippa, Stefano; Deshpande, Vikram; Lauwers, Gregory Y; Warshaw, Andrew L; Thayer, Sarah P; Iafrate, A John

    2009-03-01

    To determine whether intraductal papillary mucinous neoplasms of the pancreas (IPMNs) have a different genetic background compared with ductal adenocarcinoma (PDAC). The biologic and clinical behavior of IPMNs and IPMN-associated adenocarcinomas is different from PDAC in having a less aggressive tumor growth and significantly improved survival. Up to date, the molecular mechanisms underlying the clinical behavior of IPMNs are incompletely understood. 128 cystic pancreatic lesions were prospectively identified during the course of 2 years. From the corresponding surgical specimens, 57 IPMNs were separated and subdivided by histologic criteria into those with low-grade dysplasia, moderate dysplasia, high-grade dysplasia, and invasive cancer. Twenty specimens were suitable for DNA isolation and subsequent performance of array CGH. While none of the IPMNs with low-grade dysplasia displayed detectable chromosomal aberrations, IPMNs with moderate and high-grade dysplasia showed frequent copy number alterations. Commonly lost regions were located on chromosome 5q, 6q, 10q, 11q, 13q, 18q, and 22q. The incidence of loss of chromosome 5q, 6q, and 11q was significantly higher in IPMNs with high-grade dysplasia or invasion compared with PDAC. Ten of 13 IPMNs with moderate dysplasia or malignancy had loss of part or all of chromosome 6q, with a minimal deleted region between linear positions 78.0 and 130.0. This study is the first to use array CGH to characterize IPMNs. Recurrent cytogenetic alterations were identified and were different than those described in PDAC. Array CGH may help distinguish between these 2 entities and give insight into the differences in their biology and prognosis.

  5. Hereditary pancreatic adenocarcinoma. A clinical perspective.

    Science.gov (United States)

    Brand, R E; Lynch, H T

    2000-05-01

    Although the total number of patients in these various high-risk groups is relatively small, they nevertheless provide excellent models for studying the cause, natural history, pathogenesis, and treatment of pancreatic cancer. These patients would also benefit greatly from procedures capable of detecting cancer at an early stage. This knowledge would be useful for the much commoner sporadic form of pancreatic cancer, in which diagnosis is almost always late and prognosis fatal. With early diagnosis, surgical resection before the cancer's extension beyond the organ's anatomic confines could be curative. The establishment of a National Familial Pancreatic Cancer Registry is essential and would increase the availability of these invaluable families for medical research.

  6. Nanoparticle albumin-bound (nab-paclitaxel for the treatment of pancreas ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Narayanan V

    2015-01-01

    Full Text Available Vignesh Narayanan,1 Colin D Weekes1,2 1Division of Medical Oncology, Department of Medicine, 2Developmental Therapeutics Program, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA Abstract: Pancreatic adenocarcinoma is a leading cause of cancer-related mortality worldwide, and surgical resection offers the only chance of cure. Since the majority of patients have unresectable disease at presentation, the emphasis has been on identifying effective chemotherapy regimens to prolong survival and control tumor burden. Gemcitabine has been the cornerstone of treatment ever since it was discovered to be an active agent in advanced pancreatic cancer nearly two decades ago, but the overall prognosis in patients with metastatic disease remains dismal. A dense fibrotic stroma around the tumor devoid of vasculature and the resultant hypoxic tumor microenvironment are implicated in the chemotherapy-resistant nature of this malignancy. In recent years, a growing body of literature has further elucidated several aspects of pancreatic tumor biology, such as its ability to utilize albumin from the peritumoral tissues to support its metabolic needs. High-pressure homogenization of paclitaxel with nanoparticle albumin results in the formation of soluble 130 nm complexes with albumin acting as the carrier for the otherwise hydrophobic paclitaxel. Once these complexes reach the tumor milieu, they act by depleting the tumor stroma. In addition, paclitaxel is also transported into the tumor cell along with albumin, where it then exerts its antineoplastic activity. Nanoparticle albumin-bound (nab-paclitaxel also increases gemcitabine levels inside the tumor cells by inhibiting cytidine deaminase, the enzyme that degrades gemcitabine. This review focuses on proposed mechanisms of efficacy of nab-paclitaxel in pancreatic cancer and discusses the preclinical and clinical studies of relevance. Keywords: pancreatic

  7. Organoid Models of Human and Mouse Ductal Pancreatic Cancer

    NARCIS (Netherlands)

    Boj, Sylvia F.; Hwang, Chang-Il; Baker, Lindsey A.; Chio, Iok In Christine; Engle, Dannielle D.; Corbo, Vincenzo; Jager, Myrthe; Ponz-Sarvise, Mariano; Tiriac, Herve; Spector, Mona S.; Gracanin, Ana; Oni, Tobiloba; Yu, Kenneth H.; van Boxtel, Ruben; Huch, Meritxell; Rivera, Keith D.; Wilson, John P.; Feigin, Michael E.; Oehlund, Daniel; Handly-Santana, Abram; Ardito-Abraham, Christine M.; Ludwig, Michael; Elyada, Ela; Alagesan, Brinda; Biffi, Giulia; Yordanov, Georgi N.; Delcuze, Bethany; Creighton, Brianna; Wright, Kevin; Park, Youngkyu; Morsink, Folkert H. M.; Molenaar, IQ; Borel Rinkes, Inne H.; Cuppen, Edwin; Hao, Yuan; Jin, Ying; Nijman, Isaac J.; Iacobuzio-Donahue, Christine; Leach, Steven D.; Pappin, Darryl J.; Hammell, Molly; Klimstra, David S.; Basturk, Olca; Hruban, Ralph H.; Offerhaus, George Johan; Vries, Robert G. J.; Clevers, Hans; Tuveson, David A.

    2015-01-01

    Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and

  8. Therapeutic Endoscopic Ultrasonography: Intratumoral Injection for Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Lawrence A. Shirley

    2013-01-01

    Full Text Available Pancreatic adenocarcinoma is an aggressive disease that has poor outcomes despite maximal traditional therapies. Thus, treatment of this cancer demands innovative strategies to be used in addition to standing therapies in order to provide new avenues of care. Here, we describe the technique of using endoscopic ultrasound in order to directly inject both novel and conventional therapies into pancreatic tumors. We detail the rationale behind this strategy and the many benefits it provides. We then describe our technique in detail, including our experience injecting the AdV-tk adenoviral vector to create an in situ vaccine effect.

  9. Imaging of pancreatic adenocarcinoma with emphasis on multidetector CT

    International Nuclear Information System (INIS)

    Smith, S.L.; Rajan, P.S.

    2004-01-01

    Pancreatic adenocarcinoma is the fourth most frequent cause of cancer-related death. The incidence is increasing and the overall survival has altered little in recent years. Moreover, patients usually present late with inoperable disease and curative resection by standard pancreatico-duodenectomy (Whipple's procedure) is associated with significant morbidity. It should only be attempted in that small group of patients lacking radiological evidence of advanced disease. Despite the recent advances in body magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS), computed tomography (CT) is the mainstay of staging in most centres and the recent development of multidetector CT machines (MDCT) has raised hope of an improvement in preoperative staging. This review focuses on the CT of pancreatic adenocarcinoma with particular emphasis on examination technique and on those criteria that determine resectability

  10. Imaging of pancreatic adenocarcinoma with emphasis on multidetector CT

    Energy Technology Data Exchange (ETDEWEB)

    Smith, S.L. E-mail: simon.smith@ipsh-tr.anglox.nhs.uk; Rajan, P.S

    2004-01-01

    Pancreatic adenocarcinoma is the fourth most frequent cause of cancer-related death. The incidence is increasing and the overall survival has altered little in recent years. Moreover, patients usually present late with inoperable disease and curative resection by standard pancreatico-duodenectomy (Whipple's procedure) is associated with significant morbidity. It should only be attempted in that small group of patients lacking radiological evidence of advanced disease. Despite the recent advances in body magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS), computed tomography (CT) is the mainstay of staging in most centres and the recent development of multidetector CT machines (MDCT) has raised hope of an improvement in preoperative staging. This review focuses on the CT of pancreatic adenocarcinoma with particular emphasis on examination technique and on those criteria that determine resectability.

  11. Curcumin Modulates Pancreatic Adenocarcinoma Cell-Derived Exosomal Function

    Science.gov (United States)

    Osterman, Carlos J. Diaz; Lynch, James C.; Leaf, Patrick; Gonda, Amber; Ferguson Bennit, Heather R.; Griffiths, Duncan; Wall, Nathan R.

    2015-01-01

    Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin’s effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through

  12. Assessment of pancreatic adenocarcinoma: use of low-dose whole pancreatic CT perfusion and individualized dual-energy CT scanning

    International Nuclear Information System (INIS)

    Li, Hai-ou; Guo, Jun; Li, Xiao; Qi, Yao-dong; Wang, Xi-ming; Xu, Zhuo-dong; Liu, Cheng; Chen, Jiu-hong

    2015-01-01

    The objective of this study was to investigate the value of low-dose whole pancreatic computed tomography (CT) perfusion integrated with individualized dual-energy CT (DECT) scanning in the diagnosis of pancreatic adenocarcinoma. Twenty patients with pancreatic adenocarcinoma underwent pancreatic CT perfusion as well as individualized dual-phase DECT pancreatic scans. Perfusion characteristics of non-tumourous pancreatic parenchyma and pancreatic adenocarcinoma were analysed. Weighted-average 120 kVp images and the optimal monoenergetic images in dual phase were reconstructed and the contrast noise ratio (CNR) of pancreas-to-tumour were compared. There were significant difference on blood flow as well as blood volume between pancreatic adenocarcinoma and the non-tumourous pancreatic parenchyma (P < 0.05), whereas no difference on permeability (P > 0.05). CNRs of pancreas-to-tumour in individualized pancreatic phase were significantly higher than those in venous phase (P < 0.05), and CNRs of optimal monoenergetic images were higher than those on weighted-average 120 kVp images (P < 0.05) in both phase. Total effective radiation dose of CT examination was around 9.32–13.75 mSv. Low-dose whole pancreatic CT perfusion can provide functional information, and the individualized pancreatic phase DECT scan is the optimal method for detecting pancreatic adenocarcinomas. The integration of the two techniques has great value in clinical application.

  13. Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

    Science.gov (United States)

    Rohloff, J; Zinke, J; Schoppmeyer, K; Tannapfel, A; Witzigmann, H; Mössner, J; Wittekind, C; Caca, K

    2002-01-01

    Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients. British Journal of Cancer (2002) 86, 1270–1275. DOI: 10.1038/sj/bjc/6600232 www.bjcancer.com © 2002 Cancer Research UK PMID:11953884

  14. Implications of inaccurate clinical nodal staging in pancreatic adenocarcinoma.

    Science.gov (United States)

    Swords, Douglas S; Firpo, Matthew A; Johnson, Kirsten M; Boucher, Kenneth M; Scaife, Courtney L; Mulvihill, Sean J

    2017-07-01

    Many patients with stage I-II pancreatic adenocarcinoma do not undergo resection. We hypothesized that (1) clinical staging underestimates nodal involvement, causing stage IIB to have a greater percent of resected patients and (2) this stage-shift causes discrepancies in observed survival. The Surveillance, Epidemiology, and End Results (SEER) research database was used to evaluate cause-specific survival in patients with pancreatic adenocarcinoma from 2004-2012. Survival was compared using the log-rank test. Single-center data on 105 patients who underwent resection of pancreatic adenocarcinoma without neoadjuvant treatment were used to compare clinical and pathologic nodal staging. In SEER data, medium-term survival in stage IIB was superior to IB and IIA, with median cause-specific survival of 14, 9, and 11 months, respectively (P < .001). Seventy-two percent of stage IIB patients underwent resection vs 28% in IB and 36% in IIA (P < .001). In our institutional data, 12.4% of patients had clinical evidence of nodal involvement vs 69.5% by pathologic staging (P < .001). Among clinical stage IA-IIA patients, 71.6% had nodal involvement by pathologic staging. Both SEER and institutional data support substantial underestimation of nodal involvement by clinical staging. This finding has implications in decisions regarding neoadjuvant therapy and analysis of outcomes in the absence of pathologic staging. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Anomalous pancreatic ductal system allowing distal bowel gas with duodenal atresia

    Directory of Open Access Journals (Sweden)

    Shruti Sevak

    2017-11-01

    Bypass of the atretic duodenal segment through an anomalous pancreatic ductal system is a rare anomaly described in the literature in only a handful of cases. This case report highlights the importance of considering duodenal atresia and pancreaticobiliary enteric bypass in the differential diagnosis of neonates presenting with partial duodenal obstruction. On ultrasound, the presence of gas in the biliary tree or pancreatic duct should alert the physician to the possibility of duodenal atresia with congenital pancreaticobiliary duct anomalies that allow for bypass of enteric contents, including air, into more distal bowel, thereby creating a gas pattern aptly described as double bubble with distal gas.

  16. FEATURES OF ISLET-LIKE CLUSTERS GENERATION IN PANCREATIC DUCTAL CELL MOLOLAYER CULTURING

    Directory of Open Access Journals (Sweden)

    L. A. Kirsanova

    2012-01-01

    Full Text Available Newborn rabbit pancreatic cell monolayer was obtained as we described earlier.The cultivated epithelial cells were shown by immunofluorescence to express special ductal marker CK19 and were insulin-and glucagon- negative for 10–15 days. A few fusiforms of nestin-positive cells were found in monolayer. Over 2 weeks in serum-free medium the plaques of epithelial cells became crowded and formed 3-dimentional structures – islet- like clusters. Islet-like clusters contain some insulin- and glucagon-positive cells recognized by immunohysto- chemistry staining. Pancreatic endocrine cell generation in 3-dimentional structures is discussed. 

  17. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells.

    Science.gov (United States)

    Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-Ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

    2013-11-19

    Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.

  18. Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Rémy Nicolle

    2017-11-01

    Full Text Available Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively. Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

  19. Preoperative CEA and CA 19-9 are prognostic markers for survival after curative resection for ductal adenocarcinoma of the pancreas - a retrospective tumor marker prognostic study.

    Science.gov (United States)

    Distler, Marius; Pilarsky, Eva; Kersting, Stephan; Grützmann, Robert

    2013-01-01

    The prognosis for patients with ductal adenocarcinoma of the pancreas (PDAC) remains poor even after curative resection. Carbohydrate antigen 19-9 (CA 19-9) and the carcinoembryonic antigen (CEA) are the most widely used serum-based tumor markers for the diagnosis and follow up of pancreatic cancer. In our analysis we aim to assess the prognostic value of a combination of both tumor markers in patients with pancreatic ductal adenocarcinoma (PDAC). Between 01/1995 and 08/2012 we performed a total of 264 pancreatic resections due to PDAC. Patients were stratified into 3 groups in regard to their preoperative tumor marker levels. Survival was compared between the groups using Kaplan Meier analysis and log rank test. Univariate subgroup analysis and multivariate analysis were performed. For 259 cases complete follow up could be obtained. In patients with low preoperative CEA and CA 19-9 levels (group 1 n = 91) the mean survival was 33.3 month (CI 95% 25.1-41.5). If one of the analyzed tumor markers (CEA/CA19-9) was preoperatively elevated above the cut-off level (group 2 n = 106) mean survival was 28.5 month (CI 95% 22.1-35.1). 62 patients showed preoperative elevation of both, CEA and CA 19-9 (group 3); mean survival in this group was 23.9 month (CI 95% 13.9-33.9), p > 0.01. Multivariate analysis confirmed preoperative CEA/CA 19-9 level as independent prognostic factor (HR 1.299). Preoperative CEA and CA 19-9 levels correlate with patient prognosis after curative pancreatic resection due to PDAC. This is especially true for the most frequently pT 3/4 stages of PDAC. Even if CEA and CA 19-9 might not be appropriate for screening, its serum levels should therefore be determined prior to operation and taken into account when resectability or operability is doubtful. Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  20. Second primary pancreatic ductal carcinoma in the remnant pancreas after pancreatectomy for pancreatic ductal carcinoma: High cumulative incidence rates at 5 years after pancreatectomy.

    Science.gov (United States)

    Ishida, Jun; Toyama, Hirochika; Matsumoto, Ippei; Asari, Sadaki; Goto, Tadahiro; Terai, Sachio; Nanno, Yoshihide; Yamashita, Azusa; Mizumoto, Takuya; Ueda, Yuki; Kido, Masahiro; Ajiki, Tetsuo; Fukumoto, Takumi; Ku, Yonson

    2016-01-01

    The aim of this study was to determine the incidence rate and clinical features of second primary pancreatic ductal carcinoma (SPPDC) in the remnant pancreas after pancreatectomy for pancreatic ductal carcinoma (PDC). Data of patients undergoing R0 resection for PDC at a single high-volume center were reviewed. SPPDC was defined as a tumor in the remnant pancreas after R0 resection for PDC, and SPPDC met at least one of the following conditions: 1) the time interval between initial pancreatectomy and development of a new tumor was 3 years or more; 2) the new tumor was not located in contact with the pancreatic stump. We investigated the clinical features and treatment outcomes of patients with SPPDC. This study included 130 patients who underwent surgical resection for PDC between 2005 and 2014. Six (4.6%) patients developed SPPDC. The cumulative 3- and 5-year incidence rates were 3.1% and 17.7%, respectively. Four patients underwent remnant pancreatectomy for SPPDC. They were diagnosed with the disease in stage IIA or higher and developed recurrence within 6 months after remnant pancreatectomy. One patient received carbon ion radiotherapy and survived 45 months. One patient refused treatment and died 19 months after the diagnosis of SPPDC. The incidence rate of SPPDC is not negligible, and the cumulative 5-year incidence rate of SPPDC is markedly high. Post-operative surveillance of the remnant pancreas is critical for the early detection of SPPDC, even in long-term survivors after PDC resection. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  1. Gastro-pancreaticojejunostomy for treatment of pancreatic ductal obstruction in a post-Whipple procedure patient.

    Science.gov (United States)

    Rodrigues-Pinto, Eduardo; Grimm, Ian S; Baron, Todd H

    2015-01-01

    We report a case of a woman with a medical history of classic Whipple surgery who underwent endoscopic ultrasound (EUS)-guided pancreatic drainage due to smouldering acute pancreatitis secondary to an obstructing pancreatic ductal stone. A gastro-pancreaticojejunostomy anastomosis was created anterogradely, with dilation of both the anastomoses in the same procedure, with subsequent decompression of the pancreatic duct. Endoscopic retrograde pancreatography (ERP) is often impossible to perform in patients with post-Whipple procedure anatomy due to inaccessibility to the pancreaticojejunostomy anastomosis. EUS-guided pancreatic drainage may be offered in these patients in whom the pancreatic duct cannot be accessed at ERP. It has been used as a platform for access to and drainage of the pancreatic duct either by rendezvous or transmural drainage. However, only one of four patients achieve successful completion of the rendezvous procedure. There are limited data regarding safety and long-term outcome of this procedure, as well as scant guidelines on the optimal time for leaving stents in place. We believe definitive endoscopic therapy should be attempted, whenever possible, after relief of obstruction. In our case, we expect that stent occlusion is inevitable and that long-term drainage is possible due to drainage occurring between the stent and the stone.

  2. Influències clíniques i ambientals en la prevalença de mutacions en l'oncogèn K-ras en pacients amb adenocarcinoma ductal de pàncrees

    OpenAIRE

    Crous Bou, Marta

    2009-01-01

    Descripció del recurs: 27 gener 2010 Antecedents La prevenció primària de l'adenocarcinoma ductal de pàncrees (ADP) està limitada per la falta de coneixement sobre la seva etiologia. El factor de risc més ben establert és el consum de tabac, però explica només una petita proporció de casos. Es discuteix el paper d'altres factors etiològics com els antecedents patològics de diabetis i pancreatitis, la dieta, determinades exposicions ambientals o laborals, i els factors hereditaris. Mutacio...

  3. New concepts in diagnosis and therapy of pancreatic adenocarcinoma

    International Nuclear Information System (INIS)

    Laghi, Andrea

    2011-01-01

    This book adopts a multidisciplinary approach to examine in detail a range of interesting new concepts in the diagnosis and therapy of pancreatic adenocarcinoma. Its primary goals are to offer a valuable source of information for clinicians involved in the management of patients with pancreatic adenocarcinoma and to provide a modern guide to the disease for those who are interested in updating their knowledge, including fellows and senior residents. The book is divided into three parts. The first part provides an epidemiological and clinical overview of the disease, followed by an update on pathological findings, including new discoveries in the area of molecular biology. The second part, on diagnosis, offers detailed and comprehensive information on the advantages and disadvantages of different imaging techniques, including nuclear medicine and endoscopic ultrasound. Each diagnostic strategy is critically reviewed with regard to cost-effectiveness. The concluding part of the book, on therapy, gives a panoramic overview of the various therapeutic options, from surgery to chemotherapy and palliative approaches based on interventional endoscopy and radiology. (orig.)

  4. SMAD4 regulates cell motility through transcription of N-cadherin in human pancreatic ductal epithelium.

    Directory of Open Access Journals (Sweden)

    Ya'an Kang

    Full Text Available Expression of the cellular adhesion protein N-cadherin is a critical event during epithelial-mesenchymal transition (EMT. The SMAD4 protein has been identified as a mediator of transforming growth factor-β (TGF-β superfamily signaling, which regulates EMT, but the mechanisms linking TGF-β signaling to N-cadherin expression remain unclear. When the TGF-β pathway is activated, SMAD proteins, including the common mediator SMAD4, are subsequently translocated into the nucleus, where they influence gene transcription via SMAD binding elements (SBEs. Here we describe a mechanism for control of CDH2, the gene encoding N-cadherin, through the canonical TGFβ-SMAD4 pathway. We first identified four previously undescribed SBEs within the CDH2 promoter. Using telomerase immortalized human pancreatic ductal epithelium, we found that TGF-β stimulation prompted specific SMAD4 binding to all four SBEs. Luciferase reporter and SMAD4-knockdown experiments demonstrated that specific SMAD4 binding to the SBE located at -3790 bp to -3795 bp within the promoter region of CDH2 was necessary for TGF-β-stimulated transcription. Expression of N-cadherin on the surface of epithelial cells facilitates motility and invasion, and we demonstrated that knockdown of SMAD4 causes decreased N-cadherin expression, which results in diminished migration and invasion of human pancreatic ductal epithelial cells. Similar reduction of cell motility was produced after CDH2 knockdown. Together, these findings suggest that SMAD4 is critical for the TGF-β-driven upregulation of N-cadherin and the resultant invasive phenotype of human pancreatic ductal epithelial cells during EMT.

  5. Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits?

    Science.gov (United States)

    Merchant, Nipun B; Rymer, Jennifer; Koehler, Elizabeth AS; Ayers, G Daniel; Castellanos, Jason; Kooby, David A; Weber, Sharon H; Cho, Clifford S; Schmidt, C Max; Nakeeb, Atilla; Matos, Jesus M; Scoggins, Charles R; Martin, Robert CG; Kim, Hong Jin; Ahmad, Syed A; Chu, Carrie K; McClaine, Rebecca; Bednarski, Brian K; Staley, Charles A; Sharp, Kenneth; Parikh, Alexander A

    2014-01-01

    BACKGROUND The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n = 374) and those receiving adjuvant CRT (n = 299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p = 0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p = 0.034). CONCLUSIONS This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival. PMID:19476845

  6. Suppression of IL-6 Gene by shRNA Augments Gemcitabine Chemosensitization in Pancreatic Adenocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Hai-Bo Xing

    2018-01-01

    Full Text Available Pancreatic adenocarcinoma has an exceedingly poor prognosis, accounting for five-year survival of less than 5%. Presently, improving the efficacy of pancreatic adenocarcinoma treatment has been the focus of medical researchers worldwide. Recently, it has been suggested that deregulation of interleukin- (IL- 6 is caused by a key gene involved in the beginning and development of pancreatic adenocarcinoma. Herein, we investigated whether suppression of IL-6 could augment gemcitabine sensitivity in the PANC-1 cells. We found considerably higher expression of IL-6 in pancreatic adenocarcinoma tissues than that in the adjacent nontumorous tissues. Suppression of IL-6 by shRNA resulted in apoptosis as well as inhibition of cell proliferation and tumorigenicity. In addition, suppression of IL-6 remarkably promoted antitumor effect of gemcitabine, indicating that the combination of shRNA targeting IL-6 with gemcitabine may provide a potential clinical approach for pancreatic cancer therapy.

  7. Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition1

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D.; Tinder, Teresa L.; Subramani, Durai B.; Bradley, Judy M.; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2013-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer. PMID:19109152

  8. Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma.

    Science.gov (United States)

    Inami, Koichi; Kajino, Kazunori; Abe, Masaaki; Hagiwara, Yoshiaki; Maeda, Masahiro; Suyama, Masafumi; Watanabe, Sumio; Hino, Okio

    2008-12-01

    ERC/mesothelin gene (MSLN) encodes a precursor protein, which is cleaved by proteases to generate N-ERC/mesothelin and C-ERC/mesothelin. N-ERC/mesothelin is a soluble protein, also known as megakaryocyte-potentiating factor, which is released into extracellular space. N-ERC/mesothelin is known to be a serum marker of mesothelioma. We have previously developed an enzyme-linked immunosorbent assay system for N-ERC/mesothelin, which can detect mesothelioma. C-ERC/mesothelin is expressed in normal mesothelial cell, pancreatic cancers, ovarian cancers, mesotheliomas and some other cancers. Pancreatic ductal carcinoma remains a fatal disease because its diagnosis often occurs very late. In this study, we examined ERC/mesothelin expression in human pancreatic cancer cell lines (MIA-PaCa2, PK-1, KP-3, TCC-PAN2, PK-59 and PK-45H) by reverse transcription-polymerase chain reaction and immunoblotting and N-ERC/mesothelin concentration in the supernatant of cultured cancer cells by the ELISA system. We also investigated C-ERC/mesothlein expression in human pancreatic ductal carcinoma tissues by immunostaining using 5B2 anti-mesothelin monoclonal antibody and N-ERC/mesothelin concentration in sera obtained from patients with pancreatic ductal carcinoma via ELISA. In vitro, N-ERC/mesothelin concentration in cell culture medium nearly correlated with the expression level of C-ERC/mesothelin. Although C-ERC/mesothelin was frequently expressed in human pancreatic ductal carcinoma, serum N-ERC/mesothelin concentration of cancer patients was equivalent to healthy controls. N-ERC/mesothelin was not useful as a serum marker of pancreatic ductal carcinoma, but because of frequent expression, C-ERC/mesothelin might be useful as a target of molecular imaging and immunotherapy.

  9. Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies?

    Science.gov (United States)

    Lombardo, Dominique; Silvy, Françoise; Crenon, Isabelle; Martinez, Emmanuelle; Collignon, Aurélie; Beraud, Evelyne; Mas, Eric

    2018-02-23

    Pancreatic adenocarcinomas and diabetes mellitus are responsible for the deaths of around two million people each year worldwide. Patients with chronic pancreatitis do not die directly of this disease, except where the pathology is hereditary. Much current literature supports the involvement of bile salt-dependent lipase (BSDL), also known as carboxyl ester lipase (CEL), in the pathophysiology of these pancreatic diseases. The purpose of this review is to shed light on connections between chronic pancreatitis, diabetes, and pancreatic adenocarcinomas by gaining an insight into BSDL and its variants. This enzyme is normally secreted by the exocrine pancreas, and is diverted within the intestinal lumen to participate in the hydrolysis of dietary lipids. However, BSDL is also expressed by other cells and tissues, where it participates in lipid homeostasis. Variants of BSDL resulting from germline and/or somatic mutations (nucleotide insertion/deletion or nonallelic homologous recombination) are expressed in the pancreas of patients with pancreatic pathologies such as chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We discuss the possible link between the expression of BSDL variants and these dramatic pancreatic pathologies, putting forward the suggestion that BSDL and its variants are implicated in the cell lipid metabolism/reprogramming that leads to the dyslipidemia observed in chronic pancreatitis, MODY-8, and pancreatic adenocarcinomas. We also propose potential strategies for translation to therapeutic applications.

  10. Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia 1

    OpenAIRE

    Pitarresi, Jason R.; Liu, Xin; Sharma, Sudarshana M.; Cuiti?o, Maria C.; Kladney, Raleigh D.; Mace, Thomas A.; Donohue, Sydney; Nayak, Sunayana G.; Qu, Chunjing; Lee, James; Woelke, Sarah A.; Trela, Stefan; LaPak, Kyle; Yu, Lianbo; McElroy, Joseph

    2016-01-01

    Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin?positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue...

  11. Hepatocyte growth factor signaling in intrapancreatic ductal cells drives pancreatic morphogenesis.

    Directory of Open Access Journals (Sweden)

    Ryan M Anderson

    Full Text Available In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908 , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

  12. FDG PET imaging of Ela1-myc mice reveals major biological differences between pancreatic acinar and ductal tumours

    International Nuclear Information System (INIS)

    Abasolo, Ibane; Pujal, Judit; Navarro, Pilar; Rabanal, Rosa M.; Serafin, Anna; Millan, Olga; Real, Francisco X.

    2009-01-01

    The aim was to evaluate FDG PET imaging in Ela1-myc mice, a pancreatic cancer model resulting in the development of tumours with either acinar or mixed acinar-ductal phenotype. Transversal and longitudinal FDG PET studies were conducted; selected tissue samples were subjected to autoradiography and ex vivo organ counting. Glucose transporter and hexokinase mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR); Glut2 expression was analysed by immunohistochemistry. Transversal studies showed that mixed acinar-ductal tumours could be identified by FDG PET several weeks before they could be detected by hand palpation. Longitudinal studies revealed that ductal - but not acinar - tumours could be detected by FDG PET. Autoradiographic analysis confirmed that tumour areas with ductal differentiation incorporated more FDG than areas displaying acinar differentiation. Ex vivo radioactivity measurements showed that tumours of solely acinar phenotype incorporated more FDG than pancreata of non-transgenic littermates despite the fact that they did not yield positive PET images. To gain insight into the biological basis of the differential FDG uptake, glucose transporter and hexokinase transcript expression was studied in microdissected tumour areas enriched for acinar or ductal cells and validated using cell-specific markers. Glut2 and hexokinase I and II mRNA levels were up to 20-fold higher in ductal than in acinar tumours. Besides, Glut2 protein overexpression was found in ductal neoplastic cells but not in the surrounding stroma. In Ela1-myc mice, ductal tumours incorporate significantly more FDG than acinar tumours. This difference likely results from differential expression of Glut2 and hexokinases. These findings reveal previously unreported biological differences between acinar and ductal pancreatic tumours. (orig.)

  13. FDG PET imaging of Ela1-myc mice reveals major biological differences between pancreatic acinar and ductal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Abasolo, Ibane [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Pujal, Judit; Navarro, Pilar [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Rabanal, Rosa M.; Serafin, Anna [Universitat Autonoma de Barcelona, Departament de Medicina i Cirurgia Animals, Barcelona (Spain); Millan, Olga [Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Real, Francisco X. [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas, Madrid (Spain)

    2009-07-15

    The aim was to evaluate FDG PET imaging in Ela1-myc mice, a pancreatic cancer model resulting in the development of tumours with either acinar or mixed acinar-ductal phenotype. Transversal and longitudinal FDG PET studies were conducted; selected tissue samples were subjected to autoradiography and ex vivo organ counting. Glucose transporter and hexokinase mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR); Glut2 expression was analysed by immunohistochemistry. Transversal studies showed that mixed acinar-ductal tumours could be identified by FDG PET several weeks before they could be detected by hand palpation. Longitudinal studies revealed that ductal - but not acinar - tumours could be detected by FDG PET. Autoradiographic analysis confirmed that tumour areas with ductal differentiation incorporated more FDG than areas displaying acinar differentiation. Ex vivo radioactivity measurements showed that tumours of solely acinar phenotype incorporated more FDG than pancreata of non-transgenic littermates despite the fact that they did not yield positive PET images. To gain insight into the biological basis of the differential FDG uptake, glucose transporter and hexokinase transcript expression was studied in microdissected tumour areas enriched for acinar or ductal cells and validated using cell-specific markers. Glut2 and hexokinase I and II mRNA levels were up to 20-fold higher in ductal than in acinar tumours. Besides, Glut2 protein overexpression was found in ductal neoplastic cells but not in the surrounding stroma. In Ela1-myc mice, ductal tumours incorporate significantly more FDG than acinar tumours. This difference likely results from differential expression of Glut2 and hexokinases. These findings reveal previously unreported biological differences between acinar and ductal pancreatic tumours. (orig.)

  14. Improved long-term outcomes after resection of pancreatic adenocarcinoma: a comparison between two time periods.

    Science.gov (United States)

    Serrano, Pablo E; Cleary, Sean P; Dhani, Neesha; Kim, Peter T W; Greig, Paul D; Leung, Kenneth; Moulton, Carol-Anne; Gallinger, Steven; Wei, Alice C

    2015-04-01

    Despite reduced perioperative mortality and routine use of adjuvant therapy following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), improvement in long-term outcome has been difficult to ascertain. This study compares outcomes in patients undergoing resection for PDAC within a single, high-volume academic institution over two sequential time periods. Retrospective review of patients with resected PDAC, in two cohorts: period 1 (P1), 1991-2000; and period 2 (P2), 2001-2010. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine prognostic factors associated with long-term survival. Survival was evaluated using Kaplan-Meier analyses. A total of 179 pancreatectomies were performed during P1 and 310 during P2. Perioperative mortality was 6.7 % (12/179) in P1 and 1.6 % (5/310) in P2 (p = 0.003). P2 had a greater number of lymph nodes resected (17 [0-50] vs. 7 [0-31]; p P2 (p P2 (p < 0.001). Factors associated with improved long-term survival remain comparable over time. Short- and long-term survival for patients with resected PDAC has improved over time due to decreased perioperative mortality and increased use of adjuvant therapy, although the proportion of 5-year survivors remains small.

  15. Locally advanced pancreatic adenocarcinoma. Chemoradiotherapy, reevaluation and secondary resection

    International Nuclear Information System (INIS)

    Delpero, J.R.; Turrini, O.

    2006-01-01

    Induction chemoradiotherapy (CRT) may down-stage locally advanced pancreatic tumors but secondary resections are unfrequent. However some responders' patients may benefit of a RO resection. Patients and methods. We report 18 resections among 29 locally advanced pancreatic cancers; 15 patients were treated with neo-adjuvant 5-FU-cisplatin based (13) or taxotere based (2 patients) chemoradiotherapy (45 Gy), and 3 patients without histologically proven adenocarcinoma were resected without any preoperative treatment. Results. The morbidity rate was 28% and the mortality rate was 7%; one patient died after resection (5.5%) and one died after exploration (9%). The RO resection rate was 50%. The median survival for the resected patients was not reached and the actuarial survival at 3 years was 59%. Two specimens showed no residual tumor and the two patients were alive at 15 and 46 months without recurrence; one specimen showed less than 10% viable tumoral cells and the patient was alive at 36 months without recurrence. A mesenteric infarction was the cause of a late death at 3 years in a disease free patient (radiation induced injury of the superior mesenteric artery). The median survival of the 11 non-resected patients was 21 months and the actuarial survival at 2 years was 0%. When the number of the resected patients (18) was reported to the entire cohort of the patients with locally advanced pancreatic cancer treated during the same period in our institution, the secondary resectability rate was 9%. Conclusion. Preoperative chemoradiotherapy identifies poor surgical candidates through observation and may enhance the margin status of patients undergoing secondary resection for locally advanced tumors. However it remains difficult to evaluate the results in the literature because of the variations in the definitions of resectability. The best therapeutic strategy remains to be defined, because the majority of patients ultimately succumb with distant metastatic disease

  16. Pancreatic adenocarcinoma: dual-phase helical CT with surgical and histopathologic correlation

    International Nuclear Information System (INIS)

    Kim, Eun A; Yoon, Kwon Ha; Park, Seong Hoon; Yun, Ki Jung; Won, Jong Jin

    2003-01-01

    To determine the accuracy of dual-phase helical CT in assessing the resectability of pancreatic ductal adenocarcinoma, and to correlate the CT findings with the surgical and histopathologic findings. Thirty patients with pathologically proven cancer of the pancreas underwent arterial-and portal-phase helical CT scanning, and in the two of these, single-level dynamic CT was performed during celiac and superior mesenteric arteriography. In 17 patients who underwent surgery for potentially resectable cancer of the pancreatic head, tumor resectability was assessed. The CT findings were analyzed and correlated with these of surgery and histopathology. In 13 (76%) of the 17 patients who underwent surgery, tumors were resectable. Their average size was 2.76 cm (arterial phase), 2.30 cm (portal phase), and 2.48 cm (pathologically determined) and the overall accuracy of helical CT for assessing resectability was 87%. In all patients, the central portion of the tumors exhibited hypoattenuation at both phases; the peripheral portion showed hypoattenuation at the arterial phase and iso- (n=10) or hyperattenuation (n=3) at the portal phase. Single-level dynamic CT depicted a persistently hypoattenuating central portion and progressive and prolonged enhancement of the periphery. CT-histopathologic correlation showed that central hypoattenuation indicated the presence of tumor cells, necrosis (n=3) and mucin (n=4), while the peripheral iso- or hyperattenuated areas seen at the portal phase represented fibrosis and inflammatory infiltration. Histopathologic examination revealed tumoral infiltration of peripancreatic fat tissue (n=11) and microvascular invasion of major peripancreatic vessels (n=7). The dual-phase helical CT is useful in the determination of resectability in pancreas cancer and CT findings represent well the histopathologic features of pancreas cancer

  17. Pancreatic adenocarcinoma: dual-phase helical CT with surgical and histopathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun A; Yoon, Kwon Ha; Park, Seong Hoon; Yun, Ki Jung; Won, Jong Jin [Wonkwang University School of Medicine, Iksan (Korea, Republic of)

    2003-03-01

    To determine the accuracy of dual-phase helical CT in assessing the resectability of pancreatic ductal adenocarcinoma, and to correlate the CT findings with the surgical and histopathologic findings. Thirty patients with pathologically proven cancer of the pancreas underwent arterial-and portal-phase helical CT scanning, and in the two of these, single-level dynamic CT was performed during celiac and superior mesenteric arteriography. In 17 patients who underwent surgery for potentially resectable cancer of the pancreatic head, tumor resectability was assessed. The CT findings were analyzed and correlated with these of surgery and histopathology. In 13 (76%) of the 17 patients who underwent surgery, tumors were resectable. Their average size was 2.76 cm (arterial phase), 2.30 cm (portal phase), and 2.48 cm (pathologically determined) and the overall accuracy of helical CT for assessing resectability was 87%. In all patients, the central portion of the tumors exhibited hypoattenuation at both phases; the peripheral portion showed hypoattenuation at the arterial phase and iso- (n=10) or hyperattenuation (n=3) at the portal phase. Single-level dynamic CT depicted a persistently hypoattenuating central portion and progressive and prolonged enhancement of the periphery. CT-histopathologic correlation showed that central hypoattenuation indicated the presence of tumor cells, necrosis (n=3) and mucin (n=4), while the peripheral iso- or hyperattenuated areas seen at the portal phase represented fibrosis and inflammatory infiltration. Histopathologic examination revealed tumoral infiltration of peripancreatic fat tissue (n=11) and microvascular invasion of major peripancreatic vessels (n=7). The dual-phase helical CT is useful in the determination of resectability in pancreas cancer and CT findings represent well the histopathologic features of pancreas cancer.

  18. Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma.

    Science.gov (United States)

    2015-10-01

    The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed. These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

  19. Whole blood DNA aberrant methylation in pancreatic adenocarcinoma shows association with the course of the disease: a pilot study.

    Directory of Open Access Journals (Sweden)

    Albertas Dauksa

    Full Text Available Pancreatic tumors are usually diagnosed at an advanced stage in the progression of the disease, thus reducing the survival chances of the patients. Non-invasive early detection would greatly enhance therapy and survival rates. Toward this aim, we investigated in a pilot study the power of methylation changes in whole blood as predictive markers for the detection of pancreatic tumors. We investigated methylation levels at selected CpG sites in the CpG rich regions at the promoter regions of p16, RARbeta, TNFRSF10C, APC, ACIN1, DAPK1, 3OST2, BCL2 and CD44 in the blood of 30 pancreatic tumor patients and in the blood of 49 matching controls. In addition, we studied LINE-1 and Alu repeats using degenerate amplification approach as a surrogate marker for genome-wide methylation. The site-specific methylation measurements at selected CpG sites were done by the SIRPH method. Our results show that in the patient's blood, tumor suppressor genes were slightly but significantly higher methylated at several CpG sites, while repeats were slightly less methylated compared to control blood. This was found to be significantly associated with higher risk for pancreatic ductal adenocarcinoma. Additionally, high methylation levels at TNFRSCF10C were associated with positive perineural spread of tumor cells, while higher methylation levels of TNFRSF10C and ACIN1 were significantly associated with shorter survival. This pilot study shows that methylation changes in blood could provide a promising method for early detection of pancreatic tumors. However, larger studies must be carried out to explore the clinical usefulness of a whole blood methylation based test for non-invasive early detection of pancreatic tumors.

  20. Chronic Continuous Exenatide Infusion Does Not Cause Pancreatic Inflammation and Ductal Hyperplasia in Non-Human Primates

    Science.gov (United States)

    Fiorentino, Teresa Vanessa; Owston, Michael; Abrahamian, Gregory; La Rosa, Stefano; Marando, Alessandro; Perego, Carla; Di Cairano, Eliana S.; Finzi, Giovanna; Capella, Carlo; Sessa, Fausto; Casiraghi, Francesca; Paez, Ana; Adivi, Ashwin; Davalli, Alberto; Fiorina, Paolo; Guardado Mendoza, Rodolfo; Comuzzie, Anthony G.; Sharp, Mark; DeFronzo, Ralph A.; Halff, Glenn; Dick, Edward J.; Folli, Franco

    2016-01-01

    In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67–positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67–positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67–positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30–positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates. PMID:25447052

  1. Metastasis of the epididymis and spermatic cord from pancreatic adenocarcinoma: A rare entity. Description of a case and revision of literature.

    Science.gov (United States)

    Di Franco, Carmelo Agostino; Rovereto, Bruno; Porru, Daniele; Zoccarato, Valeria; Regina, Cesare; Cebrelli, Tiziano; Fiorello, Nicolò; Viglio, Alessandra; Galvagno, Lavinia; Marchetti, Carlo; Ringressi, Andrea; Barletta, Davide; Giliberto, Giovanni

    2018-03-31

    Metastatic epididymal and spermatic cord adenocarcinoma from epithelial tumors are a rare condition. The most frequent primary cancers are prostate, lung, kidney, gastrointestinal tumors and breast. In literature, there are very low number of cases reporting metastasis from pancreatic cancer to epididymis and spermatic cord. We report a case of 70-years old man with history of left orchiectomy for undescended testicle, who presented to our department with a palpable nodule in the right scrotum. Scrotal ultrasound revealed an inhomogeneous hypoechoic nodule of epididymis and/or spermatic cord. Neoplastic markers showed high levels of CEA (carcinoembryonic antigen) and bHCG (beta Human Chorionic Gonadotropin). The patient underwent right surgical scrotal exploration with orchifunicolectomy. Pathologic examination revealed pathologic tissue showing rare glandular structures. Immunohistochemistry profile was compatible with malign epithelial neoplasm with glandular differentiation. Total body CT-scan revealed pathologic tissue in pancreas between head and body and a suspect pathologic lesion in liver and 18-FDG PET-scan confirmed the pancreatic neoplastic mass and a suspect secondary hepatic lesion. Biopsy of pancreatic pathologic area was positive for ductal pancreatic adenocarcinoma. The patient was sent to oncologic evaluation and started chemotherapy. Malignancies of epididymis and spermatic cord are rare entities and, in literature, very low number of cases of metastasis from pancreatic carcinoma to epididymis and spermatic cord are described. Early differential diagnosis is fundamental mostly in those patients with age range unusual for testis cancers.

  2. Exocrine pancreatic insufficiency in a yellow-naped Amazon (Amazona ochrocephala) with pancreatic adenocarcinoma.

    Science.gov (United States)

    Ritchey, J W; Degernes, L A; Brown, T T

    1997-01-01

    This report describes exocrine pancreatic insufficiency in a yellow-naped Amazon (Amazona ochrocephala) with complete effacement of the pancreas by a pancreatic adenocarcinoma. The bird presented with a 3-month history of weight loss and voluminous, foul-smelling droppings. Clinically, routine hematologic findings were normal and fecal tests were performed to evaluate exocrine pancreatic function. The fecal function tests were positive for neutral and split fats and negative for trypsin. Oral administration of corn oil did not result in elevation of blood triglyceride levels. Two days later, the triglyceride tolerance test was repeated using corn oil mixed with pancreatic enzymes. This time, there was a 70% elevation of blood triglyceride levels. Because of a poor prognosis, the bird was euthanatized. At necropsy, the pancreas was diffusely enlarged, white, nodular, and firm. The liver contained multiple, 1-2-mm-diameter, randomly located, tan nodules. Microscopically, the pancreas was effaced by numerous lobules of neoplastic ductular structures surrounded by abundant fibrous connective tissue. In the liver, the hepatic parenchyma was replaced by multiple, well-demarcated, nonencapsulated foci of neoplastic tissue similar to that in the pancreas.

  3. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia

    Directory of Open Access Journals (Sweden)

    Gregory M. Springett

    2015-12-01

    Interpretation: VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer.

  4. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma.

    Science.gov (United States)

    Lowery, Maeve A; Kelsen, David P; Capanu, Marinela; Smith, Sloane C; Lee, Jonathan W; Stadler, Zsofia K; Moore, Malcolm J; Kindler, Hedy L; Golan, Talia; Segal, Amiel; Maynard, Hannah; Hollywood, Ellen; Moynahan, MaryEllen; Salo-Mullen, Erin E; Do, Richard Kinh Gian; Chen, Alice P; Yu, Kenneth H; Tang, Laura H; O'Reilly, Eileen M

    2018-01-01

    BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC). Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1-28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety. Sixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43-77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57-1.83) and median OS was 3.1 months (95% CI 1.9-4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1). Veliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195). Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Maintenance Therapy with Trastuzumab in Her2 Positive Metastatic Parotid Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Muhammad Shahid Iqbal

    2014-01-01

    Full Text Available Salivary ductal carcinomas (SDCs are extremely rare and aggressive malignancies, accounting for approximately 6% of all salivary gland malignancies. One distinct feature is their resemblance to ductal carcinomas of breast. A significant percentage of SDCs overexpress Her2 and the use of targeted therapy with trastuzumab can be considered in these patients. We report a rare case of long term disease control with trastuzumab in Her2 positive metastatic parotid ductal carcinoma. Our case also highlights that isolated brain metastasis should be managed aggressively to allow optimal local control when systemic disease is under remission with trastuzumab. We have also reviewed the published literature on the use of trastuzumab in SDCs.

  6. Numb Chin Syndrome Leading to a Diagnosis of Salivary Ductal Adenocarcinoma: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Lei Wu

    2017-07-01

    Full Text Available Numb chin syndrome (NCS refers to a rare sensory neuropathy characterized by numbness of the chin within the distribution of the mental or inferior alveolar nerve. Although NCS is usually caused by a benign process, it should not be underestimated and a thorough diagnostic evaluation for a new or known progressive malignancy should always be performed. Here, we report a case of salivary ductal adenocarcinoma that mimicked a pulpitis and periodontitis in its early presentation accompanied by numbness of chin. The course and diagnosis of this case are discussed, and a brief review of the literature is presented. It is hoped for clinicians to keep the malignant possibility of NCS in mind and take a thorough examination.

  7. Structural imaging of the pancreas in rat using micro-CT: application to a non-invasivelongitudinal evaluation of pancreatic ductal carcinoma monitoring

    Directory of Open Access Journals (Sweden)

    Akladios CY

    2013-04-01

    Full Text Available The aim of the study was to evaluate the feasibility of a longitudinal non-invasive monitoring of rat pancreatic ductal adenocarcinoma (PDAC using microCTscans (μCT. The identification of the pancreatic gland on (μCT was performed at first using contrast products (Fenestra LC and VC, v/v at a dosage of 0.5 ml/Kg of body weight. Then orthotopic PDAC developed in adult Lewis rat was detected and monitored. In vivo μCT measurement of tumor was compared to actual size ex vivo in 12 rats. Gemcitabine treatment of PDAC was monitored at two week intervals until defined endpoints (liver metastasis or ascitis in 10 rats versus 10 controls. μCT had a 100% positive predictive value in the detection of orthotropic PDAC. Regression analysis showed a linear correlation between ex vivo and in vivo μCT tumor measurements. Longitudinal evaluation of tumor progression showed a reduction in tumor growth (P<0.05 at 8 weeks and a slightly prolonged survival (P=0.15 under gemcitabine treatment. In conclusion μCT appears to be a cost-effective mean for preclinical study of PDAC saving time, animals, while respecting animal welfare. It could be considered as an efficient tool in anticancer drug research and development.

  8. Hospital-level Variation in Utilization of Surgery for Clinical Stage I-II Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Swords, Douglas S; Mulvihill, Sean J; Skarda, David E; Finlayson, Samuel R G; Stoddard, Gregory J; Ott, Mark J; Firpo, Matthew A; Scaife, Courtney L

    2017-07-11

    To (1) evaluate rates of surgery for clinical stage I-II pancreatic ductal adenocarcinoma (PDAC), (2) identify predictors of not undergoing surgery, (3) quantify the degree to which patient- and hospital-level factors explain differences in hospital surgery rates, and (4) evaluate the association between adjusted hospital-specific surgery rates and overall survival (OS) of patients treated at different hospitals. Curative-intent surgery for potentially resectable PDAC is underutilized in the United States. Retrospective cohort study of patients ≤85 years with clinical stage I-II PDAC in the 2004 to 2014 National Cancer Database. Mixed effects multivariable models were used to characterize hospital-level variation across quintiles of hospital surgery rates. Multivariable Cox proportional hazards models were used to estimate the effect of adjusted hospital surgery rates on OS. Of 58,553 patients without contraindications or refusal of surgery, 63.8% underwent surgery, and the rate decreased from 2299/3528 (65.2%) in 2004 to 4412/7092 (62.2%) in 2014 (P < 0.001). Adjusted hospital rates of surgery varied 6-fold (11.4%-70.9%). Patients treated at hospitals with higher rates of surgery had better unadjusted OS (median OS 10.2, 13.3, 14.2, 16.5, and 18.4 months in quintiles 1-5, respectively, P < 0.001, log-rank). Treatment at hospitals in lower surgery rate quintiles 1-3 was independently associated with mortality [Hazard ratio (HR) 1.10 (1.01, 1.21), HR 1.08 (1.02, 1.15), and HR 1.09 (1.04, 1.14) for quintiles 1-3, respectively, compared with quintile 5] after adjusting for patient factors, hospital type, and hospital volume. Quality improvement efforts are needed to help hospitals with low rates of surgery ensure that their patients have access to appropriate surgery.

  9. Identification of gene expression profiling associated with erlotinib-related skin toxicity in pancreatic adenocarcinoma patients

    Energy Technology Data Exchange (ETDEWEB)

    Caba, Octavio, E-mail: ocaba@ujaen.es [Department of Health Sciences, University of Jaen, Jaen (Spain); Irigoyen, Antonio, E-mail: antonioirigoyen@yahoo.com [Department of Medical Oncology, Virgen de la Salud Hospital, Toledo (Spain); Jimenez-Luna, Cristina, E-mail: crisjilu@ugr.es [Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada (Spain); Benavides, Manuel, E-mail: manuel.benavides.sspa@juntadeandalucia.es [Department of Medical Oncology, Virgen de la Victoria Hospital, Malaga (Spain); Ortuño, Francisco M., E-mail: fortuno@ugr.es [Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada (Spain); Gallego, Javier, E-mail: j.gallegoplazas@gmail.com [Department of Medical Oncology, General Universitario de Elche Hospital, Alicante (Spain); Rojas, Ignacio, E-mail: irojas@ugr.es [Department of Computer Architecture and Computer Technology, Research Center for Information and Communications Technologies, University of Granada, Granada (Spain); Guillen-Ponce, Carmen, E-mail: carmen.guillen@salud.madrid.org [Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid (Spain); Torres, Carolina, E-mail: ctorres@uic.edu [Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL (United States); Aranda, Enrique, E-mail: enrique.aranda@imibic.org [Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba (Spain); Prados, Jose, E-mail: jcprados@ugr.es [Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada (Spain)

    2016-11-15

    Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients. The study included 34 PDAC patients treated with erlotinib: 21 patients developed any grade of SR, while 13 patients did not (controls). Before administering any chemotherapy regimen and the development of SR, we collected RNA from peripheral blood samples of all patients and studied the differential gene expression pattern using the Illumina microarray platform HumanHT-12 v4 Expression BeadChip. Seven genes (FAM46C, IFITM3, GMPR, DENND6B, SELENBP1, NOL10, and SIAH2), involved in different pathways including regulatory, migratory, and signalling processes, were downregulated in PDAC patients with SR. Our results suggest the existence of a gene expression profiling significantly correlated with erlotinib-induced SR in PDAC that could be used as prognostic indicator in this patients. - Highlights: • Skin rash (SR) is the most characteristic side effect of erlotinib in PDAC patients. • Erlotinib-induced SR has been associated with a better clinical outcome. • Gene expression profiling was used to determine who will develop this manifestation. • 7 genes involved in different pathways were downregulated in PDAC patients with SR. • Our profile correlated with erlotinib-induced SR in PDAC could be used for prognosis.

  10. Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence.

    Science.gov (United States)

    Ferguson, Margaret D; Dong, Lei; Wan, Jim; Deneve, Jeremiah L; Dickson, Paxton V; Behrman, Stephen W; Shibata, David; Martin, Mike G; Glazer, Evan S

    2018-02-10

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations-gene mutations, variations in copy number, and changes in gene expression-has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student's t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson's χ 2 . Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p molecular alterations warrants further investigation.

  11. Simultaneous Occurrence of Pancreatic Adenocarcinoma and Brunner's Gland Adenoma in a Siberian Tiger (Panthera tigris altaica).

    Science.gov (United States)

    Gombač, M; Dolenšek, T; Jaušovec, D; Kvapil, P; Švara, T; Pogačnik, M

    2015-11-01

    We describe a case of pancreatic adenocarcinoma and Brunner's gland adenoma in an 18-year-old male Siberian tiger (Panthera tigris altaica) from the Ljubljana Zoo. The tiger was humanely destroyed due to weakness and progressive weight loss. Necropsy examination revealed a large, grey, predominantly necrotic mass replacing the major part of the pancreatic body. Microscopically, the mass was unencapsulated, poorly demarcated, highly cellular and composed of highly pleomorphic, cuboidal to tall columnar cells with basal, round or oval, moderately anisokaryotic nuclei with prominent nucleoli and moderate to large amounts of eosinophilic cytoplasm. The tumour was diagnosed as pancreatic tubular adenocarcinoma with infiltration into the duodenum and mesentery. There were tumour emboli in mesenteric blood vessels and hepatic metastases. The non-affected part of the pancreas exhibited severe chronic pancreatitis. In addition, one firm white neoplastic nodule was observed in the duodenal wall. The nodule was set in the tunica muscularis and was unencapsulated, well demarcated and highly cellular, and consisted of a closely packed layer of normal Brunner's glands and a centrally positioned group of irregularly branched tubules with small amounts of debris in the lumen. The neoplastic nodule was diagnosed as Brunner's gland adenoma. The present case is, to the best of our knowledge, the first report of concurrent pancreatic adenocarcinoma and Brunner's gland adenoma, most probably induced by chronic pancreatitis, either in man or animals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L., E-mail: rodney.rouse@fda.hhs.gov

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  13. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    International Nuclear Information System (INIS)

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L.

    2012-01-01

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  14. Prenyltransferase inhibitor radiosensitization of pancreatic ductal carcinoma (PaCa) cells

    International Nuclear Information System (INIS)

    Brunner, T.B.; Hahn, S.M.; Rustgi, A.K.

    2003-01-01

    Farnesyltransferase inhibitors (FTIs) radiosensitize tumor cell lines expressing activated H-Ras. K-Ras however remains active after FTI treatment due to prenylation by geranylgeranyltransferase. Up to 90% of pancreatic carcinomas (PaCa) are mutant in K-ras. We hypothesized that combined FTI and geranylgeranyltransferase inhibitor (GGTI) treatment could radiosensitize PaCa cells. Nine human PaCa lines (7 K-ras-mutant, 2 ras-wt) and transgenic mouse pancreatic ductal cells (PDC) expressing wt-ras or mutant K-ras were tested in clonogenic assays with combined FTI-A +/- GGTI-B (Merck and Co Inc.). Inhibition of PI3- kinase (with LY294002) or inhibition of MEK1/2 (with U0126) served to assess the significance of the PI3-kinase and MAPK to radiation survival in these cells. H- and K-Ras prenylation status and changes in phosphorylation of AKT and MAPK were monitored as were changes in cell cycle distribution. FTI+GGTI treatment achieved inhibition of K-Ras prenylation in all PaCa cell lines. This treatment radiosensitized the K-ras mutant cell lines AsPC-1, Capan-2, MiaPaCa-2 and PSN-1, PancM, but not Capan-1 or the ras-wt cell lines (BxPC-3, HS766T, PDC-wt). L-778,123, a dual action inhibitor, sensitized all K-ras mutant cells. Surprisingly, PancM, Panc-1, MiaPaCa-2 and PDC K-Ras cells were radiosensitized by FTI treatment alone. R11577, another FTI without GGTI activity, also sensitized Panc-1 and MiaPaCa-2 and additionally AsPC-1 cells. Radiosensitization was also achieved after treatment with LY294002 in all PaCa lines expressing mutant-K-ras and the ras-wt line BxPC-3 overexpressing Akt2. However these lines were not sensitized by U0126. FTI+GGTI sensitize K-ras mt PaCa cell lines to radiation. PI3-kinase signaling but not MAPK signaling appears to contribute to radiation survival in PaCa cells. Radiosensitization of certain PaCa cells by FTI alone indicates that alternate pathways or farnesylated targets other than K-Ras may also be involved in radiation survival

  15. Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery.

    Science.gov (United States)

    Swords, Douglas S; Zhang, Chong; Presson, Angela P; Firpo, Matthew A; Mulvihill, Sean J; Scaife, Courtney L

    2018-04-01

    Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. The 2004-2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I-II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1-14 days), medium (15-42), and long (43-120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe. Published by Elsevier Inc.

  16. Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma.

    Science.gov (United States)

    Dugnani, Erica; Balzano, Gianpaolo; Pasquale, Valentina; Scavini, Marina; Aleotti, Francesca; Liberati, Daniela; Di Terlizzi, Gaetano; Gandolfi, Alessandra; Petrella, Giovanna; Reni, Michele; Doglioni, Claudio; Bosi, Emanuele; Falconi, Massimo; Piemonti, Lorenzo

    2016-12-01

    To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. Insulin resistance is associated with the aggressiveness of PDAC.

  17. Epithelial-to-Mesenchymal Transition in Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Carla Cano

    2010-01-01

    Full Text Available Epithelial to mesenchymal transition (EMT is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/aggressiveness, and the drug resistance of pancreatic cancer cells.

  18. Laparoscopic distal pancreatectomy for adenocarcinoma: safe and reasonable?

    Science.gov (United States)

    Postlewait, Lauren M.

    2015-01-01

    As a result of technological advances during the past two decades, surgeons now use minimally invasive surgery (MIS) approaches to pancreatic resection more frequently, yet the role of these approaches for pancreatic ductal adenocarcinoma resections remains uncertain, given the aggressive nature of this malignancy. Although there are no controlled trials comparing MIS technique to open surgical technique, laparoscopic distal pancreatectomy for pancreatic adenocarcinoma is performed with increasing frequency. Data from retrospective studies suggest that perioperative complication profiles between open and laparoscopic distal pancreatectomy are similar, with perhaps lower blood loss and fewer wound infections in the MIS group. Concerning oncologic outcomes, there appear to be no differences in the rate of achieving negative margins or in the number of lymph nodes (LNs) resected when compared to open surgery. There are limited recurrence and survival data on laparoscopic compared to open distal pancreatectomy for pancreatic adenocarcinoma, but in the few studies that assess long term outcomes, recurrence rates and survival outcomes appear similar. Recent studies show that though laparoscopic distal pancreatectomy entails a greater operative cost, the associated shorter length of hospital stay leads to decreased overall cost compared to open procedures. Multiple new technologies are emerging to improve resection of pancreatic cancer. Robotic pancreatectomy is feasible, but there are limited data on robotic resection of pancreatic adenocarcinoma, and outcomes appear similar to laparoscopic approaches. Additionally fluorescence-guided surgery represents a new technology on the horizon that could improve oncologic outcomes after resection of pancreatic adenocarcinoma, though published data thus far are limited to animal models. Overall, MIS distal pancreatectomy appears to be a safe and reasonable approach to treating selected patients with pancreatic ductal

  19. Whole genomes redefine the mutational landscape of pancreatic cancer

    OpenAIRE

    Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K.; Kassahn, Karin S.; Bailey, Peter; Johns, Amber L.; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.

    2015-01-01

    Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (...

  20. Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for pancreatic and colorectal adenocarcinoma

    DEFF Research Database (Denmark)

    Baraniskin, Alexander; Nöpel-Dünnebacke, Stefanie; Ahrens, Maike

    2013-01-01

    Improved non-invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non-coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as biomarkers for non-invasive cancer diagnosis. Analyzing serum derived from nude mice implanted...... with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR-1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR-1246 assays with RNA fragments derived from U...... that hsa-miR-1246 is likely a pseudo microRNA. In a next step, RNU2-1f was measured by qRT-PCR and normalized to cel-54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity...

  1. Platinum-Based Therapy in Adenosquamous Pancreatic Cancer: Experience at Two Institutions

    OpenAIRE

    Andre Luiz De Souza; Muhammad Wasif Saif

    2014-01-01

    Adenosquamous carcinoma of the pancreas is a rare type of pancreatic cancer. Although its molecular biology profile hasbeen shown to be similar to pancreatic ductal adenocarcinoma tumors, it has different prognostic features. There is noconsensus or guidelines to treat this tumor differently from pancreatic adenocarcinoma, but therapies based on gemcitabineand platinum chemotherapeutics such as cisplatin and oxaliplatin have been used based on results of a few case reports. Wediscuss the Abst...

  2. Incremental value of secretin-enhanced magnetic resonance cholangiopancreatography in detecting ductal communication in a population with high prevalence of small pancreatic cysts

    Energy Technology Data Exchange (ETDEWEB)

    Rastegar, Neda; Matteoni-Athayde, Luciana G.; Eng, John [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States); Takahashi, Naoki [Mayo Clinic (United States); Tamm, Eric P. [MD Anderson Cancer Center (United States); Mortele, Koenraad J. [Beth Israel Deaconess Medical Center (United States); Syngal, Sapna [Dana Farber Cancer Institute (United States); Margolis, Daniel [University of California, Los Angeles (United States); Lennon, Anne Marie; Wolfgang, Christopher L.; Fishman, Elliot K.; Hruban, Ralph H.; Goggins, Michael; Canto, Marcia I. [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States); Kamel, Ihab R., E-mail: ikamel@jhmi.edu [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States)

    2015-04-15

    Highlights: •Secretin improved visualization of ductal communication of a cystic pancreatic lesion. •No association between cysts and gender, ethnicity or type of high risk. •Incremental value of secretin could offset the added cost and time. -- Abstract: Purpose: We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts. Methods: Standard MRCP protocol was performed with and without secretin using 1.5 T units in subjects undergoing pancreatic screening because of a strong family history of pancreatic cancer as part of the multicenter Cancer of the Pancreas Screening-3 trial (CAPS 3). All studies were reviewed prospectively by two independent readers who recorded the presence and number of pancreatic cysts, the presence of visualized ductal communication before and after secretin, and the degree of confidence in the diagnoses. Result: Of 202 individuals enrolled (mean age 56 years, 46% males), 93 (46%) had pancreatic cysts detected by MRCP, and 64 of the 93 had pre-and post-secretin MRCP images available for comparison. Data from the 128 readings show that 6 (6/128 = 4.7%) had ductal communication visualized only on the secretin studies compared to pre-secretin studies (odds ratio 1.28, p = 0.04). In addition, there was a statistically significant increase in confidence in reporting ductal communication after secretin compared to before secretin (p < 0.0005). Conclusion: At 1.5 T MRI, the use of secretin can improve the visualization of ductal communication of cystic pancreatic lesions.

  3. Incremental value of secretin-enhanced magnetic resonance cholangiopancreatography in detecting ductal communication in a population with high prevalence of small pancreatic cysts

    International Nuclear Information System (INIS)

    Rastegar, Neda; Matteoni-Athayde, Luciana G.; Eng, John; Takahashi, Naoki; Tamm, Eric P.; Mortele, Koenraad J.; Syngal, Sapna; Margolis, Daniel; Lennon, Anne Marie; Wolfgang, Christopher L.; Fishman, Elliot K.; Hruban, Ralph H.; Goggins, Michael; Canto, Marcia I.; Kamel, Ihab R.

    2015-01-01

    Highlights: •Secretin improved visualization of ductal communication of a cystic pancreatic lesion. •No association between cysts and gender, ethnicity or type of high risk. •Incremental value of secretin could offset the added cost and time. -- Abstract: Purpose: We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts. Methods: Standard MRCP protocol was performed with and without secretin using 1.5 T units in subjects undergoing pancreatic screening because of a strong family history of pancreatic cancer as part of the multicenter Cancer of the Pancreas Screening-3 trial (CAPS 3). All studies were reviewed prospectively by two independent readers who recorded the presence and number of pancreatic cysts, the presence of visualized ductal communication before and after secretin, and the degree of confidence in the diagnoses. Result: Of 202 individuals enrolled (mean age 56 years, 46% males), 93 (46%) had pancreatic cysts detected by MRCP, and 64 of the 93 had pre-and post-secretin MRCP images available for comparison. Data from the 128 readings show that 6 (6/128 = 4.7%) had ductal communication visualized only on the secretin studies compared to pre-secretin studies (odds ratio 1.28, p = 0.04). In addition, there was a statistically significant increase in confidence in reporting ductal communication after secretin compared to before secretin (p < 0.0005). Conclusion: At 1.5 T MRI, the use of secretin can improve the visualization of ductal communication of cystic pancreatic lesions

  4. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

    Science.gov (United States)

    Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T

    2017-01-01

    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. PMID:28404095

  5. Primary clear cell ductal adenocarcinoma of the pancreas: A case report and clinicopathologic literature review

    Directory of Open Access Journals (Sweden)

    Yashpal Modi

    2014-01-01

    Full Text Available We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classification, primary clear cell carcinoma of the pancreas is classified as a rare "miscellaneous" carcinoma. The tumor was observed in the distal body and tail of the pancreas of a 74-year-old woman. The histopathology of tumor cells showed well-defined cell membranes, clear cytoplasm, and prominent cell boundaries. Immunohistochemical (IHC staining showed positive reactions to antibodies against vimentin, cytokeratin 7 (CK-7, mucicarmine (MUC-1, periodic acid-Schiff (PAS, periodic acid-Schiff with diastase (PASD, carcinoembryonic antigen (CEA, and Carbohydrate Antigen 19-9 (CA 19-9. On the other hand, IHC staining was negative for alpha-fetoprotein (AFP, cytokeratin 20 (CK-20, HMB45, chromogranin, and synaptophysin. The patient was subsequently diagnosed with a primary solid-type pancreatic clear cell carcinoma with hepatic metastasis. Herein, we report this rare case and include a review of the current literature of this tumor.

  6. Dual-energy perfusion-CT of pancreatic adenocarcinoma

    International Nuclear Information System (INIS)

    Klauß, M.; Stiller, W.; Pahn, G.; Fritz, F.; Kieser, M.; Werner, J.; Kauczor, H.U.; Grenacher, L.

    2013-01-01

    Purpose: To evaluate the feasibility of dual-energy CT (DECT)-perfusion of pancreatic carcinomas for assessing the differences in perfusion, permeability and blood volume of healthy pancreatic tissue and histopathologically confirmed solid pancreatic carcinoma. Materials and methods: 24 patients with histologically proven pancreatic carcinoma were examined prospectively with a 64-slice dual source CT using a dynamic sequence of 34 dual-energy (DE) acquisitions every 1.5 s (80 ml of iodinated contrast material, 370 mg/ml, flow rate 5 ml/s). 80 kV p , 140 kV p , and weighted average (linearly blended M0.3) 120 kV p -equivalent dual-energy perfusion image data sets were evaluated with a body-perfusion CT tool (Body-PCT, Siemens Medical Solutions, Erlangen, Germany) for estimating perfusion, permeability, and blood volume values. Color-coded parameter maps were generated. Results: In all 24 patients dual-energy CT-perfusion was. All carcinomas could be identified in the color-coded perfusion maps. Calculated perfusion, permeability and blood volume values were significantly lower in pancreatic carcinomas compared to healthy pancreatic tissue. Weighted average 120 kV p -equivalent perfusion-, permeability- and blood volume-values determined from DE image data were 0.27 ± 0.04 min −1 vs. 0.91 ± 0.04 min −1 (p −1 vs. 0.67 ± 0.05 *0.5 min −1 (p = 0.06) and 0.49 ± 0.07 min −1 vs. 1.28 ± 0.11 min −1 (p p the standard deviations of the kV p 120 kV p -equivalent values were manifestly smaller. Conclusion: Dual-energy CT-perfusion of the pancreas is feasible. The use of DECT improves the accuracy of CT-perfusion of the pancreas by fully exploiting the advantages of enhanced iodine contrast at 80 kV p in combination with the noise reduction at 140 kV p . Therefore using dual-energy perfusion data could improve the delineation of pancreatic carcinomas

  7. Association studies of the copy-number variable ß-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Taudien Stefan

    2012-11-01

    Full Text Available Abstract Background Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV and copy-number variants (CNV of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case–control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF cluster copy number (CN, and pancreatic ductal adenocarcinoma (PDAC and chronic pancreatitis (CP. Results Two groups of PDAC (N=70 and CP (N=60 patients were compared to matched healthy control groups CARLA1 (N=232 and CARLA2 (N=160, respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification. Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively. The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher’s exact test P=0.027, but not between CP and CARLA2 (P=0.867. Conclusion Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.

  8. Functional and morphological evolution of remnant pancreas after resection for pancreatic adenocarcinoma.

    Science.gov (United States)

    Park, Shin-Young; Park, Keun-Myoung; Shin, Woo Young; Choe, Yun-Mee; Hur, Yoon-Seok; Lee, Keon-Young; Ahn, Seung-Ik

    2017-07-01

    Functional and morphological evolution of remnant pancreas after resection for pancreatic adenocarcinoma is investigated.The medical records of 45 patients who had undergone radical resection for pancreatic adenocarcinoma from March 2010 to September 2013 were reviewed retrospectively. There were 34 patients in the pancreaticoduodenectomy (PD) group and 10 patients in the distal pancreatectomy (DP) group. One patient received total pancreatectomy. The endocrine function was measured using the glucose tolerance index (GTI), which was derived by dividing daily maximum serum glucose fluctuation by daily minimum glucose. Remnant pancreas volume (RPV) was estimated by considering pancreas body and tail as a column, and head as an ellipsoid, respectively. The pancreatic atrophic index (PAI) was defined as the ratio of pancreatic duct width to total pancreas width. Representative indices of each patient were compared before and after resection up to 2 years postoperatively.The area under receiver operating characteristic curve of GTI for diagnosing DM was 0.823 (95% confidence interval, 0.699-0.948, P < .001). Overall, GTI increased on postoperative day 1 (POD#1, mean ± standard deviation, 1.79 ± 1.40 vs preoperative, 1.02 ± 1.41; P = .001), and then decreased by day 7 (0.89 ± 1.16 vs POD#1, P < .001). In the PD group, the GTI on POD#14 became lower than preoperative (0.51 ± 0.38 vs 0.96 ± 1.37; P = .03). PAI in the PD group was significantly lower at 1 month postoperatively (0.22 ± 0.12 vs preoperative, 0.38 ± 0.18; P < .001). In the PD group, RPV was significantly lower at 1 month postoperatively (25.3 ± 18.3 cm vs preoperative, 32.4 ± 20.1 cm; P = .02), due to the resolution of pancreatic duct dilatation. RPV of the DP group showed no significant change. GTI was negatively related to RPV preoperatively (r = -0.317, P = .04), but this correlation disappeared postoperatively (r = -0

  9. The efficacy of fat suppressed and gadolinium enhanced dynamic MR imaging in pancreatic adenocarcinomas

    International Nuclear Information System (INIS)

    Gabata, Toshifumi

    1994-01-01

    The efficacy of both fat suppressed T1-weighted imaging (T1WI) and dynamic gadolinium-enhanced MR imaging (dynamic MRI) was compared with conventional MR sequences and dynamic CT in 22 patients with histologically proven pancreatic adenocarcinoma (PAC). In the control group of 30 patients without pancreatic disease, the pancreas was shown as a markedly higher signal intensity on fat suppressed T1WI than on conventional MR sequences. The signal noise ratio (SNR) of the normal pancreas and the contrast noise ratio (CNR) between the normal pancreas and muscle were significantly higher on fat suppressed T1WI than the other MR sequences. In the group of PAC patients without chronic pancreatitis (n=14), CNR between the tumor and the normal pancreas significantly differed among imaging techniques, including fat suppressed T1WI, dynamic MRI, and the other conventional MR sequences. In the group of PAC with chronic pancreatitis (n=8), CNR between the tumor and the associated chronic pancreatitis was remarkably diminished on both fat suppressed T1WI and conventional T1WI; however, it was significantly higher on dynamic MRI than the other pulse sequences. The early phase of dynamic MRI clearly identified the tumors in the group of PAC. The capability of conventional T1WI and dynamic CT to demonstrate peripancreatic tumor extension was significantly higher than that of fat suppressed T1WI. In conclusion, fat suppressed T1WI and dynamic MRI were useful in detecting pancreatic carcinoma. (N.K.)

  10. The role of contrast-enhanced endoscopic ultrasound in pancreatic adenocarcinoma

    DEFF Research Database (Denmark)

    Saftoiu, Adrian; Vilmann, Peter; Bhutani, Manoop S

    2016-01-01

    contrast agents for early detection, tridimensional and fusion techniques for enhanced staging and resectability assessment but also novel applications of perfusion imaging for monitoring ablative therapy, improved local detection through EUS-guided sampling of portal vein flow or enhanced drug delivery......Contrast-enhanced endoscopic ultrasound (CE-EUS) allows characterization, differentiation, and staging of focal pancreatic masses. The method has a high sensitivity and specificity for the diagnosis of pancreatic adenocarcinoma which is visualized as hypo-enhanced as compared to the rest...... of the parenchyma while chronic pancreatitis and neuroendocrine tumors are generally either iso-enhanced or hyper-enhanced. The development of contrast-enhanced low mechanical index harmonic imaging techniques used in real time during endoscopic ultrasound (EUS) allowed perfusion imaging and the quantification...

  11. Multiple Pharmacological Properties of a Novel Parthenin Analog P16 as Evident by its Cytostatic and Antiangiogenic Potential Against Pancreatic Adenocarcinoma PANC -1 Cells.

    Science.gov (United States)

    Goswami, Akshra; Shah, Bhahwal Ali; Batra, Navneet; Kumar, Ajay; Guru, Santosh Kumar; Bhushan, Shashi; Malik, Fayaz Ahmad; Joshi, Amit; Singh, Jagtar

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest types of cancers. Median survival rate is very poor with the currently available chemotherapeutical regimens. Therefore, discovery of new antineoplastic agents against PDA is one of the focused areas of contemporary research. The present study was undertaken to explore the antitumour activity of a potent parthenin analog P16. Among PANC-1, Mia PaCa-2 and AsPC-1 pancreatic cancer cells, PANC-1 showed highest sensitivity to P16 with an IC50 value of 3.4 μM. Time dependent cell cycle studies revealed that P16 suppressed the growth of PANC-1 cells by arresting the progression through the cell cycle in G2/M phase via downregulation of cyclin B1 and cyclin A. However, P16 did not alter the expressions of CDK-1 and CDC25C in PANC-1 cells. The P16 induced cell cycle arrest, which consequently, led to induction of apoptosis, which was accompanied by activation of caspase-9 and -3. Interestingly, PANC-1 cells displayed increasing loss of mitochondrial potential, which seemed to be correlated to the activation of caspase-3. Additionally, P16 was also able to down-regulate the cell migration in PANC-1 cells. Furthermore, P16 treatment of hypoxic PANC-1 cells strongly suppressed the expression of proangiogenic factors VEGFR-2, HIF1α and HIF1β. Antiangiogenic ability of P16 was also reflected in the human umbilical vascular endothelial cells (HUVECs), where it effectively suppressed the migration and inhibited the formation of the tube in a matrigel based assay. Therefore, cytostatic and antiangiogenic properties of P16 against pancreatic adenocarcinoma cells make it a suitable candidate for further investigation.

  12. The influence of matrix properties on growth and morphogenesis of human pancreatic ductal epithelial cells in 3D

    Science.gov (United States)

    Raza, Asad; Ki, Chang Seok; Lin, Chien-Chi

    2013-01-01

    A highly tunable synthetic biomimetic hydrogel platform was developed to study the growth and morphogenesis of pancreatic ductal epithelial cells (PDEC) under the influence of a myriad of instructive cues. A PDEC line, PANC-1, was used as a model system to illustrate the importance of matrix compositions on cell fate determination. PANC-1 is an immortalized ductal epithelial cell line widely used in the study of pancreatic tumor cell behaviors. PANC-1 cells are also increasingly explored as a potential cell source for endocrine differentiation. Thus far, most studies related to PANC-1, among other PDEC lines, are performed on 2D culture surfaces. Here, we evaluated the effect of matrix compositions on PANC-1 cell growth and morphogenesis in 3D. Specifically, PANC-1 cells were encapsulated in PEG-based hydrogels prepared by step-growth thiol-ene photopolymerization. It was found that thiol-ene hydrogels provided a cytocompatible environment for encapsulation and 3D culture of PANC-1 cells. In contrast to a monolayer morphology on 2D culture surfaces, PANC-1 cells formed clusters in 3D thiol-ene hydrogels within 4 days of culture. After culturing for 10 days, however, the growth and structures of these clusters were significantly impacted by gel matrix properties, including sensitivity of the matrix to proteases, stiffness of the matrix, and ECM-mimetic motifs. The use of matrix metalloproteinase (MMP) sensitive linker or the immobilization of fibronectin-derived RGDS ligand in the matrix promoted PANC-1 cell growth and encouraged them to adopt ductal cyst-like structures. On the other hand, the encapsulated cells formed smaller and more compact aggregates in non-MMP responsive gels. The incorporation of laminin-derived YIGSR peptide did not enhance cell growth and caused the cells to form compact aggregates. Immobilized YIGSR also enhanced the expression of epithelial cell markers including β-catenin and E-cadherin. These studies have established PEG

  13. Clinicopathologic assessment of pancreatic ductal carcinoma located at the head of the pancreas, in relation to embryonic development.

    Science.gov (United States)

    Okamura, Yukiyasu; Fujii, Tsutomu; Kanzaki, Akiyuki; Yamada, Suguru; Sugimoto, Hiroyuki; Nomoto, Shuji; Takeda, Shin; Nakao, Akimasa

    2012-05-01

    Pancreaticoduodenectomy is performed for pancreatic head cancer that originated from the dorsal or ventral primordium. Although the extent of lymph node (LN) dissection is the same irrespective of the origin, the lymphatic continuities may differ between the 2 primordia. Between March 2003 and September 2010, 152 patients underwent pancreaticoduodenectomy for pancreatic cancer. One hundred six patients were assigned into 2 groups according to tumor location on preoperative computed tomography, and their clinical and pathological features were retrospectively analyzed in view of the embryonic development of the pancreas. Sixty of 106 patients were classified with tumors that were derived from the dorsal pancreas (D group) and 46 from the ventral pancreas (V group). The frequency of LN involvement around the middle colic artery (LN 15) in the D group was higher than in the V group (P = 0.008). The rate of additional resection of the pancreas tended to be higher in the D group (P = 0.067). The present study showed the detailed pattern of spread of pancreatic ductal carcinoma to the LNs and provided important information for determining the optimal surgical strategy.

  14. Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis

    DEFF Research Database (Denmark)

    Lemaire, Laurence A; Goulley, Joan; Kim, Yung Hae

    2015-01-01

    that line the ducts during development, and in the ducts after birth, but not in differentiated endocrine or acinar cells. Genetic inactivation of Bicc1 leads to ductal cell over-proliferation and cyst formation. Transcriptome comparison between WT and Bicc1 KO pancreata, before the phenotype onset, reveals......(+) endocrine progenitor production. Its deletion leads to a late but sustained endocrine progenitor decrease, resulting in a 50% reduction of endocrine cells. We show that BICC1 functions downstream of ONECUT1 in the pathway controlling both NEUROG3(+) endocrine cell production and ductal morphogenesis...

  15. Chronic relapsing pancreatitis in a child. Use of the Puestow procedure to achieve ductal drainage.

    Science.gov (United States)

    Duncan, N D; McDonald, A; James, M; Brown, B; Mitchell, D I

    2000-09-01

    A case of chronic relapsing pancreatitis presenting in an 8-year-old African Jamaican girl is outlined. Aggressive supportive management failed to control pain and vomiting. The Puestow Procedure effectively procedure aborted these symptoms. The use of the Puestow procedure should not be inordinately delayed in chronic relapsing pancreatitis if symptoms persist, since it may not only control pain but also halt declining pancreatic function.

  16. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation

    DEFF Research Database (Denmark)

    Shih, Hung Ping; Kopp, Janel L; Sandhu, Manbir

    2012-01-01

    necessitates subsequent Sox9 downregulation and evasion from Notch activity via cell-autonomous repression of Sox9 by Ngn3. If high Notch levels are maintained, endocrine progenitors retain Sox9 and undergo ductal fate conversion. Taken together, our findings establish a novel role for Notch in initiating both...

  17. Definition and Management of Borderline Resectable Pancreatic Cancer.

    Science.gov (United States)

    Denbo, Jason W; Fleming, Jason B

    2016-12-01

    Patients with localized pancreatic ductal adenocarcinoma seek potentially curative treatment, but this group represents a spectrum of disease. Patients with borderline resectable primary tumors are a unique subset whose successful therapy requires a care team with expertise in medical care, imaging, surgery, medical oncology, and radiation oncology. This team must identify patients with borderline tumors then carefully prescribe and execute a combined treatment strategy with the highest possibility of cure. This article addresses the issues of clinical evaluation, imaging techniques, and criteria, as well as multidisciplinary treatment of patients with borderline resectable pancreatic ductal adenocarcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy.

    Science.gov (United States)

    Di Caro, Giuseppe; Cortese, Nina; Castino, Giovanni Francesco; Grizzi, Fabio; Gavazzi, Francesca; Ridolfi, Cristina; Capretti, Giovanni; Mineri, Rossana; Todoric, Jelena; Zerbi, Alessandro; Allavena, Paola; Mantovani, Alberto; Marchesi, Federica

    2016-10-01

    Tumour-associated macrophages (TAMs) play key roles in tumour progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer. In a large retrospective cohort study involving 110 patients with pancreatic ductal adenocarcinoma (PDAC), we assessed the density of CD68-TAM immune reactive area (%IRA) at the tumour-stroma interface and addressed their prognostic relevance in relation to postsurgical adjuvant chemotherapy (CTX). In vitro, we dissected the synergism of CTX and TAMs. In human PDAC, TAMs predominantly exhibited an immunoregulatory profile, characterised by expression of scavenger receptors (CD206, CD163) and production of interleukin 10 (IL-10). Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumour prognostic significance. High density of TAMs at the tumour-stroma interface positively dictated prognostic responsiveness to CTX independently of T-cell density. Accordingly, in vitro, gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression programme, inhibiting their protumoural effect and switching to an antitumour phenotype. In patients with human PDAC, neoadjuvant CTX was associated to a decreased density of CD206(+) and IL-10(+) TAMs at the tumour-stroma interface. Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX overall directly re-educates TAMs to restrain tumour progression. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide the basis for novel strategies aimed at re-educating macrophages in the context of CTX. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  19. Mapping Patterns of Local Recurrence After Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: A New Approach to Adjuvant Radiation Field Design

    Energy Technology Data Exchange (ETDEWEB)

    Dholakia, Avani S.; Kumar, Rachit [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Raman, Siva P. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Moore, Joseph A.; Ellsworth, Susannah; McNutt, Todd [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Laheru, Daniel A.; Jaffee, Elizabeth [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Cameron, John L. [Department of Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hobbs, Robert F. [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Wolfgang, Christopher L. [Department of Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

    2013-12-01

    Purpose: To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. Methods and Materials: Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach. Results: Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. Conclusions: Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy.

  20. Mapping Patterns of Local Recurrence After Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: A New Approach to Adjuvant Radiation Field Design

    International Nuclear Information System (INIS)

    Dholakia, Avani S.; Kumar, Rachit; Raman, Siva P.; Moore, Joseph A.; Ellsworth, Susannah; McNutt, Todd; Laheru, Daniel A.; Jaffee, Elizabeth; Cameron, John L.; Tran, Phuoc T.; Hobbs, Robert F.; Wolfgang, Christopher L.

    2013-01-01

    Purpose: To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. Methods and Materials: Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach. Results: Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. Conclusions: Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy

  1. Serum deprivation induces glucose response and intercellular coupling in human pancreatic adenocarcinoma PANC-1 cells.

    Science.gov (United States)

    Hiram-Bab, Sahar; Shapira, Yuval; Gershengorn, Marvin C; Oron, Yoram

    2012-03-01

    This study aimed to investigate whether the previously described differentiating islet-like aggregates of human pancreatic adenocarcinoma cells (PANC-1) develop glucose response and exhibit intercellular communication. Fura 2-loaded PANC-1 cells in serum-free medium were assayed for changes in cytosolic free calcium ([Ca]i) induced by depolarization, tolbutamide inhibition of K(ATP) channels, or glucose. Dye transfer, assayed by confocal microscopy or by FACS, was used to detect intercellular communication. Changes in messenger RNA (mRNA) expression of genes of interest were assessed by quantitative real-time polymerase chain reaction. Proliferation was assayed by the MTT method. Serum-deprived PANC-1 cell aggregates developed [Ca]i response to KCl, tolbutamide, or glucose. These responses were accompanied by 5-fold increase in glucokinase mRNA level and, to a lesser extent, of mRNAs for K(ATP) and L-type calcium channels, as well as increase in mRNA levels of glucagon and somatostatin. Trypsin, a proteinase-activated receptor 2 agonist previously shown to enhance aggregation, modestly improved [Ca]i response to glucose. Glucose-induced coordinated [Ca]i oscillations and dye transfer demonstrated the emergence of intercellular communication. These findings suggest that PANC-1 cells, a pancreatic adenocarcinoma cell line, can be induced to express a differentiated phenotype in which cells exhibit response to glucose and form a functional syncytium similar to those observed in pancreatic islets.

  2. Surgical Management of Adenocarcinoma of the Pancreatic Uncinate Process in a Cancer Hospital in Egypt

    Directory of Open Access Journals (Sweden)

    Sameh Roshdy

    2015-08-01

    Full Text Available Introduction Pancreatic carcinoma affecting the uncinate process is a challenging surgical condition. Several considerations affect the management plan, including the need for vascular resection and the ability to achieve a clear margin. Methods The data of 19 patients who had curative resection for pancreatic adenocarcinoma of the uncinate process were reviewed. Operative mortality and morbidity, and disease-free survival (DFS were calculated. Results The study population included 13 male and 6 female patients with a mean age of 55 years. Nine patients (47.4% had stage I disease, seven patients (36.8% had stage II disease, and three patients (15.8% had stage III disease. A total of 12 patients had Whipple procedure and 7 patients had total pancreatectomy. In total, there were 9 R0 and 10 R1 resections. Operative mortality rate was 10.5% (2/19, postoperative leakage rate was 21.1% (4/19, and wound sepsis rate was 21.1%. Median DFS was 19.2 months. Survival was superior in the Whipple procedure group than in the total pancreatectomy group (median survival 19 months vs 4 months, respectively. Vascular resection and retroperitoneal safety margin status did not affect disease relapse. Conclusion Non-metastatic pancreatic adenocarcinoma of the uncinate process should be offered R0 or R1 resection whenever technically feasible.

  3. Prevention of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Stefan Kuroczycki-Saniutycz

    2017-02-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA accounts for 95% of all pancreatic cancers. About 230,000 PDA cases are diagnosed worldwide each year. PDA has the lowest five-year survival rate as compared to others cancers. PDA in Poland is the fifth leading cause of death after lung, stomach, colon and breast cancer. In our paper we have analysed the newest epidemiological research, some of it controversial, to establish the best practical solution for pancreatic cancer prevention in the healthy population as well as treatment for patients already diagnosed with pancreatic cancer. We found that PDA occurs quite frequently but is usually diagnosed too late, at its advanced stage. Screening for PDA is not very well defined except in subgroups of high-risk individuals with genetic disorders or with chronic pancreatitis. We present convincing, probable, and suggestive risk factors associated with pancreatic cancer, many of which are modifiable and should be introduced and implemented in our society.

  4. CT evaluation after neoadjuvant FOLFIRINOX chemotherapy for borderline and locally advanced pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, Mathilde; Lucidarme, Oliver [Sorbonne Universites, UPMC, Department of Radiology, Hopital Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris (France); Antunes, Celia [Coimbra University Hospital, Department of Radiology, Coimbra (Portugal); Pietrasz, Daniel [Sorbonne Universites, UPMC, Department of Digestive and Hepatobiliary Surgery, Hopital Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris (France); Cassinotto, Christophe [Centre Hospitalier Universitaire de Bordeaux, Department of Diagnostic and Interventional Imaging, Hopital Haut Leveque, Bordeaux (France); Zappa, Magaly [Hopitaux Universitaires Paris Nord Val de Seine, Department of Radiology, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy (France); Sa Cunha, Antonio [Hopitaux Universitaires Paris Sud, Department of Hepatobiliary Surgery, Liver Transplant Center, Hopital Paul Brousse, Villejuif (France); Bachet, Jean-Baptiste [Sorbonnes Universites, UPMC, Department of Gastroenterology and Digestive Oncology, Hopital Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris (France)

    2017-07-15

    To assess anatomic changes on computed tomography (CT) after neoadjuvant FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) chemotherapy for secondary resected borderline resectable (BR) and locally advanced (LA) pancreatic adenocarcinoma and their accuracy to predict resectability and pathological response. Thirty-six patients with secondary resected BR/LA pancreatic adenocarcinoma after neoadjuvant FOLFIRINOX chemotherapy (± chemoradiotherapy) were retrospectively included. Two radiologists reviewed baseline and pre-surgical CTs in consensus. NCCN (National Comprehensive Cancer Network) classification, largest axis, product of the three axes (P3A), and arterial/venous involvement were studied and compared to pathological response and resection status and to disease-free survival (DFS). Thirty-one patients had R0 resection, including only six exhibiting a downstaging according to the NCCN classification. After treatment, the largest axis and P3A decreased (P < 0.0001). The pre-surgical largest axis and P3A were smaller in case of R0 resection (P = 0.019/P = 0.021). The largest axis/P3A variations were higher in case of complete pathological response (P = 0.011/P = 0.016). A decrease of the arterial/venous involvement was not able to predict R0 or ypT0N0 (P > 0.05). Progression of the vascular involvement was seen in two (5 %) patients and led to a shorter DFS. In BR/LA pancreatic adenocarcinoma after the neoadjuvant FOLFIRINOX regimen (± chemoradiotherapy), significant tumour size decreases were observed on CT. However, CT staging was not predictive of resectability and pathological response. (orig.)

  5. A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Ma Yue

    2011-03-01

    Full Text Available Abstract Background The objectives of the present study are to investigate the efficacy and safety profile of gemcitabine-based combinations in the treatment of locally advanced and metastatic pancreatic adenocarcinoma (LA/MPC. Methods We performed a computerized search using combinations of the following keywords: "chemotherapy", "gemcitabine", "trial", and "pancreatic cancer". Results Thirty-five trials were included in the present analysis, with a total of 9,979 patients accrued. The analysis showed that the gemcitabine-based combination therapy was associated with significantly better overall survival (OS (ORs, 1.15; p = 0.011, progression-free survival (PFS (ORs, 1.27; p Conclusions Gemcitabine in combination with capecitabine or oxaliplatin was associated with enhanced OS and ORR as compared with gemcitabine in monotherapy, which are likely to become the preferred standard first-line treatment of LA/MPC.

  6. Endotherapy is effective for pancreatic ductal disruption: A dual center experience.

    Science.gov (United States)

    Das, Rohit; Papachristou, Georgios I; Slivka, Adam; Easler, Jeffrey J; Chennat, Jennifer; Malin, Jessica; Herman, Justin B; Laique, Sobia N; Hayat, Umar; Ooi, Yinn Shaung; Rabinovitz, Mordechai; Yadav, Dhiraj; Siddiqui, Ali A

    2016-01-01

    Pancreatic duct (PD) disruptions occur as a result of different etiologies and can be managed medically, endoscopically, or surgically. The aim of this study was to provide an evaluation on the efficacy of endotherapy for treatment of PD disruption in a large cohort of patients and identify factors that predict successful treatment outcome. We retrospectively evaluated consecutive patients who underwent endoscopic retrograde pancreatography (ERP) for transpapillary pancreatic stent placement for PD disruption from 2008 to 2013 at two tertiary referral institutions. PD disruption was defined as extravasation of contrast from the pancreatic duct as seen on ERP. Therapeutic success was defined by resolution of PD leak on ERP, clinical, and/or imaging evaluation. We evaluated 107 patients (58% male, mean age 53 years) with PD disruption. Etiologies of PD disruption were acute pancreatitis (36%), post-operative (31%), chronic pancreatitis (29%), and trauma (4%). PD disruption was successfully bridged by a stent in 45 (44%) patients. Two patients developed post-sphincterotomy bleeding, two had stent migration, and two patients died as a result of post-ERP related complications. Placement of a PD stent was successful in 103/107 (96%) patients. Therapeutic success was achieved in 80/107 (75%) patients. Non-acute pancreatitis etiologies and absence of complete duct disruption were independent predictors of therapeutic success. Endoscopic therapy using a transpapillary stent for PD disruption is safe and effective. Absence of complete duct disruption and non-AP etiologies determine a favorable endoscopic outcome. Published by Elsevier India Pvt Ltd.

  7. Initial Misdiagnosis of Proximal Pancreatic Adenocarcinoma Is Associated with Delay in Diagnosis and Advanced Stage at Presentation.

    Science.gov (United States)

    Swords, Douglas S; Mone, Mary C; Zhang, Chong; Presson, Angela P; Mulvihill, Sean J; Scaife, Courtney L

    2015-10-01

    Delay in diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with decreased survival. The effect of an initial misdiagnosis on delay in diagnosis and stage of PDAC is unknown. This study is a retrospective review (2000-2010) from a University-based cancer center of new diagnoses of proximal PDAC. Of 313 patients, 98 (31.3 %) had an initial misdiagnosis. Misdiagnosed patients were younger, 62.8 ± 12.6 vs. 68.0 ± 10.1 (p < 0.001). The most common initial misdiagnoses were: gallbladder disease, gastroesophageal reflux disease, and peptic ulcer disease. After excluding patients with prior cholecystectomy, 14.2 % were misdiagnosed with gallbladder disease and underwent cholecystectomy before PDAC diagnosis. Misdiagnosed patients had higher rates of abdominal pain (p < 0.001), weight loss (p = 0.04), and acute pancreatitis (p < 0.001) and lower rate of jaundice (p < 0.001). Median time between symptoms to PDAC diagnosis was longer in misdiagnosed: 4.2 months vs. 1.4 (p < 0.001). Median time from contact with medical provider to axial imaging was longer in misdiagnosed (p < 0.001). Rate of stages III-IV disease at diagnosis was higher in misdiagnosed: 61.2 vs. 43.7 % (p = 0.004), with a 1.4 (95 % confidence interval (CI), 1.12-1.74) higher risk of stages III-IV disease at diagnosis; however, there was no difference in median overall survival in misdiagnosed patients (9.6 months in misdiagnosed vs. 10.3 months in correctly diagnosed, p = 0.69). Initial misdiagnosis of patients with proximal PDAC is associated with delay in diagnosis and higher risk of locally advanced or advanced disease at time of PDAC diagnosis.

  8. Pancreatic adenocarcinoma: combination of MR imaging, MR angiography and MR cholangiopancreatography for the diagnosis and assessment of resectability

    International Nuclear Information System (INIS)

    Catalano, C.; Pavone, P.; Laghi, A.; Panebianco, V.; Scipioni, A.; Fanelli, F.; Brillo, R.; Passariello, R.

    1998-01-01

    The purpose of this study was to determine the possibility of integrating MR cholangiopancreatography (MRCP) and MR angiography (MRA) to conventional MR images in the diagnosis and assessment of resectability of pancreatic adenocarcinoma. Twenty-three patients with pancreatic adenocarcinoma were prospectively examined with MR. Conventional MR images were acquired in all patients. Three-dimensional MRCP and MRA images were acquired in all patients with suspected biliary and vascular involvement. Acquisition time was less than 45 min in all cases. Images were independently evaluated by two radiologists, with final reading decided by consensus among readers. Diagnosis was confirmed with surgery in 16 patients and with percutaneous biopsy in 7. Concordance among readers was high with a kappa value of 0.83. Pancreatic adenocarcinoma was observed in all patients. Correct assessment of unresectability due to vascular involvement was found in 22 of 23 patients. Biliary obstruction was evident in 13 patients, involving the biliary and pancreatic ducts in 9 and the biliary ducts only in 4. Technical advances permit extensive use of MRI in the evaluation of abdominal pathologies. The combination of MR imaging, MRCP, and MRA can provide sufficient information for the diagnosis and assessment of resectability of pancreatic adenocarcinoma, which otherwise would require three different exams. (orig.)

  9. Evaluation of K-ras and p53 expression in pancreatic adenocarcinoma using the cancer genome atlas.

    Directory of Open Access Journals (Sweden)

    Liming Lu

    Full Text Available Genetic alterations in K-ras and p53 are thought to be critical in pancreatic cancer development and progression. However, K-ras and p53 expression in pancreatic adenocarcinoma have not been systematically examined in The Cancer Genome Atlas (TCGA Data Portal. Information regarding K-ras and p53 alterations, mRNA expression data, and protein/protein phosphorylation abundance was retrieved from The Cancer Genome Atlas (TCGA databases, and analyses were performed by the cBioPortal for Cancer Genomics. The mutual exclusivity analysis showed that events in K-ras and p53 were likely to co-occur in pancreatic adenocarcinoma (Log odds ratio = 1.599, P = 0.006. The graphical summary of the mutations showed that there were hotspots for protein activation. In the network analysis, no solid association between K-ras and p53 was observed in pancreatic adenocarcinoma. In the survival analysis, neither K-ras nor p53 were associated with both survival events. As in the data mining study in the TCGA databases, our study provides a new perspective to understand the genetic features of K-ras and p53 in pancreatic adenocarcinoma.

  10. Pancreatic cancer seeding of percutaneous needle tract

    Directory of Open Access Journals (Sweden)

    Qiao Zhou, MD

    2017-03-01

    Full Text Available A 65-year old African-American female presents with biliary ductal dilatation due to an obstructive pancreatic head mass. Percutaneous transhepatic cholangiogram performed and biliary drainage catheter placement for decompression of the biliary system. The patient had a Whipple procedure performed several months later. On follow up CT imaging, there was interval development and enlargement of a subcutaneous lesion by the right oblique muscles. Biopsy of this lesion revealed pancreatic adenocarcinoma from percutaneous seeding of the transhepatic needle tract.

  11. EUS – Fine- Needle Aspiration Biopsy (FNAB in the Diagnosis of Pancreatic Adenocarcinoma: A Review

    Directory of Open Access Journals (Sweden)

    Kalogeraki Alexandra

    2016-03-01

    such as tumors and cysts of the pancreas can be carefully evaluated using EUS and then biopsied with FNAB. There are many new applications of EUS using FNAB. Researchers are looking to deliver chemotherapeutics into small pancreatic cancers and cysts. Nerve blocks using EUS/FNAB to inject numbing medicines into the celiac ganglia, a major nerve cluster, are now routinely performed in patients with pain due to pancreatic cancer. The aim of this study is to perform a review of the literature regarding the usefulness of EUS/FNAB in the diagnosis of pancreatic adenocarcinoma.

  12. Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development.

    Science.gov (United States)

    Nakanuma, Yasuni; Sato, Yasunori

    2014-07-01

    Routine experiences suggest that cholangiocarcinomas (CCAs) show different clinicopathological behaviors along the biliary tree, and hilar CCA apparently resembles pancreatic duct adenocarcinoma (PDAC). Herein, the backgrounds for these similarities were reviewed. While all cases of PDAC, hilar CCA, intrahepatic CCA (ICCA) and CCA components of combined hepatocellular-cholangiocarcinoma (cHC-CCA) were adenocarcinomas, micropapillary patterns and columnar carcinoma cells were common in PDAC and hilar CCA, and trabecular components and cuboidal carcinoma cells were common in ICCA and CCA components of cHC-CCA. Anterior gradient protein-2 and S100P were frequently expressed in perihilar CCA and PDAC, while neural cell adhesion molecule and luminal epithelial membrane antigen were common in CCA components of c-HC-CCA. Pdx1 and Hes1 were frequently and markedly expressed aberrantly in PDAC and perihilar CCA, although their expression was rare and mild in CCA components in cHC-CCA and ICCA. Hilar CCA showed a similar postoperative prognosis to PDAC but differed from ICCA and cHC-CCA. Taken together, hilar CCA may differ from ICCA and CCA components of cHC-CCA but have a similar development to PDAC. These similarities may be explained by the unique anatomical, embryological and reactive nature of the pancreatobiliary tract. Further studies of these intractable malignancies are warranted. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  13. A Rare Multifocal Pattern of Type 2 Autoimmune Pancreatitis with Negative IgG4: A Potential Diagnostic Pitfall That May Mimic Multifocal Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Partha Hota

    2018-02-01

    Full Text Available Autoimmune pancreatitis (AIP is an increasingly recognized form of acute pancreatitis characterized by obstructive jaundice with a rapid and dramatic treatment response to steroid therapy. Recently, AIP has been divided into two distinct phenotypes: lymphoplasmocytic sclerosing pancreatitis AIP (type 1 and idiopathic duct-centric pancreatitis AIP (type 2; each of which have their own distinct demographics, diagnostic criteria, and histopathological features. We report, to the best of our knowledge, the first case of a multifocal pattern of type 2 AIP characterized with both CT and MR imaging. This rare imaging pattern of AIP may mimic the appearance of more worrisome malignant etiologies such as multifocal pancreatic adenocarcinoma or lymphoma, with overlapping imaging characteristics potentially complicating or delaying diagnosis. Therefore, recognition of this atypical pattern of AIP and avoidance of this potential diagnostic pitfall is crucial.

  14. RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Chow, Jimmy Y C; Quach, Khai T; Cabrera, Betty L; Cabral, Jennifer A; Beck, Stayce E; Carethers, John M

    2007-11-01

    Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.

  15. Biomarkers and Targeted Therapy in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Fataneh Karandish

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  16. Biomarkers and Targeted Therapy in Pancreatic Cancer.

    Science.gov (United States)

    Karandish, Fataneh; Mallik, Sanku

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  17. Differential diagnosis of small solid pancreatic lesions

    DEFF Research Database (Denmark)

    Dietrich, Christoph Frank; Sahai, Anand Vasante; D'Onofrio, Mirko

    2016-01-01

    BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at a late stage. Little is known about the incidental finding of early-stage PDAC. The aim of the current study was to determine the etiology of small solid pancreatic lesions (≤15 mm) to optimize clinical......-enhanced US allowed differential diagnosis of PDAC and non-PDAC in 189 of 219 patients (86%). CONCLUSIONS: Approximately 40% of patients with small solid pancreatic lesions had very early stage PDAC. Approximately 60% of small solid pancreatic lesions ≤15 mm are not PDAC and, therefore, do not require radical...

  18. Nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreatic cancer: utility and experience from the clinic

    Directory of Open Access Journals (Sweden)

    Kundranda MN

    2016-01-01

    Full Text Available Madappa N Kundranda, Tomislav Dragovich Division of Hematology and Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Abstract: Pancreatic ductal adenocarcinoma remains one of the deadliest epithelial cancers, primarily due to late diagnosis, early metastasis and the lack of effective treatments. With recent advances in systemic therapies, the median survival for metastatic disease has essentially doubled to approximately 1 year, and a significant number of patients are receiving multiple lines of therapy. One such first-line therapy is the combination of gemcitabine with nab-paclitaxel, which was approved by the US Food and Drug Administration in 2013. This standard option is now serving as a backbone to other novel combinations. In this review, we focus on the development of this combination, its clinical utility, and real-life experiences of managing patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine and nab-paclitaxel. Keywords: pancreatic ductal adenocarcinoma, nab-paclitaxel, MPACT trial, PRODIGE 4/ACCORD 11 trial

  19. Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

    OpenAIRE

    Lee, Jonghyeob; Snyder, Emily R.; Liu, Yinghua; Gu, Xueying; Wang, Jing; Flowers, Brittany M.; Kim, Yoo Jung; Park, Sangbin; Szot, Gregory L.; Hruban, Ralph H.; Longacre, Teri A.; Kim, Seung K.

    2017-01-01

    Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring...

  20. Covered metal stent or multiple plastic stents for refractory pancreatic ductal strictures in chronic pancreatitis: a systematic review.

    Science.gov (United States)

    Shen, Yonghua; Liu, Mingdong; Chen, Min; Li, Yunhong; Lu, Ying; Zou, Xiaoping

    2014-01-01

    Refractory chronic pancreatitis has been proposed as a challenge for endoscopists following routine single plastic stenting. However, data on the efficacy and safety of further endoscopic stenting are still controversial. The current systematic review aimed to assess the efficacy and safety of placement of fully covered self-expandable metal stent (FCSEMS) and multiple plastic stents. Databases including MEDLINE, EMBASE, the Cochrane Library, CBM, CNKI, VIP, and WANFANG Database were used to search relevant trials. Published studies were assessed by using well-defined inclusion and exclusion criteria. The process was independently performed by two investigators. A total of 5 studies provided data of 80 patients. Forest plots and publication bias were not carried out because few studies were relevant and screened studies were all case series. The technical success rate was 100% both in placement of FCSEMS and multiple plastic stents. The functional success rate after placement of FCSEMS was 100%, followed by multiple plastic stents (94.7%). Complications occurred 26.2% after FCSEMS placement, which was not described in detail in multiple plastic stents. The stent migration rate was 8.2% for FCSEMS and 10.5% for multiple plastic stents. Reintervention rate was 9.8% for FCSEMS and 15.8% for multiple plastic stents. Pain improvement rate was 85.2% for FCSEMS and 84.2% for multiple plastic stents. FCSEMS appeared to be no significant difference with multiple plastic stents in treatment of refractory chronic pancreatitis. We need to develop more investigations. Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  1. Concomitant chemo-radiation in therapeutic management of pancreatic and gastric adenocarcinoma

    International Nuclear Information System (INIS)

    Mornex, F.; Chauffert, B.

    1998-01-01

    The prognosis of pancreatic adenocarcinoma remains poor, with a 5-year survival rate lower than 5 %. Resection, the gold standard treatment, can be performed in less than 10 % of patients. Following surgery, the median survival is 12 months for the most favorable cancer patients. Concomitant chemo-radiation, as an adjuvant treatment is superior to surgery alone, in terms of survival; controlled trials are currently performed. Neo-adjuvant chemo-radiation is a new approach, potentially able to increase survival and resection rate. This work justifies the role of these schemes, in terms of modalities and potential advantages. A second part is dedicated to gastric carcinoma, with a review of the current results of chemo-radiation, whose efficiency, even though a trend can be observed, remains to be proven. Prospective adjuvant combined treatments are ongoing, in France and in the States. (authors)

  2. Adjuvant Chemoradiation Therapy After Pancreaticoduodenectomy in Elderly Patients With Pancreatic Adenocarcinoma

    International Nuclear Information System (INIS)

    Horowitz, David P.; Hsu, Charles C.; Wang Jingya; Makary, Martin A.; Winter, Jordan M.; Robinson, Ray; Schulick, Richard D.; Cameron, John L.; Pawlik, Timothy M.; Herman, Joseph M.

    2011-01-01

    Purpose: To evaluate the efficacy of adjuvant chemoradiation therapy (CRT) for pancreatic adenocarcinoma patients ≥75 years of age. Methods: The study group of 655 patients underwent pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma at the Johns Hopkins Hospital over a 12-year period (8/30/1993 to 2/28/2005). Demographic characteristics, comorbidities, intraoperative data, pathology data, and patient outcomes were collected and analyzed by adjuvant treatment status and age ≥75 years. Cox proportional hazards analysis determined clinical predictors of mortality and morbidity. Results: We identified 166 of 655 (25.3%) patients were ≥75 years of age and 489 of 655 patients (74.7%) were <75 years of age. Forty-nine patients in the elderly group (29.5%) received adjuvant CRT. For elderly patients, node-positive metastases (p = 0.008), poor/anaplastic differentiation (p = 0.012), and undergoing a total pancreatectomy (p = 0.010) predicted poor survival. The 2-year survival for elderly patients receiving adjuvant therapy was improved compared with surgery alone (49.0% vs. 31.6%, p = 0.013); however, 5-year survival was similar (11.7% vs. 19.8%, respectively, p = 0.310). After adjusting for major confounders, adjuvant therapy in elderly patients had a protective effect with respect to 2-year survival (relative risk [RR] 0.58, p = 0.044), but not 5-year survival (RR 0.80, p = 0.258). Among the nonelderly, CRT was significantly associated with 2-year survival (RR 0.60, p < 0.001) and 5-year survival (RR 0.69, p < 0.001), after adjusting for confounders. Conclusions: Adjuvant therapy after PD is significantly associated with increased 2-year but not 5-year survival in elderly patients. Additional studies are needed to select which elderly patients are likely to benefit from adjuvant CRT.

  3. Stereotactic body radiotherapy in the treatment of Pancreatic Adenocarcinoma in elderly patients

    International Nuclear Information System (INIS)

    Kim, Carolyn H; Ling, Diane C; Wegner, Rodney E; Flickinger, John C; Heron, Dwight E; Zeh, Herbert; Moser, Arthur J; Burton, Steven A

    2013-01-01

    Treatment of pancreatic adenocarcinoma in the elderly is often complicated by comorbidities that preclude surgery, chemotherapy and/or conventional external beam radiation therapy (EBRT). Stereotactic body radiotherapy (SBRT) has thus garnered interest in this setting. A retrospective review of 26 patients of age ≥ 80 with pancreatic adenocarcinoma treated with definitive SBRT+/-chemotherapy from 2007–2011 was performed. Twenty-seven percent of patients were stage I, 38% were stage II, 27% were stage III and 8% were stage IV. Patients most commonly received 24 Gy/1 fraction or 30-36 Gy/3 fractions. Kaplan-Meier was used to estimate overall survival (OS), local control (LC), cause specific survival (CSS) and freedom-from-metastatic disease (FFMD). The median age was 86 (range 80–91), and median follow-up was 11.6 months (3.5-24.6). The median planning target volume was 21.48 cm 3 (6.1-85.09). Median OS was 7.6 months with 6/12 month OS rates of 65.4%/34.6%, respectively. Median LC was 11.5 months, 6-month and 12-month actuarial LC rates were 60.1% and 41.2%, respectively. There were no independent predictors for LC, but there was a trend for improved LC with prescription dose greater than 20 Gy (p = 0.063). Median CSS was 6.3 months, and 6-month and 12-month actuarial CSS were 53.8% and 23.1%, respectively. Median FFMD was 8.4 months, and 6-month and 12-month actuarial rates were 62.0% and 41.4%, respectively. Nine patients (47%) had local failures, 11 (58%) had distant metastasis, and 7 (37%) had both. There were no acute or late grade 3+ toxicities. Definitive SBRT is feasible, safe and effective in elderly patients who have unresectable disease, have comorbidities precluding surgery or decline surgery

  4. Expression of the antiapoptotic protein BAG3 is a feature of pancreatic adenocarcinoma and its overexpression is associated with poorer survival.

    Science.gov (United States)

    Rosati, Alessandra; Bersani, Samantha; Tavano, Francesca; Dalla Pozza, Elisa; De Marco, Margot; Palmieri, Marta; De Laurenzi, Vincenzo; Franco, Renato; Scognamiglio, Giosuè; Palaia, Raffaele; Fontana, Andrea; di Sebastiano, Pierluigi; Donadelli, Massimo; Dando, Ilaria; Medema, Jan Paul; Dijk, Frederike; Welling, Lieke; di Mola, Fabio Francesco; Pezzilli, Raffaele; Turco, Maria Caterina; Scarpa, Aldo

    2012-11-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A deeper understanding of PDAC biologic characteristics as well as novel prognostic markers are therefore required to improve outcomes. Herein we report that BAG3, a protein with recognized anti-apoptotic activity, was expressed in 346 PDACs analyzed, but was not expressed in the surrounding nonneoplastic tissue. In a cohort of 66 patients who underwent radical resection (R0), survival was significantly shorter in patients with high BAG3 expression (median, 12 months) than in those with low BAG3 expression (median, 23 months) (P = 0.001). Furthermore, we report that BAG3 expression in PDAC-derived cell lines protects from apoptosis and confers resistance to gemcitabine, offering a partial explanation for the survival data. Our results indicate that BAG3 has a relevant role in PDAC biology, and suggest that BAG3 expression level might be a potential marker for prediction of patient outcome. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Controversies in the Management of Borderline Resectable Proximal Pancreatic Adenocarcinoma with Vascular Involvement

    Directory of Open Access Journals (Sweden)

    Olga N. Tucker

    2008-01-01

    Full Text Available Synchronous major vessel resection during pancreaticoduodenectomy (PD for borderline resectable pancreatic adenocarcinoma remains controversial. In the 1970s, regional pancreatectomy advocated by Fortner was associated with unacceptably high morbidity and mortality rates, with no impact on long-term survival. With the establishment of a multidisciplinary approach, improvements in preoperative staging techniques, surgical expertise, and perioperative care reduced mortality rates and improved 5-year-survival rates are now achieved following resection in high-volume centres. Perioperative morbidity and mortality following PD with portal vein resection are comparable to standard PD, with reported 5-year-survival rates of up to 17%. Segmental resection and reconstruction of the common hepatic artery/proper hepatic artery (CHA/PHA can be performed to achieve an R0 resection in selected patients with limited involvement of the CHA/PHA at the origin of the gastroduodenal artery (GDA. PD with concomitant major vessel resection for borderline resectable tumours should be performed when a margin-negative resection is anticipated at high-volume centres with expertise in complex pancreatic surgery. Where an incomplete (R1 or R2 resection is likely neoadjuvant treatment with systemic chemotherapy followed by chemoradiation as part of a clinical trial should be offered to all patients.

  6. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

    Energy Technology Data Exchange (ETDEWEB)

    Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of); Kang, Ho Young [Department of Microbiology, Pusan National University, Busan 609-736 (Korea, Republic of); Kim, Manbok [Department of Medical Science, Dankook University College of Medicine, Cheonan 330-714 (Korea, Republic of); Koh, Sang Seok [Department of Biological Sciences, Dong-A University, Busan 604-714 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of)

    2015-04-03

    Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.

  7. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

    International Nuclear Information System (INIS)

    Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok; Kang, Ho Young; Kim, Manbok; Koh, Sang Seok; Chung, Young-Hwa

    2015-01-01

    Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells

  8. Pancreatic Polypeptide Cell Proliferation in the Pancreas and Duodenum Coexisting in a Patient With Pancreatic Adenocarcinoma Treated With a GLP-1 Analog.

    Science.gov (United States)

    Talmon, Geoffrey A; Wren, J David; Nguyen, Christophe L; Pour, Parviz M

    2017-07-01

    A partial pancreaticogastrodudenectomy was performed on a 66-year old man with type 2 diabetes mellitus because of an invasive, moderately differentiated adenocarcinoma in the head of the pancreas. In the adjacent grossly normal tissue of the uncinate process, there was a massive proliferation of pancreatic polypeptide (PP) cells confined to this region and showed invasive pattern. Strikingly, in the heaped area of his duodenum, there was a strikingly large number of PP, glucagon, a few insulin cells in a mini-islet-like patterns composed of glucagon and insulin cells. Among the etiological factors, the possible long-lasting effects of the GLP-1 analog, with which the patient was treated, are discussed. This is the first report in the literature of both the coexistence of a pancreatic adenocarcinoma and invasive PPoma and the occurrence of PP and insulin cells in human duodenal mucosa.

  9. [Application of second generation dual-source computed tomography dual-energy scan mode in detecting pancreatic adenocarcinoma].

    Science.gov (United States)

    Xue, Hua-dan; Liu, Wei; Sun, Hao; Wang, Xuan; Chen, Yu; Su, Bai-yan; Sun, Zhao-yong; Chen, Fang; Jin, Zheng-yu

    2010-12-01

    To analyze the clinical value of multiple sequences derived from dual-source computed tomography (DSCT) dual-energy scan mode in detecting pancreatic adenocarcinoma. Totally 23 patients with clinically or pathologically diagnosed pancreatic cancer were enrolled in this retrospective study. DSCT (Definition Flash) was used and dual-energy scan mode was used in their pancreatic parenchyma phase scan (100kVp/230mAs and Sn140kVp/178mAs) . Mono-energetic 60kev, mono-energetic 80kev, mono-energetic 100kev, mono-energetic 120kev, linear blend image, non-linear blend image, and iodine map were acquired. pancreatic parenchyma-tumor CT value difference, ratio of tumor to pancreatic parenchyma, and pancreatic parenchyma-tumor contrast to noise ratio were calculated. One-way ANOVA was used for the comparison of diagnostic values of the above eight different dual-energy derived sequences for pancreatic cancer. The pancreatic parenchyma-tumor CT value difference, ratio of tumor to pancreatic parenchyma, and pancreatic parenchyma-tumor contrast to noise ratio were significantly different among eight sequences (P<0.05) . Mono-energetic 60kev image showed the largest parenchyma-tumor CT value [ (77.53 ± 23.42) HU] , and iodine map showed the lowest tumor/parenchyma enhancement ratio (0.39?0.12) and the largest contrast to noise ratio (4.08 ± 1.46) . Multiple sequences can be derived from dual-energy scan mode with DSCT via multiple post-processing methods. Integration of these sequences may further improve the sensitivity of the multislice spiral CT in the diagnosis of pancreatic cancer.

  10. Promoter Hypermethylation and Decreased Expression of Syncytin-1 in Pancreatic Adenocarcinomas.

    Directory of Open Access Journals (Sweden)

    Qinsheng Lu

    Full Text Available Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1. Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.

  11. Clinical experience with chronomodulated infusional 5-fluorouracil chemoradiotherapy for pancreatic adenocarcinoma

    International Nuclear Information System (INIS)

    Keene, Kimberly S.; Rich, Tyvin A.; Penberthy, David R.; Shepard, Robert C.; Adams, Reid; Jones, R. Scott

    2005-01-01

    Purpose: To evaluate retrospectively the efficacy and chronic toxicities of concurrent radiotherapy and chronomodulated infusion 5-fluorouracil (5-FU) in patients with pancreatic adenocarcinoma. Methods and Materials: Twenty-eight patients with pancreatic adenocarcinoma were treated between January 1997 and May 2000 with 5-FU chronomodulated chemoradiotherapy. Chronomodulated delivery of chemotherapy was chosen on the basis of a lower toxicity profile in the treatment of GI malignancies. The median age was 64 years. Of the 28 patients, 12 were men and 16 were women. Eight patients had unresectable disease and 20 were treated after pancreatic resection. The median radiation dose was 50.4 Gy given in 28 fractions. The median field length and width was 10.6 cm and 10.9 cm, respectively. Concurrent chemotherapy with 5-FU was administered 5 d/wk, with a median total dose of 8.4 g/m 2 (300 mg/m 2 /d). Chronomodulated 5-FU delivery consisted of a low basal infusion for 16 h followed by an 8-h escalating-deescalating infusion peaking at 10 PM. Survival and recurrence data were evaluated using Kaplan-Meier actuarial analysis. Toxicities were recorded using the Radiation Therapy Oncology Group grading system. Results: The median follow-up for all patients was 26 months (range, 4-68 months). The median overall survival for the 20 patients treated postoperatively was 34 months, with a 3- and 5-year actuarial survival rate of 40% and 21%, respectively. If the 3 patients with carcinoma of the ampulla were removed from the data set, the mean overall survival in the resected patients was 34 months, with a 3-year and 5-year actuarial survival rate of 40% and 17%, respectively. The 8 unresectable patients had a median overall survival of 14 months, and none lived past 2 years. No patient experienced Grade 3 or 4 hematologic toxicity or weight loss. Five patients had nausea and dehydration requiring i.v. fluids; only one (4%) was hospitalized. Four patients required a dose reduction

  12. Angiolymphatic invasion as a prognostic fator in resected N0 pancreatic adenocarcinoma.

    Science.gov (United States)

    Almeida, Ricardo Vitor Silva de; Pacheco, Adhemar Monteiro; Silva, Rodrigo Altenfelder; Moricz, André de; Campos, Tércio de

    2017-01-01

    Pancreatic adenocarcinoma remains one of the worst digestive cancers. Surgical resection is the main target when treating a patient with curative intent. To assess angiolymphatic invasion as a prognostic factor in resected pN0 pancreatic cancer. Thirty-eight patients were submitted to pancreatoduodenectomy due to head pancreatic cancer. Tumor size, margins, lymph nodes, pTNM staging, angiolymphatic and perineural invasion were described in the pathologists' reports. Most patients were female. Overall median survival was 13 months. Gemcitabine was the regimen of choice for chemotherapy in selected patients; however, it did not improve overall survival. pR0 resection had better survival compared with pR1. Within the pN0 group, survival was significantly better in patients without angiolymphatic invasion. Angiolymphatic invasion in N0 pancreatoduodenectomy can be demonstrated by the Hematoxylin-Eosin stain and may predict a poor prognosis factor for those patients. Adenocarcinoma pancreático continua sendo um dos piores cânceres do aparelho digestivo. A ressecção cirúrgica é o principal objetivo quando se trata de intenção curativa. Avaliar a invasão angiolinfática como um fator prognóstico no câncer da cabeça do pâncreas ressecado pN0. Trinta e oito pacientes foram submetidos a duodenopancreatectomia por câncer da cabeça do pâncreas. Tamanho do tumor, margens, linfonodos, estadiamento pTNM, invasão angiolinfática e perineural foram descritos nos laudos anatomopatológicos. A maioria foi de mulheres. A sobrevida mediana global foi de 13 meses. Gencitabina foi a droga de escolha para quimioterapia nos pacientes selecionados, entretanto não aumentou a sobrevida global. Pacientes com ressecção pR0 tiveram sobrevida global superior quando comparados com ressecção pR1. Dentro do grupo de pacientes com pN0, a sobrevida foi significativamente melhor no grupo de pacientes que não apresentavam invasão angiolinfática. A invasão angiolinfática da

  13. Imaging modalities in the diagnosis of pancreatic adenocarcinoma: A systematic review and meta-analysis of sensitivity, specificity and diagnostic accuracy.

    Science.gov (United States)

    Toft, James; Hadden, William J; Laurence, Jerome M; Lam, Vincent; Yuen, Lawrence; Janssen, Anna; Pleass, Henry

    2017-07-01

    Pancreatic cancer, primarily pancreatic ductal adenocarcinoma (PDAC), accounts for 2.4% of cancer diagnoses and 5.8% of cancer death annually. Early diagnoses can improve 5-year survival in PDAC. The aim of this systematic review was to determine the sensitivity, specificity and diagnostic accuracy values for MRI, CT, PET&PET/CT, EUS and transabdominal ultrasound (TAUS) in the diagnosis of PDAC. A systematic review was undertaken to identify studies reporting sensitivity, specificity and/or diagnostic accuracy for the diagnosis of PDAC with MRI, CT, PET, EUS or TAUS. Proportional meta-analysis was performed for each modality. A total of 5399 patients, 3567 with PDAC, from 52 studies were included. The sensitivity, specificity and diagnostic accuracy were 93% (95% CI=88-96), 89% (95% CI=82-94) and 90% (95% CI=86-94) for MRI; 90% (95% CI=87-93), 87% (95% CI=79-93) and 89% (95% CI=85-93) for CT; 89% (95% CI=85-93), 70% (95% CI=54-84) and 84% (95% CI=79-89) for PET; 91% (95% CI=87-94), 86% (95% CI=81-91) and 89% (95% CI=87-92) for EUS; and 88% (95% CI=86-90), 94% (95% CI=87-98) and 91% (95% C=87-93) for TAUS. This review concludes all modalities, except for PET, are equivalent within 95% confidence intervals for the diagnosis of PDAC. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Proteomics portrait of archival lesions of chronic pancreatitis.

    Directory of Open Access Journals (Sweden)

    Sheng Pan

    Full Text Available Chronic pancreatitis is a chronic inflammatory disorder of the pancreas. The etiology is multi-fold, but all lead to progressive scarring and loss of pancreatic function. Early diagnosis is difficult; and the understanding of the molecular events that underlie this progressive disease is limited. In this study, we investigated differential proteins associated with mild and severe chronic pancreatitis in comparison with normal pancreas and pancreatic cancer. Paraffin-embedded formalin-fixed tissues from five well-characterized specimens each of normal pancreas (NL, mild chronic pancreatitis (MCP, severe chronic pancreatitis (SCP and pancreatic ductal adenocarcinoma (PDAC were subjected to proteomic analysis using a "label-free" comparative approach. Our results show that the numbers of differential proteins increase substantially with the disease severity, from mild to severe chronic pancreatitis, while the number of dysregulated proteins is highest in pancreatic adenocarcinoma. Important functional groups and biological processes associated with chronic pancreatitis and cancer include acinar cell secretory proteins, pancreatic fibrosis/stellate cell activation, glycoproteins, and inflammatory proteins. Three differential proteins were selected for verification by immunohistochemistry, including collagen 14A1, lumican and versican. Further canonical pathway analysis revealed that acute phase response signal, prothrombin activation pathway, and pancreatic fibrosis/pancreatic stellate cell activation pathway were the most significant pathways involved in chronic pancreatitis, while pathways relating to metabolism were the most significant pathways in pancreatic adenocarcinoma. Our study reveals a group of differentially expressed proteins and the related pathways that may shed light on the pathogenesis of chronic pancreatitis and the common molecular events associated with chronic pancreatitis and pancreatic adenocarcinoma.

  15. Pancreatic neuroendocrine tumour (PNET): Staging accuracy of MDCT and its diagnostic performance for the differentiation of PNET with uncommon CT findings from pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Hoon; Lee, Jeong Min; Han, Joon Koo; Choi, Byung-Ihn [Seoul National University Hospital, Department of Radiology, 101 Daehangno, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Institute of Radiation Medicine, Seoul (Korea, Republic of); Eun, Hyo Won [Yonsei University College of Medicine, Department of Radiology, Severance Hospital, Seodaemun-ku, Seoul (Korea, Republic of); Kim, Young Jae [Soonchunhyang University Hospital, Department of Radiology, 657 Hannam-Dong, Youngsan-Ku, Seoul (Korea, Republic of)

    2016-05-15

    To investigate staging accuracy of multidetector CT (MDCT) for pancreatic neuroendocrine tumour (PNET) and diagnostic performance for differentiation of PNET from pancreatic adenocarcinoma. We included 109 patients with surgically proven PNET (NETG1 = 66, NETG2 = 31, NEC = 12) who underwent MDCT. Two reviewers assessed stage and presence of predefined CT findings. We analysed the relationship between CT findings and tumour grade. Using PNETs with uncommon findings, we also estimated the possibility of PNET or adenocarcinoma. Accuracy for T stage was 85-88 % and N-metastasis was 83-89 %. Common findings included well circumscribed, homogeneously enhanced, hypervascular mass, common in lower grade tumours (p < 0.05). Uncommon findings included ill-defined, heterogeneously enhanced, hypovascular mass and duct dilation, common in higher grade tumours (p < 0.05). Using 31 PNETs with uncommon findings, diagnostic performance for differentiation from adenocarcinoma was 0.760-0.806. Duct dilatation was an independent predictor for adenocarcinoma (Exp(B) = 4.569). PNETs with uncommon findings were associated with significantly worse survival versus PNET with common findings (62.7 vs. 95.7 months, p < 0.001). MDCT is useful for preoperative evaluation of PNET; it not only accurately depicts the tumour stage but also prediction of tumour grade, because uncommon findings were more common in higher grade tumours. (orig.)

  16. Diffusion-weighted MR imaging of the pancreas: optimizing b-value for visualization of pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fukukura, Yoshihiko; Shindo, Toshikazu; Hakamada, Hiroto; Takumi, Koji; Umanodan, Tomokazu; Nakajo, Masanori; Kamimura, Kiyoshisa; Umanodan, Aya; Ideue, Junnichi; Yoshiura, Takashi [Kagoshima University Graduate School of Medical and Dental Sciences, Department of Radiology, Kagoshima City (Japan)

    2016-10-15

    To determine the optimal b-value of 3.0-T diffusion-weighted imaging (DWI) for visualizing pancreatic adenocarcinomas Fifty-five patients with histologically confirmed pancreatic adenocarcinoma underwent DWI with different b-values (b = 500, 1000, 1500, and 2000 s/mm{sup 2}) at 3.0 T. For each b-value, we retrospectively evaluated DWI findings of pancreatic adenocarcinomas (clear hyperintensity relative to the surrounding pancreas, hyperintensity with an unclear distal border, and isointensity) and image quality, and measured tumour-to-pancreas signal intensity (SI) ratios. DWI findings, image quality, and tumour-to-pancreas SI ratios were compared between the four b-values. There was a significantly higher incidence of tumours showing clear hyperintensity on DWI with b-value of 1500 s/mm{sup 2} than on that with b-value of 1000 s/mm{sup 2} (P < 0.001), and on DWI with b-value of 1000 s/mm{sup 2} than on that with b-value of 500 s/mm{sup 2} (P < 0.001). The tumour-to-distal pancreas SI ratio was higher with b-value of 1500 s/mm{sup 2} than with b-value of 1000 s/mm{sup 2} (P < 0.001), and with b-value of 1000 s/mm{sup 2} than with b-value of 500 s/mm{sup 2} (P < 0.001). A lower image quality was obtained at increasing b-values (P < 0.001); the lowest scores were observed with b-value of 2000 s/mm{sup 2}. The use of b = 1500 s/mm{sup 2} for 3.0-T DWI can improve the delineation of pancreatic adenocarcinomas. (orig.)

  17. Diffusion-weighted MR imaging of the pancreas: optimizing b-value for visualization of pancreatic adenocarcinoma

    International Nuclear Information System (INIS)

    Fukukura, Yoshihiko; Shindo, Toshikazu; Hakamada, Hiroto; Takumi, Koji; Umanodan, Tomokazu; Nakajo, Masanori; Kamimura, Kiyoshisa; Umanodan, Aya; Ideue, Junnichi; Yoshiura, Takashi

    2016-01-01

    To determine the optimal b-value of 3.0-T diffusion-weighted imaging (DWI) for visualizing pancreatic adenocarcinomas Fifty-five patients with histologically confirmed pancreatic adenocarcinoma underwent DWI with different b-values (b = 500, 1000, 1500, and 2000 s/mm"2) at 3.0 T. For each b-value, we retrospectively evaluated DWI findings of pancreatic adenocarcinomas (clear hyperintensity relative to the surrounding pancreas, hyperintensity with an unclear distal border, and isointensity) and image quality, and measured tumour-to-pancreas signal intensity (SI) ratios. DWI findings, image quality, and tumour-to-pancreas SI ratios were compared between the four b-values. There was a significantly higher incidence of tumours showing clear hyperintensity on DWI with b-value of 1500 s/mm"2 than on that with b-value of 1000 s/mm"2 (P < 0.001), and on DWI with b-value of 1000 s/mm"2 than on that with b-value of 500 s/mm"2 (P < 0.001). The tumour-to-distal pancreas SI ratio was higher with b-value of 1500 s/mm"2 than with b-value of 1000 s/mm"2 (P < 0.001), and with b-value of 1000 s/mm"2 than with b-value of 500 s/mm"2 (P < 0.001). A lower image quality was obtained at increasing b-values (P < 0.001); the lowest scores were observed with b-value of 2000 s/mm"2. The use of b = 1500 s/mm"2 for 3.0-T DWI can improve the delineation of pancreatic adenocarcinomas. (orig.)

  18. Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

    Science.gov (United States)

    Papageorgiou, A; Lialiaris, Th; Stergiou, E; Stergiou, I; Tsigris, C; Kourti, A; Geromichalos, G; Stravoravdi, P; Trafalis, D; Athanassiou, A E; Pitsas, A; Camoutsis, Ch

    2008-01-01

    In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

  19. Concurrent Radiotherapy and Gemcitabine for Unresectable Pancreatic Adenocarcinoma: Impact of Adjuvant Chemotherapy on Survival

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Kazuhiko, E-mail: kogawa@med.u-ryukyu.ac.jp [Department of Radiology, University of the Ryukyus, Okinawa (Japan); Ito, Yoshinori [Department of Radiation Oncology, National Cancer Center, Tokyo (Japan); Hirokawa, Naoki [Department of Radiology, Sapporo Medical University, Sapporo (Japan); Shibuya, Keiko [Department of Radiation Oncology and Image-Applied Therapy, Kyoto University, Kyoto (Japan); Kokubo, Masaki [Department of Radiation Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe (Japan); Ogo, Etsuyo [Department of Radiation Oncology, Kurume University, Kurume (Japan); Shibuya, Hitoshi [Department of Radiology, Tokyo Medical and Dental University, Tokyo (Japan); Saito, Tsutomu [Department of Radiation Oncology, Nihon University Itabashi Hospital, Tokyo (Japan); Onishi, Hiroshi [Department of Radiology, Yamanashi University, Yamanashi (Japan); Karasawa, Katsuyuki [Department of Radiation Oncology, Tokyo Metropolitan Komagome Hospital, Tokyo (Japan); Nemoto, Kenji [Department of Radiation Oncology, Yamagata University, Yamagata (Japan); Nishimura, Yasumasa [Department of Radiation Oncology, Kinki University School of Medicine, Osaka (Japan)

    2012-06-01

    Purpose: To retrospectively analyze results of concurrent chemoradiotherapy (CCRT) using gemcitabine (GEM) for unresectable pancreatic adenocarcinoma. Methods and Materials: Records of 108 patients treated with concurrent external beam radiotherapy (EBRT) and GEM were reviewed. The median dose of EBRT in all 108 patients was 50.4 Gy (range, 3.6-60.8 Gy), usually administered in conventional fractionations (1.8-2 Gy/day). During radiotherapy, most patients received GEM at a dosage of 250 to 350 mg/m{sup 2} intravenously weekly for approximately 6 weeks. After CCRT, 59 patients (54.6%) were treated with adjuvant chemotherapy (AC), mainly with GEM. The median follow-up for all 108 patients was 11.0 months (range, 0.4-37.9 months). Results: Initial responses after CCRT for 85 patients were partial response: 26 patients, no change: 51 patients and progressive disease: 8 patients. Local progression was observed in 35 patients (32.4%), and the 2-year local control (LC) rate in all patients was 41.9%. Patients treated with total doses of 50 Gy or more had significantly more favorable LC rates (2-year LC rate, 42.9%) than patients treated with total doses of less than 50 Gy (2-year LC rate, 29.6%). Regional lymph node recurrence was found in only 1 patient, and none of the 57 patients with clinical N0 disease had regional lymph node recurrence. The 2-year overall survival (OS) rate and the median survival time in all patients were 23.5% and 11.6 months, respectively. Patients treated with AC had significantly more favorable OS rates (2-year OS, 31.8%) than those treated without AC (2-year OS, 12.4%; p < 0.0001). On multivariate analysis, AC use and clinical T stage were significant prognostic factors for OS. Conclusions: CCRT using GEM yields a relatively favorable LC rate for unresectable pancreatic adenocarcinoma, and CCRT with AC conferred a survival benefit compared to CCRT without AC.

  20. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary

    Directory of Open Access Journals (Sweden)

    Nicolas Chuvin

    2017-09-01

    Full Text Available Background & Aims: Transforming growth factor beta (TGFβ acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA in the pancreatic acinar compartment. Results: We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. Keywords: Pancreas, Cancer, TGFβ, Acinar-to-Ductal Metaplasia, KRASG12D

  1. Locally advanced pancreatic duct adenocarcinoma: pancreatectomy with planned arterial resection based on axial arterial encasement.

    Science.gov (United States)

    Perinel, J; Nappo, G; El Bechwaty, M; Walter, T; Hervieu, V; Valette, P J; Feugier, P; Adham, M

    2016-12-01

    Pancreatectomy with arterial resection for locally advanced pancreatic duct adenocarcinoma (PDA) is associated with high morbidity and is thus considered as a contraindication. The aim of our study was to report our experience of pancreatectomy with planned arterial resection for locally advanced PDA based on specific selection criteria. All patients receiving pancreatectomy for PDA between October 2008 and July 2014 were reviewed. The patients were classified into group 1, pancreatectomy without vascular resection (66 patients); group 2, pancreatectomy with isolated venous resection (31 patients), and group 3, pancreatectomy with arterial resection for locally advanced PDA (14 patients). The primary selection criteria for arterial resection was the possibility of achieving a complete resection based on the extent of axial encasement, the absence of tumor invasion at the origin of celiac trunk (CT) and superior mesenteric artery (SMA), and a free distal arterial segment allowing reconstruction. Patient outcomes and survival were analyzed. Six SMA, two CT, four common hepatic artery, and two replaced right hepatic artery resections were undertaken. The preferred arterial reconstruction was splenic artery transposition. Group 3 had a higher preoperative weight loss, a longer operative time, and a higher incidence of intraoperative blood transfusion. Ninety-day mortality occurred in three patients in groups 1 and 2. There were no statistically significant differences in the incidence, grade, and type of complications in the three groups. Postoperative pancreatic fistula and postpancreatectomy hemorrhage were also comparable. In group 3, none had arterial wall invasion and nine patients had recurrence (seven metastatic and two loco-regional). Survival and disease-free survival were comparable between groups. Planned arterial resection for PDA can be performed safely with a good outcome in highly selected patients. Key elements for defining the resectability is based on

  2. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    Science.gov (United States)

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  3. Efficacy of irreversible electroporation in human pancreatic adenocarcinoma: advanced murine model

    Directory of Open Access Journals (Sweden)

    Prejesh Philips

    Full Text Available Irreversible electroporation (IRE is a promising cell membrane ablative modality for pancreatic cancer. There have been recent concerns regarding local recurrence and the potential use of IRE as a debulking (partial ablation modality. We hypothesize that incomplete ablation leads to early recurrence and a more aggressive biology. We created the first ever heterotopic murine model by inoculating BALB/c nude mice in the hindlimb with a subcutaneous injection of Panc-1 cells, an immortalized human pancreatic adenocarcinoma cell line. Tumors were allowed to grow from 0.75 to 1.5 cm and then treated with the goal of complete ablation or partial ablation using standard IRE settings. Animals were recovered and survived for 2 days (n = 6, 7 (n = 6, 14 (n = 6, 21 (n = 6, 30 (n = 8, and 60 (n = 8 days. All 40 animals/tumors underwent successful IRE under general anesthesia with muscle paralysis. The mean tumor volume of the animals undergoing ablation was 1,447.6 mm3 ± 884. Histologically, in the 14-, 21-, 30-, and 60-day survival groups the entire tumor was nonviable, with a persistent tumor nodule completely replaced fibrosis. In the group treated with partial ablation, incomplete electroporation/recurrences (N = 10 animals were seen, of which 66% had confluent tumors and this was a significant predictor of recurrence (P < 0.001. Recurrent tumors were also significantly larger (mean 4,578 mm3 ± SD 877 versus completed electroporated tumors 925.8 ± 277, P < 0.001. Recurrent tumors had a steeper growth curve (slope = 0.73 compared with primary tumors (0.60, P = 0.02. Recurrent tumors also had a significantly higher percentage of EpCAM expression, suggestive of stem cell activation. Tumors that recur after incomplete electroporation demonstrate a biologically aggressive tumor that could be more resistant to standard of care chemotherapy. Clinical correlation of this data is limited, but should be considered when IRE of pancreatic cancer is being

  4. Nickel nanowires induced and reactive oxygen species mediated apoptosis in human pancreatic adenocarcinoma cells

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    Kleve MG

    2011-07-01

    Full Text Available Md. Zakir Hossain1, Maurice G Kleve21Applied Biosciences (Bionanotechnology Research, Department of Applied Science, 2Molecular Biotechnology and Microscopy Laboratory, Department of Biology, University of Arkansas at Little Rock, Little Rock, Arkansas, USABackground: The ability to evade apoptosis is one of the key properties of cancer. The apoptogenic effect of nickel nanowires (Ni NWs on cancer cell lines has never been adequately addressed. Due to the unique physicochemical characteristics of Ni NWs, we envision the development of a novel anticancer therapeutics specifically for pancreatic cancer. Thus, we investigated whether Ni NWs induce ROS-mediated apoptosis in human pancreatic adenocarcinoma (Panc-1 cells. Methods: In this study Ni NWs were fabricated using the electrodeposition method. Synthesized Ni NWs were physically characterized by energy dispersive X-ray analysis, UV-Vis spectroscopy of NanoDrop 2000 (UV-Vis, magnetization study, scanning electron microscopy, and transmission electron microscopy. Assessment of morphological apoptotic characteristics by phase contrast microscopy (PCM, Ni-NWs-induced apoptosis staining with ethidium bromide (EB and acridine orange (AO followed by fluorescence microscopy (FM was performed. For molecular biological and biochemical characterization, Panc-1 cell culture and cytotoxic effect of Ni NWs were determined by using 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT assay. Quantitative apoptosis was analyzed by flow cytometry staining with propidium iodide through cell cycle arrest and generation of ROS using 2', 7'-dichlorofluorescein diacetate fluorescence intensity. In all experiments, Panc-1 cancer cells without any treatment were used as the negative controls.Results: The intracellular uptake of Ni NWs through endocytosis by Panc-1 cells was observed by PCM. EB and AO staining of FM and MTT assay qualitatively and quantitatively confirmed the extent of apoptosis. Flow

  5. Does adjuvant therapy improve overall survival for stage IA/B pancreatic adenocarcinoma?

    Science.gov (United States)

    Ostapoff, Katherine T; Gabriel, Emmanuel; Attwood, Kristopher; Kuvshinoff, Boris W; Nurkin, Steven J; Hochwald, Steven N

    2017-07-01

    Current guidelines recommend adjuvant chemotherapy for resected pancreatic adenocarcinoma (PDAC). However, no studies have addressed its survival benefit for stage I patients as they comprise IA or IB PDAC were identified. Median OS was 60.3 months (mo) for stage IA and 36.9 mo for IB. 45.5% received adjuvant chemotherapy; 19.9% received adjuvant chemoradiation. There was OS benefit for both stage IA/IB patients with adjuvant chemotherapy (HR = 0.73 and 0.76 for IA and IB, respectively, p = 0.002 and IA disease (n = 1,477, 37.8%), age ≥70 (p < 0.001), higher grade (p < 0.001), ≤10 lymph nodes examined (p = 0.008), positive margins (p < 0.001), and receipt of adjuvant chemoradiation (p = 0.002) were associated with worse OS. For stage IB patients (n = 2,432, 62.2%), similar associations were observed with the exception of adjuvant chemoradiation whereby there was no significant association (p = 0.35). Adjuvant chemotherapy was associated with an OS benefit for patients with stage I PDAC; adjuvant chemoradiation was either of no benefit or associated with worse OS. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

  6. Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use

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    Elena Ferris Villanueva

    2015-02-01

    Full Text Available Objective: To evaluate the results obtained with the combined use of nab-paclitaxel and gemcitabine in the treatment of patients with metastatic pancreatic adenocarcinoma. Materials and methods: Retrospective observational study. Patients treated with nab-paclitaxel and gemcitabine between January of 2013 and January of 2014 were selected. Demographical and clinical data were gathered. Results: 15 patients (mean age 59,4 ± 10,3 years were included. All patients received the combination of nab-paclitaxel and gemcitabine in first-line metastatic disease. Nine received adjuvant treatment before the disease was metastatic. The median progression-free survival rate with combined nab-paclitaxel and gemcitabine was 5,6 months (95% CI: 4,44 - 8,03. In two patients the treatment was stopped due to toxicity. Conclusions: The treatment with nab-paclitaxel and gemcitabine in our patients resulted in progression-free survival rates similar to those published in clinical trials with good treatment tolerability

  7. Verteporfin heterogeneity in pancreatic adenocarcinoma and the relationship to tumor vasculature and collagen distribution

    Science.gov (United States)

    Vincent, Phuong; Xie, Rui; Nieskoski, Michael; Marra, Kayla; Gunn, Jason; Pogue, Brian W.

    2018-02-01

    Photodynamic therapy (PDT) has emerged as one promising treatment regimen for several cancer types, with a clinical trial ongoing in pancreatic adenocarcinoma (PDAC). PDT treatment efficacy mainly depends on the combination of light delivery, oxygen availability and photosensitizer uptake, each of which can be limited in pancreas cancer. Therefore, increasing drug uptake in the tumor would make an important impact on treatment outcome. This study was conducted to focus on the issue with drug resistance by examining the relationship between photosensitizer verteporfin and tissue parameters such as collagen and vascular patency. Verteporfin uptake in the tumors was assessed by fluorescence imaging while collagen content and patent vessel area fraction were quantified by evaluating Masson's Trichrome and Lectin pathology staining images. Two tumor cell lines - AsPC-1 and BxPC-3 - were modeled in nude mice to investigate the impact of different tumor microenvironments. Experimental results highlighted the correlation between vascular patency and verteporfin uptake. Collagen content was found to be an independent factor within each tumor line, but a comparison across two tumor types suggested that collagen area of greater than 10% of tumor cross section reflected a lower verteporfin uptake. It was observed that whole-slice tumor quantifications have showcased some interesting trends which could be greatly enhanced and further supported by regional analysis.

  8. Diagnosing pancreatic cancer: the role of percutaneous biopsy and CT

    International Nuclear Information System (INIS)

    Amin, Z.; Theis, B.; Russell, R.C.G.; House, C.; Novelli, M.; Lees, W.R.

    2006-01-01

    Aims: To determine the sensitivity and complications of percutaneous biopsy of pancreatic masses, and whether typical computed tomography (CT) features of adenocarcinoma can reliably predict this diagnosis. Materials and methods: A 5 year retrospective analysis of percutaneous core biopsies of pancreatic masses and their CT features was undertaken. Data were retrieved from surgical/pathology databases; medical records and CT reports and images. Results: Three hundred and three patients underwent 372 biopsies; 56 of 87 patients had repeat biopsies. Malignancy was diagnosed in 276 patients, with ductal adenocarcinoma in 259 (85%). Final sensitivity of percutaneous biopsy for diagnosing pancreatic neoplasms was 90%; for repeat biopsy it was 87%. Complications occurred in 17 (4.6%) patients, in three of whom the complications were major (1%): one abscess, one duodenal perforation, one large retroperitoneal bleed. CT features typical of ductal adenocarcinoma were: hypovascular pancreatic mass with bile and/or pancreatic duct dilatation. Atypical CT features were: isodense or hypervascular mass, calcification, non-dilated ducts, cystic change, and extensive lymphadenopathy. Defining typical CT features of adenocarcinoma as true-positives, CT had a sensitivity of 68%, specificity of 95%, positive predictive value (PPV) of 98%, and negative predictive value of 41% for diagnosing pancreatic adenocarcinoma. Conclusion: Final sensitivity of percutaneous biopsy for establishing the diagnosis was 90%. CT features typical of pancreatic adenocarcinoma had high specificity and PPV. On some occasions, especially in frail patients with co-morbidity, it might be reasonable to assume a diagnosis of pancreatic cancer if CT features are typical, and biopsy only if CT shows atypical features

  9. Diagnosing pancreatic cancer: the role of percutaneous biopsy and CT

    Energy Technology Data Exchange (ETDEWEB)

    Amin, Z.; Theis, B.; Russell, R.C.G.; House, C.; Novelli, M.; Lees, W.R

    2006-12-15

    Aims: To determine the sensitivity and complications of percutaneous biopsy of pancreatic masses, and whether typical computed tomography (CT) features of adenocarcinoma can reliably predict this diagnosis. Materials and methods: A 5 year retrospective analysis of percutaneous core biopsies of pancreatic masses and their CT features was undertaken. Data were retrieved from surgical/pathology databases; medical records and CT reports and images. Results: Three hundred and three patients underwent 372 biopsies; 56 of 87 patients had repeat biopsies. Malignancy was diagnosed in 276 patients, with ductal adenocarcinoma in 259 (85%). Final sensitivity of percutaneous biopsy for diagnosing pancreatic neoplasms was 90%; for repeat biopsy it was 87%. Complications occurred in 17 (4.6%) patients, in three of whom the complications were major (1%): one abscess, one duodenal perforation, one large retroperitoneal bleed. CT features typical of ductal adenocarcinoma were: hypovascular pancreatic mass with bile and/or pancreatic duct dilatation. Atypical CT features were: isodense or hypervascular mass, calcification, non-dilated ducts, cystic change, and extensive lymphadenopathy. Defining typical CT features of adenocarcinoma as true-positives, CT had a sensitivity of 68%, specificity of 95%, positive predictive value (PPV) of 98%, and negative predictive value of 41% for diagnosing pancreatic adenocarcinoma. Conclusion: Final sensitivity of percutaneous biopsy for establishing the diagnosis was 90%. CT features typical of pancreatic adenocarcinoma had high specificity and PPV. On some occasions, especially in frail patients with co-morbidity, it might be reasonable to assume a diagnosis of pancreatic cancer if CT features are typical, and biopsy only if CT shows atypical features.

  10. MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors.

    Science.gov (United States)

    Gradiz, Rui; Silva, Henriqueta C; Carvalho, Lina; Botelho, Maria Filomena; Mota-Pinto, Anabela

    2016-02-17

    Studies using cell lines should always characterize these cells to ensure that the results are not distorted by unexpected morphological or genetic changes possibly due to culture time or passage number. Thus, the aim of this study was to describe those MIA PaCa-2 and PANC-1 cell line phenotype and genotype characteristics that may play a crucial role in pancreatic cancer therapeutic assays, namely neuroendocrine chemotherapy and peptide receptor radionuclide therapy. Epithelial, mesenchymal, endocrine and stem cell marker characterization was performed by immunohistochemistry and flow cytometry, and genotyping by PCR, gene sequencing and capillary electrophoresis. MIA PaCa-2 (polymorphism) expresses CK5.6, AE1/AE3, E-cadherin, vimentin, chromogranin A, synaptophysin, SSTR2 and NTR1 but not CD56. PANC-1 (pleomorphism) expresses CK5.6, MNF-116, vimentin, chromogranin A, CD56 and SSTR2 but not E-cadherin, synaptophysin or NTR1. MIA PaCA-1 is CD24(-), CD44(+/++), CD326(-/+) and CD133/1(-), while PANC-1 is CD24(-/+), CD44(+), CD326(-/+) and CD133/1(-). Both cell lines have KRAS and TP53 mutations and homozygous deletions including the first 3 exons of CDKN2A/p16(INK4A), but no SMAD4/DPC4 mutations or microsatellite instability. Both have neuroendocrine differentiation and SSTR2 receptors, precisely the features making them suitable for the therapies we propose to assay in future studies.

  11. Mutational spectrum of intraepithelial neoplasia in pancreatic heterotopia.

    Science.gov (United States)

    Ma, Changqing; Gocke, Christopher D; Hruban, Ralph H; Belchis, Deborah A

    2016-02-01

    Heterotopic pancreatic parenchyma recapitulates the normal pancreas in extrapancreatic locations and, on rare occasions, can even give rise to pancreatic adenocarcinoma. The genetic signatures of pancreatic adenocarcinoma and its precursor lesions are well characterized. We explored the genetic alterations in precursor lesions (intraductal papillary mucinous neoplasms [IPMN], pancreatic intraepithelial neoplasia [PanIN]) in patients with pancreatic heterotopias but without concomitant pancreatic ductal adenocarcinomas. This allowed us to determine whether the stereotypical dysplasia--infiltrating carcinoma sequence also occurs in these extrapancreatic foci. Seven cases of heterotopic pancreas with ductal precursor lesions were identified. These included 2 IPMNs with focal high-grade dysplasia and 5 PanINs with low- to moderate-grade dysplasia (PanIN grades 1-2). Neoplastic epithelium was microdissected and genomic DNA was extracted. Sequencing of commonly mutated hotspots (KRAS, TP53, CDKN2A, SMAD4, BRAF, and GNAS) in pancreatic ductal adenocarcinoma and its precursor lesions was performed. Both IPMNs were found to have KRAS codon 12 mutations. The identification of KRAS mutations suggests a genetic pathway shared with IPMN of the pancreas. No mutations were identified in our heterotopic PanINs. One of the possible mechanisms for the development of dysplasia in these lesions is field effect. At the time of these resections, there was no clinical or pathologic evidence of a prior or concomitant pancreatic lesion. However, a clinically undetectable lesion is theoretically possible. Therefore, although a field effect cannot be excluded, there was no evidence for it in this study. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

    Science.gov (United States)

    Céspedes, María Virtudes; Guillén, María José; López-Casas, Pedro Pablo; Sarno, Francesca; Gallardo, Alberto; Álamo, Patricia; Cuevas, Carmen; Hidalgo, Manuel; Galmarini, Carlos María; Allavena, Paola; Avilés, Pablo; Mangues, Ramón

    2016-01-01

    ABSTRACT We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies. PMID:27780828

  13. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models

    Directory of Open Access Journals (Sweden)

    María Virtudes Céspedes

    2016-12-01

    Full Text Available We explored whether the combination of lurbinectedin (PM01183 with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii specific depletion of tumor-associated macrophages (TAMs. We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR. Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI=0.66] and SW-1990 (CI=0.80 tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX, cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop ‘molecularly targeted’ combination strategies.

  14. Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump

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    Zeng XL

    2016-06-01

    Full Text Available Xian-Liang Zeng,* Huan-Huan Wang,* Mao-Bin Meng, Zhi-Qiang Wu, Yong-Chun Song, Hong-Qing Zhuang, Dong Qian, Feng-Tong Li, Lu-Jun Zhao, Zhi-Yong Yuan, Ping Wang Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China *These authors contributed equally to this work Background and aim: The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Patients and methods: Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results: Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6% within a median of 8 days (range, 1–14 days after SBRT. Nine patients (37.5% experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. Conclusion: SBRT is a safe and

  15. Eriocalyxin B induces apoptosis and cell cycle arrest in pancreatic adenocarcinoma cells through caspase- and p53-dependent pathways

    International Nuclear Information System (INIS)

    Li, Lin; Yue, Grace G.L.; Lau, Clara B.S.; Sun, Handong; Fung, Kwok Pui; Leung, Ping Chung; Han, Quanbin; Leung, Po Sing

    2012-01-01

    Pancreatic cancer is difficult to detect early and responds poorly to chemotherapy. A breakthrough in the development of new therapeutic agents is urgently needed. Eriocalyxin B (EriB), isolated from the Isodon eriocalyx plant, is an ent-kaurane diterpenoid with promise as a broad-spectrum anti-cancer agent. The anti-leukemic activity of EriB, including the underlying mechanisms involved, has been particularly well documented. In this study, we demonstrated for the first time EriB's potent cytotoxicity against four pancreatic adenocarcinoma cell lines, namely PANC-1, SW1990, CAPAN-1, and CAPAN-2. The effects were comparable to that of the chemotherapeutic camptothecin (CAM), but with much lower toxicity against normal human liver WRL68 cells. EriB's cytoxicity against CAPAN-2 cells was found to involve caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Moreover, the p53 pathway was found to be activated by EriB in these cells. Furthermore, in vivo studies showed that EriB inhibited the growth of human pancreatic tumor xenografts in BALB/c nude mice without significant secondary adverse effects. These results suggest that EriB should be considered a candidate for pancreatic cancer treatment. -- Highlights: ► We study Eriocalyxin B (EriB)'s cytotoxic effects on pancreatic cancer cell lines. ► EriB inhibits cell proliferation via mediation of apoptosis and cell cycle arrest. ► The effects are involved in caspase-dependent apoptosis and p53 pathway. ► In vivo study also shows EriB inhibits the growth of human pancreatic tumor. ► EriB can be a good candidate for chemotherapy in pancreatic cancer.

  16. Eriocalyxin B induces apoptosis and cell cycle arrest in pancreatic adenocarcinoma cells through caspase- and p53-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Li, Lin [School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong (China); Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong (China); Yue, Grace G.L. [Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong (China); Lau, Clara B.S. [Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); Sun, Handong [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, CAS, Yunnan (China); Fung, Kwok Pui [School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong (China); Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong (China); Leung, Ping Chung [Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong (China); Han, Quanbin, E-mail: simonhan@hkbu.edu.hk [Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong (China); State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong (China); School of Chinese Medicine, The Hong Kong Baptist University, Hong Kong (China); Leung, Po Sing, E-mail: psleung@cuhk.edu.hk [School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong (China)

    2012-07-01

    Pancreatic cancer is difficult to detect early and responds poorly to chemotherapy. A breakthrough in the development of new therapeutic agents is urgently needed. Eriocalyxin B (EriB), isolated from the Isodon eriocalyx plant, is an ent-kaurane diterpenoid with promise as a broad-spectrum anti-cancer agent. The anti-leukemic activity of EriB, including the underlying mechanisms involved, has been particularly well documented. In this study, we demonstrated for the first time EriB's potent cytotoxicity against four pancreatic adenocarcinoma cell lines, namely PANC-1, SW1990, CAPAN-1, and CAPAN-2. The effects were comparable to that of the chemotherapeutic camptothecin (CAM), but with much lower toxicity against normal human liver WRL68 cells. EriB's cytoxicity against CAPAN-2 cells was found to involve caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Moreover, the p53 pathway was found to be activated by EriB in these cells. Furthermore, in vivo studies showed that EriB inhibited the growth of human pancreatic tumor xenografts in BALB/c nude mice without significant secondary adverse effects. These results suggest that EriB should be considered a candidate for pancreatic cancer treatment. -- Highlights: ► We study Eriocalyxin B (EriB)'s cytotoxic effects on pancreatic cancer cell lines. ► EriB inhibits cell proliferation via mediation of apoptosis and cell cycle arrest. ► The effects are involved in caspase-dependent apoptosis and p53 pathway. ► In vivo study also shows EriB inhibits the growth of human pancreatic tumor. ► EriB can be a good candidate for chemotherapy in pancreatic cancer.

  17. Pancreatic Reference Set Application: Kazufumi Honda-National Cancer Center (2014) — EDRN Public Portal

    Science.gov (United States)

    Among human malignancies, invasive ductal adenocarcinoma of the pancreas has the worst prognosis,with a 5-year survival rate of less than 10%. Most patients with early stage pancreatic cancer have no clinical symptoms; therefore, many of them develop progressive disease that is not detected until the late stage. To improve the survival rate of pancreatic cancer, non-invasive diagnostic methods that detect the disease in its early stage must be developed.

  18. Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer.

    Science.gov (United States)

    Tempero, Margaret A; Klimstra, David; Berlin, Jordan; Hollingsworth, Tony; Kim, Paula; Merchant, Nipun; Moore, Malcolm; Pleskow, Doug; Wang-Gillam, Andrea; Lowy, Andrew M

    2013-02-01

    Pancreatic ductal adenocarcinoma is the most aggressive of all epithelial malignancies. In contrast to the favorable trends seen in most other common malignancies, the five-year survival of patients with this disease remains only 6%, a statistic that has changed minimally for decades. Only two drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in the last 15 years, and there are no established strategies for early detection.

  19. Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma.

    Science.gov (United States)

    Kim, Hyunki; Zhai, Guihua; Samuel, Sharon L; Rigell, Christopher J; Umphrey, Heidi R; Rana, Samir; Stockard, Cecil R; Fineberg, Naomi S; Zinn, Kurt R

    2012-02-01

    The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models.

  20. Use of Respiratory-Correlated Four-Dimensional Computed Tomography to Determine Acceptable Treatment Margins for Locally Advanced Pancreatic Adenocarcinoma

    International Nuclear Information System (INIS)

    Goldstein, Seth D.; Ford, Eric C.; Duhon, Mario; McNutt, Todd; Wong, John; Herman, Joseph M.

    2010-01-01

    Purpose: Respiratory-induced excursions of locally advanced pancreatic adenocarcinoma could affect dose delivery. This study quantified tumor motion and evaluated standard treatment margins. Methods and Materials: Respiratory-correlated four-dimensional computed tomography images were obtained on 30 patients with locally advanced pancreatic adenocarcinoma; 15 of whom underwent repeat scanning before cone-down treatment. Treatment planning software was used to contour the gross tumor volume (GTV), bilateral kidneys, and biliary stent. Excursions were calculated according to the centroid of the contoured volumes. Results: The mean ± standard deviation GTV excursion in the superoinferior (SI) direction was 0.55 ± 0.23 cm; an expansion of 1.0 cm adequately accounted for the GTV motion in 97% of locally advanced pancreatic adenocarcinoma patients. Motion GTVs were generated and resulted in a 25% average volume increase compared with the static GTV. Of the 30 patients, 17 had biliary stents. The mean SI stent excursion was 0.84 ± 0.32 cm, significantly greater than the GTV motion. The xiphoid process moved an average of 0.35 ± 0.12 cm, significantly less than the GTV. The mean SI motion of the left and right kidneys was 0.65 ± 0.27 cm and 0.77 ± 0.30 cm, respectively. At repeat scanning, no significant changes were seen in the mean GTV size (p = .8) or excursion (p = .3). Conclusion: These data suggest that an asymmetric expansion of 1.0, 0.7, and 0.6 cm along the respective SI, anteroposterior, and medial-lateral directions is recommended if a respiratory-correlated four-dimensional computed tomography scan is not available to evaluate the tumor motion during treatment planning. Surrogates of tumor motion, such as biliary stents or external markers, should be used with caution.

  1. Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes.

    Science.gov (United States)

    Alidjinou, E K; Engelmann, I; Bossu, J; Villenet, C; Figeac, M; Romond, M-B; Sané, F; Hober, D

    2017-10-03

    Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

  2. Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Nina V Chaika

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma.We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites.Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer.

  3. SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Moz, Stefania; Basso, Daniela; Bozzato, Dania; Galozzi, Paola; Navaglia, Filippo; Negm, Ola H; Arrigoni, Giorgio; Zambon, Carlo-Federico; Padoan, Andrea; Tighe, Paddy; Todd, Ian; Franchin, Cinzia; Pedrazzoli, Sergio; Punzi, Leonardo; Plebani, Mario

    2016-10-25

    Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor β1 (TGFβ1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGFβ1 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGFβ1 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/β-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGFβ1 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-κB and PI3K/AKT in response to TGFβ1 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/β-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGFβ1 and S100A8/A9 mainly inhibit NF-κB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner.

  4. Infiltration of peritumoural but tumour-free parenchyma with IgG4-positive plasma cells in hilar cholangiocarcinoma and pancreatic adenocarcinoma.

    Science.gov (United States)

    Resheq, Yazid J; Quaas, Alexander; von Renteln, Daniel; Schramm, Christoph; Lohse, Ansgar W; Lüth, Stefan

    2013-10-01

    Recently, new guidelines for diagnosing IgG4-associated cholangitis have been published devaluing the diagnostic significance of IgG4-positive plasma cells and steroid trials. We sought to evaluate the utility of IgG4-positive plasma cells in discriminating IgG4-associated cholangitis from hilar cholangiocarcinoma and autoimmune pancreatitis from pancreatic adenocarcinoma under conditions when malignancy is likely to be missed. Resection specimens obtained from patients with hilar cholangiocarcinoma, pancreatic adenocarcinoma or hepatocellular carcinoma were re-evaluated for IgG4-positivity. Histological analysis focussed on peritumoural but tumour-free sections. Perioperative biochemical and clinical data were reviewed. Nineteen patients with hilar cholangiocarcinoma and 29 patients with pancreatic adenocarcinoma were eligible for histological re-evaluation. Six of 19 (32%) patients with hilar cholangiocarcinoma and 5 of 29 (17%) patients with pancreatic adenocarcinoma were IgG4-positive (≥20 IgG4-positive plasma cells per high power field). Patients with IgG4-positive hilar cholangiocarcinoma showed significantly higher levels of serum total bilirubin (3.6mg/dl vs. 1.8mg/dl; Philar cholangiocarcinoma. IgG4-positive plasma cells are of limited utility especially in distinguishing hilar cholangiocarcinoma from IgG4-associated cholangitis even when combined with clinical parameters and may be misleading under conditions when malignancy is missed. Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  5. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

    International Nuclear Information System (INIS)

    Kalinina, Tatyana; Simon, Ronald; Otto, Benjamin; Dierlamm, Judith; Schwarzenbach, Heidi; Effenberger, Katharina E; Bockhorn, Maximilian; Izbicki, Jakob R; Yekebas, Emre F; Güngör, Cenap; Thieltges, Sabrina; Möller-Krull, Maren; Murga Penas, Eva Maria; Wicklein, Daniel; Streichert, Thomas; Schumacher, Udo; Kalinin, Viacheslav

    2010-01-01

    Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line. The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp -/- /rag2 -/- mice. Sensitivity towards chemotherapy was analysed by MTT assay. PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp -/- /rag2 -/- mice resulted in formation of primary tumors and spontaneous lung metastasis. The established PaCa 5061 cell line and its injection into pfp -/- /rag2 -/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease

  6. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea; Pedersen, Stine Helene Falsig; Novak, Ivana

    2015-01-01

    of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour. METHODS: We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human...

  7. Increased Tissue and Circulating Levels of Dipeptidyl Peptidase-IV Enzymatic Activity in Patients with Pancreatic Ductal Adenocarcinoma

    Czech Academy of Sciences Publication Activity Database

    Bušek, P.; Vaníčková, Z.; Hrabal, P.; Brabec, Marek; Frič, P.; Zavoral, M.; Škrha, J.; Kmochová, K.; Laclav, M.; Bunganič, B.; Augustyns, K.; Van Der Veken, P.; Šedo, A.

    2016-01-01

    Roč. 16, č. 5 (2016), s. 829-838 ISSN 1424-3903 Grant - others:GA MZd(CZ) NT14254 Institutional support: RVO:67985807 Keywords : Diabetes mellitus * Fibroblast activation protein alpha * Peptide hydrolases * Plasma * Stromal cells Subject RIV: FD - Oncology ; Hematology Impact factor: 2.724, year: 2016

  8. The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1

    International Nuclear Information System (INIS)

    Genrich, Geeske; Kruppa, Marcus; Lenk, Lennart; Helm, Ole; Broich, Anna; Freitag-Wolf, Sandra; Röcken, Christoph; Sipos, Bence; Schäfer, Heiner; Sebens, Susanne

    2016-01-01

    Nuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible transcription factor being essential in regulating cell homeostasis. Thus, acute induction of Nrf2 in epithelial cells exposed to inflammation confers protection from oxidative cell damage and mutagenesis supporting an anti-tumorigenic role for Nrf2. However, pancreatic ductal adenocarcinoma (PDAC) is characterized by persistent Nrf2 activity conferring therapy resistance which points to a pro-tumorigenic role of Nrf2. A similar dichotomous role in tumorigenesis is described for the Transforming Growth Factor-beta 1 (TGF-β1). The present study therefore aimed at elucidating whether the switch of Nrf2 function towards a tumor promoting one relates to the modulation of TGF-β1 induced cell responses and whether this might occur early in PDAC development. In situ analysis comprised immunohistochemical stainings of activated (phosphorylated) Nrf2 and Ki67 in pancreatic tissues containing normal ducts and pancreatic intraepithelial neoplasia (PanINs). In vitro, Nrf2 levels in benign (H6c7-pBp), premalignant (H6c7-kras) and malignant (Colo357) pancreatic ductal epithelial cells were modulated by Nrf2 specific siRNA or Nrf2 overexpression. Then, the effect of Nrf2 alone and in combination with TGF-β1 on cell growth and survival was investigated by cell counting, Ki67 staining and apoptosis assays. The underlying cell signaling was investigated by western blotting. Statistical analysis was performed by Shapiro-Wilk test for normal distribution. Parametric data were analyzed by one-way ANOVA, while non-parametric data were analyzed by Kruskal-Wallis one-way ANOVA on ranks. Significantly elevated expression of activated Nrf2 and Ki67 could be detected in PanINs but not in normal pancreatic ductal epithelium. While the effect of Nrf2 on basal cell growth of H6c7-pBp, H6c7-kras and Colo357 cells was minor, it clearly attenuated the growth inhibiting effects of TGF-β1 in all cell lines. This enhanced

  9. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T

    2016-11-01

    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Magnetic Resonance Cholangiopancreatography: Image Quality, Ductal Morphology, and Value of Additional T2- and T1-weighted Sequences for the Assessment of Suspected Pancreatic Cancer

    International Nuclear Information System (INIS)

    Lopez Haenninen, E.; Ricke, H.; Amthauer, H.; Roettgen, R.; Boehmig, M.; Langrehr, J.; Pech, M.; Denecke, T.; Rosewicz, S.; Felix, R.

    2005-01-01

    Purpose: To assess image quality and duct morphology on magnetic resonance cholangiopancreatography (MRCP) and also the value of additional T2- and T1-weighted sequences for differentiation of benignity and malignancy in patients with suspected pancreatic tumors. Material and Methods: One-hundred-and-fourteen patients received MRCP and unenhanced and contrast material-enhanced MR imaging. MR results were analyzed independently by two blinded readers, and subsequently correlated with the results from surgery, biopsy, and follow-up. Assessment included the evaluation of image quality, duct visualization and morphology, and the differentiation of pancreatic lesion status (benign versus malignant).Results: Overall, 49 patients had benign final diagnoses, while 65 had a malignant diagnosis. Image quality of single-shot thick-slab MRCP was rated significantly better than the MIP images of multisection MRCP. With MRCP alone, the two readers' accuracy in the assessment of pancreatic lesion status was 72% (95% CI, 64% to 83%) and 69% (95% CI, 56% to 77%), respectively; with the addition of T2- and T1-weighted images the accuracy significantly improved to 89% (95% CI, 82% to 95%) and 84% (95% CI, 77% to 92%) for readers 1 and 2, respectively. Conclusion: Single-shot thick-slab MRCP and multisection MRCP provide complementary results; however, single-shot MRCP had superior image quality. Moreover, assessment of ductal morphology with MRCP alone facilitated the diagnosis of different pathologic conditions of the pancreatobiliary system in the majority of patients. However, with the addition of T2- and T1-weighted sequences the overall diagnostic accuracy was significantly improved and thus we consider that a comprehensive MR approach should comprise both MRCP techniques and parenchymal sequences

  11. Ductal carcinoma of the parotid gland.

    Science.gov (United States)

    Eriksen, H E; Greisen, O; Hastrup, N

    1987-06-01

    A case of ductal carcinoma of the parotid gland is described. The medical literature contains only 13 previous reports on this kind of adenocarcinoma of the parotid gland. The tumour is characterized by its histologic resemblance to ductal carcinomas of the breast and prostate. The course of previously described cases suggests that this tumour has a highly aggressive biological behaviour.

  12. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin

    International Nuclear Information System (INIS)

    Cho, Il-Rae; Koh, Sang Seok; Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong; Choi, Young-Whan; Horio, Yoshiyuki; Oh, Sangtaek; Chung, Young-Hwa

    2012-01-01

    Highlights: ► SIRT1 inhibits protein levels of β-catenin and its transcriptional activity. ► Nuclear localization of SIRT1 is not required for the decrease of β-catenin expression. ► SIRT1-mediated degradation of β-catenin is not required for GSK-3β and Siah-1 but for proteosome. ► SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of β-catenin, we postulated that β-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target β-catenin in a colon cancer model, suppresses β-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of β-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced β-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of β-catenin. Treatment with MG132, a proteasomal inhibitor, restored β-catenin protein levels, suggesting that SIRT1-mediated degradation of β-catenin requires proteasomal activity. It was reported that inhibition of GSK-3β or Siah-1 stabilizes β-catenin in colon cancer cells, but suppression of GSK-3β or Siah-1 using siRNA in the presence of resveratrol instead diminished β-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3β and Siah-1 are not involved in SIRT1-mediated degradation of β-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target

  13. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Young-Whan [Department of Horticultural Bioscience, Pusan National University, Miryang 627-706 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Oh, Sangtaek [Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer SIRT1 inhibits protein levels of {beta}-catenin and its transcriptional activity. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for the decrease of {beta}-catenin expression. Black-Right-Pointing-Pointer SIRT1-mediated degradation of {beta}-catenin is not required for GSK-3{beta} and Siah-1 but for proteosome. Black-Right-Pointing-Pointer SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of {beta}-catenin, we postulated that {beta}-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target {beta}-catenin in a colon cancer model, suppresses {beta}-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of {beta}-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced {beta}-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of {beta}-catenin. Treatment with MG132, a proteasomal inhibitor, restored {beta}-catenin protein levels, suggesting that SIRT1-mediated degradation of {beta}-catenin requires proteasomal activity. It was reported that inhibition of GSK-3{beta} or Siah-1 stabilizes {beta}-catenin in colon cancer cells, but suppression of GSK-3{beta} or Siah-1 using siRNA in the presence of resveratrol instead diminished {beta}-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3{beta} and Siah-1 are not involved in SIRT1

  14. Reirradiation with stereotactic body radiation therapy after prior conventional fractionation radiation for locally recurrent pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Amanda J. Koong

    2017-01-01

    Conclusions: Our report shows that SBRT for reirradiation of locally recurrent pancreas adenocarcinoma is a feasible option with good local control and acceptable toxicity rates, especially with a multifraction schedule.

  15. Extended Pancreatectomy: Does It Have a Role in the Contemporary Management of Pancreatic Adenocarcinoma?

    Science.gov (United States)

    Kaiser, Joerg; Hackert, Thilo; Büchler, Markus W

    2017-01-01

    Pancreatic cancer is a low-incident but highly mortal disease. Surgery is still the preferred treatment option for resectable pancreatic cancer as it offers the only realistic chance for cure. As many patients present with locally advanced disease, which is generally considered as not amenable to surgical treatment, it is important to know the limits of surgical therapy in this disease. In this review, the indication and outcomes of extended pancreatectomies as well as the alternative treatment options for locally advanced pancreatic cancer are described. Furthermore, controversies as well as ongoing and future directions for the treatment options of locally advanced pancreatic cancer are discussed. Extended pancreatectomy can be performed with higher morbidity and mortality rates in patients with locally advanced pancreatic cancer compared to patients undergoing formal pancreatic resections. These procedures offer significant advantages with respect to both perioperative results and to long-term outcome when compared to chemotherapy. Due to the higher morbidity and mortality rates, these operations should be limited to specialist units with great experience in pancreatic surgery as well as experience in peri- and post-operative management of patients with pancreatic diseases. © 2017 S. Karger AG, Basel.

  16. Computed tomography-guided cryoablation of local recurrence after primary resection of pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Claudio Pusceddu

    2015-06-01

    Full Text Available The optimal management of local recurrences after primary resection of pancreatic cancer still remains to be clarified. A 58-yearold woman developed an isolated recurrence of pancreatic cancer six year after distal pancreatectomy. Re-resection was attempted but the lesion was deemed unresectable at surgery. Then chemotherapy was administrated without obtaining a reduction of the tumor size nor an improvement of the patient’s symptoms. Thus the patient underwent percutaneous cryoablation under computed tomography (CT-guidance obtaining tumor necrosis and a significant improvement in the quality of life. A CT scan one month later showed a stable lesion with no contrast enhancement. While the use of percutaneous cryoblation has widened its applications in patients with unresectable pancreatic cancer, it has never been described for the treatment of local pancreatic cancer recurrence after primary resection. Percutaneous cryoablation deserves further studies in the multimodality treatment of local recurrence after primary pancreatic surgery.

  17. TU-G-BRA-06: PET-Based Treatment Response Assessement for Neoadjuvent Chemoradiation for Pancreatic Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dalah, E; Tai, A; Oshima, K; Hall, W; Erickson, B; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2015-06-15

    Purpose: To address the limitations of the conventional response evaluation criteria in solid tumors (RECIST), and validate PET response criteria in solid tumors (PERCIST1.0). We analyze the relationship between the pathological treatment response (PTR) and PERCIST1.0 for patients treated with neoadjuvent chemoradiation (nCR) for pancreatic adenocarcinoma. Methods: The pre- and post-nCR CT and PET data for a total of 8 patients with resectable, or borderline resectable pancreatic head adenocarcinoma treated with nCR were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade1, 2 or 3 (G1, G2 or G3) for good, moderate, and poor responses, respectively. RECIST-based PET (RECISTPET), and PERCIST1.0 were defined using lean body mass normalized SUV (nSUVlb). RECIST-based CT (RECISTCT) was defined by contouring the whole pancreas head (CTPH). Pre- and post-nSUVlb and SUVbw, PERCIST 1.0, were correlated with PTR using Pearson’s correlation coefficient test. Results: The average mean and SD in nSUVlb for all 8 patients analyzed were lower in post-nCR (1.35±0.34) compared to those at pre-nCR (1.38±0.20). Using PERCIST1.0, 5/8 patients showed stable metabolic disease (SMD), 2/8 partial metabolic response (PMR), and 1/8 progressive metabolic disease (PMD). Using RECISTPET 4/8 showed stable disease (STD), 4/8 partial response (PR), whereas 8/8 showed stable disease (STD) using RECISTCT. PTR were correlated with PERCIST1.0 (R=0.3780/P=0.6071). Pathological tumor size was correlated with RECISTCT (R=0.0727/P=0.8679), and RECISTPET, R=−0.3333/P=0.3798. Conclusion: Chemoradiation treatment response assessment based on metabolic tumor activities using PRECIST1.0 and RECISTPET appears to provide better agreement with pathological assessment as compared to the conventional CT-based assessment using RECISTCT. The integration of these additional radiographic metrics in assessing treatment

  18. Para-[{sup 123}I]iodo-L-phenylalanine in patients with pancreatic adenocarcinoma. Tumour uptake, whole-body kinetics, dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Hellwig, D.; Gouverneur, E.; Schaefer, A.; Kirsch, C.M.; Samnick, S. [Dept. of Nuclear Medicine, Saarland Univ. Medical Center, Homburg (Germany); Raedle, J.; Menges, M. [Dept. of Internal Medicine II (Gastroenterology), Saarland Univ. Medical Center, Homburg (Germany)

    2008-07-01

    Recently, p-[{sup 123}I]iodo-L-phenylalanine (IPA) was clinically validated for brain tumour imaging. Preclinical studies demonstrated uptake of IPA into pancreatic adenocarcinoma suggesting its diagnostic application in patients with pancreatic tumours. The aim was to study the tumour uptake of IPA in patients with pancreatic adenocarcinoma and to analyse its biodistribution and dosimetry to assess the radiation dose resulting from its diagnostic use. Patients, methods: Seven patients with pancreatic adenocarcinoma underwent whole-body scintigraphies and SPECT up to 24 h after administration of 250 MBq of IPA. Tumour uptake of IPA was assessed visually. Time activity curves and the corresponding residence times were determined for whole-body, kidneys, liver, spleen, lung, heart content, brain, and testes. Mean absorbed doses for various organs and the effective dose were assessed based on the MIRD formalism using OLINDA/EXM. Results: IPA exhibited no accumulation in proven manifestations of pancreatic adenocarcinomas. IPA was exclusively eliminated by the urine and showed a delayed clearance from blood. Residence times were 0.26 {+-} 0.09 h for kidneys, 0.38 {+-} 0.19 h for liver, 0.15 {+-} 0.07 h for spleen, 0.51 {+-} 0.20 h for lungs, 0.22 {+-} 0.07 h for heart content, 0.11 {+-} 0.05 h for brain, 0.014 {+-} 0.005 h for testes and 6.4 {+-} 2.2 h for the remainder. The highest absorbed doses were determined in the urinary bladder wall and in the kidneys. According to the ICRP 60 the effective dose resulting from 250 MBq IPA was 3.6 {+-} 0.7 mSv. Conclusion: Para-[{sup 123}I]iodo-L-phenylalanine can be used in diagnostic nuclear medicine with acceptable radiation doses. Besides its proven validity for brain tumour imaging, IPA does not appear to be suitable as tracer for pancreatic cancer. (orig.)

  19. Imaging of pancreatic tumors

    International Nuclear Information System (INIS)

    Brambs, Hans-Juergen; Juchems, Markus

    2010-01-01

    Ductal adenocarcinoma is the most frequent solid tumor of the pancreas. This tumor has distinct features including early obstruction of the pancreatic duct, diminished enhancement after administration of contrast material due to desmoplastic growth, high propensity to infiltrate adjacent structures and to metastasize into the liver and the peritoneum. Hormone active endocrine tumors cause specific clinical symptoms. Imaging is aimed at localization of these hypervascular tumors. Non hormone active tumors are most frequently malignant and demonstrate very varying features. Cystic pancreatic tumors are increasingly detected by means of cross sectional imaging. Exact classification can be achieved with knowledge of the macropathology and considering clinical presentation as well as age and gender of the patients. (orig.)

  20. Danish Pancreatic Cancer Database

    DEFF Research Database (Denmark)

    Fristrup, Claus; Detlefsen, Sönke; Palnæs Hansen, Carsten

    2016-01-01

    : Death is monitored using data from the Danish Civil Registry. This registry monitors the survival status of the Danish population, and the registration is virtually complete. All data in the database are audited by all participating institutions, with respect to baseline characteristics, key indicators......AIM OF DATABASE: The Danish Pancreatic Cancer Database aims to prospectively register the epidemiology, diagnostic workup, diagnosis, treatment, and outcome of patients with pancreatic cancer in Denmark at an institutional and national level. STUDY POPULATION: Since May 1, 2011, all patients...... with microscopically verified ductal adenocarcinoma of the pancreas have been registered in the database. As of June 30, 2014, the total number of patients registered was 2,217. All data are cross-referenced with the Danish Pathology Registry and the Danish Patient Registry to ensure the completeness of registrations...

  1. Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer

    OpenAIRE

    Wang, Qi; Li, Juanjuan; Wu, Wei; Shen, Ruizhe; Jiang, He; Qian, Yuting; Tang, Yanping; Bai, Tingting; Wu, Sheng; Wei, Lumin; Zang, Yi; Zhang, Ji; Wang, Lifu

    2016-01-01

    The importance of Pituitary homeobox 2 (Pitx2) in malignancy remains enigmatic, and Pitx2 has not been previously implicated in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed gene expression profiling of human PDAC tissues and identified Pitx2 as a promising candidate. Pitx2 expression was decreased from 2.6- to 19-fold in human PDAC tissues from microarray units. Immunochemistry staining showed that Pitx2 expression was moderate to intense in normal pancreatic and pancr...

  2. Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Sole, Claudio V. [Instituto de Radiomedicina (IRAM), Department of Radiation Oncology, Santiago (Chile); Complutense University, School of Medicine, Madrid (Spain); Calvo, Felipe A. [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Department of Oncology, Madrid (Spain); Atahualpa, Freddy; Gonzalez-Bayon, Luis; Garcia-Sabrido, Jose Luis [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, General Surgery Service III, Madrid (Spain); Berlin, Alejandro [Clinica Alemana de Santiago, Department of Radiation Oncology, Santiago (Chile); Herranz, Rafael [Hospital General Universitario Gregorio Maranon, Department of Radiation Oncology, Madrid (Spain)

    2014-10-08

    To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surgery with or without external beam radiotherapy (EBRT). From January 1995 to December 2012, 95 patients with adenocarcinoma of the pancreas and locoregional disease [clinical stage IB-IIA (n = 45; 47 %), IIB-IIIC (n = 50; 53 %)] were treated with curative resection [R0 (n = 52; 55 %), R1 (n = 43, 45 %)] and CT with (n = 60; 63 %) or without (n = 35; 37 %) EBRT (45-50.4 Gy). Additionally, 29 patients (48 %) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). With a median follow-up of 17.2 months (range, 1-182), 2-year overall survival (OS), disease-free survival (DFS), and locoregional control were 28, 20, and 53 %, respectively. Univariate analyses showed that IIB-IIIC stage (HR, 2.23; p = 0.04), R1 margin resection status (HR, 2.09; p = 0.04), no vascular resection (HR, 0.42; p = 0.02), and not receiving external beam radiotherapy (HR, 2.70; p = 0.004) were associated with locoregional recurrence. In the multivariate analysis, only R1 margin resection status (HR, 2.63; p = 0.009) and not receiving EBRT (HR, 2.91; p = 0.002) retained significance with regard to locoregional recurrence. We observed no difference in toxicity between patients treated with or without EBRT (p = 0.44). Overall treatment mortality was 3 %. No long-term treatment-related death occurred. Although adjuvant CT is still the standard of care for resected pancreatic tumors, OS remains modest owing to the high risk of distant metastases. Locoregional treatment needs to be tested in the context of more efficient systemic therapy. (orig.) [German] Zur Evaluierung von Prognosefaktoren im Rahmen von Langzeitresultaten bei Patienten mit reseziertem Pankreaskarzinom und verabreichter Chemotherapie (CT) mit oder ohne zusaetzlicher externer Radiotherapie (EBRT). Von Januar 1995 bis Dezember

  3. Characterization of pancreatic lesions from MT-tgf alpha, Ela-myc and MT-tgf alpha/Ela-myc single and double transgenic mice.

    Science.gov (United States)

    Liao, Dezhong Joshua; Wang, Yong; Wu, Jiusheng; Adsay, Nazmi Volkan; Grignon, David; Khanani, Fayyaz; Sarkar, Fazlul H

    2006-07-05

    In order to identify good animal models for investigating therapeutic and preventive strategies for pancreatic cancer, we analyzed pancreatic lesions from several transgenic models and made a series of novel findings. Female MT-tgf alpha mice of the MT100 line developed pancreatic proliferation, acinar-ductal metaplasia, multilocular cystic neoplasms, ductal adenocarcinomas and prominent fibrosis, while the lesions in males were less severe. MT-tgf alpha-ES transgenic lines of both sexes developed slowly progressing lesions that were similar to what was seen in MT100 males. In both MT100 and MT-tgf alpha-ES lines, TGF alpha transgene was expressed mainly in proliferating ductal cells. Ela-myc transgenic mice with a mixed C57BL/6, SJL and FVB genetic background developed pancreatic tumors at 2-7 months of age, and half of the tumors were ductal adenocarcinomas, similar to what was reported originally by Sandgren et al 1. However, in 20% of the mice, the tumors metastasized to the liver. MT100/Ela-myc and MT-tgf alpha-ES/Ela-myc double transgenic mice developed not only acinar carcinomas and mixed carcinomas as previously reported but also various ductal-originated lesions, including multilocular cystic neoplasms and ductal adenocarcinomas. The double transgenic tumors were more malignant and metastasized to the liver at a higher frequency (33%) compared with the Ela-myc tumors. Sequencing of the coding region of p16ink4, k-ras and Rb cDNA in small numbers of pancreatic tumors did not identify mutations. The short latency for tumor development, the variety of tumor morphology and the liver metastases seen in Ela-myc and MT-tgf alpha/Ela-myc mice make these animals good models for investigating new therapeutic and preventive strategies for pancreatic cancer.

  4. Comparison of circulating MMP-9, TIMP-1 and CA19-9 in the detection of pancreatic cancer

    DEFF Research Database (Denmark)

    Jørgensen, Maiken Thyregod; Brunner, Nils; Schaffalitzky de Muckadell, Ove B.

    2010-01-01

    , TIMP-1 and CA19-9 in detecting pancreatic ductal adenocarcinoma were 58.82%, 47.1% and 86%, respectively, with specificities of 34.6%, 69.2% and 73%. The AUCs of MMP-9, TIMP-1 and CA19-9 were 0.50, 0.64 and 0.84, respectively. Combining the three markers did not significantly improve detection......Background/Aim: The performance of the circulating tumor markers carbohydrate antigen 19-9 (CA19-9), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were evaluated separately and in combination for their potential value in detecting pancreatic ductal...... adenocarcinoma. PATIENTS AND METHODS: The patients had symptoms of pancreatic cancer. The discriminative strength of MMP-9 and TIMP-1 were compared to that of CA19-9 using receiver operating characteristics curves, area under the curves (AUC), specificity and sensitivity. RESULTS: The sensitivities of MMP-9...

  5. Surgical and molecular pathology of pancreatic neoplasms.

    Science.gov (United States)

    Hackeng, Wenzel M; Hruban, Ralph H; Offerhaus, G Johan A; Brosens, Lodewijk A A

    2016-06-07

    Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

  6. Impact of a portal/superior mesenteric vein resection during pancreatico-duodenectomy for pancreatic head adenocarcinoma.

    Science.gov (United States)

    Dumitrascu, T; Dima, S; Brasoveanu, V; Stroescu, C; Herlea, V; Moldovan, S; Ionescu, M; Popescu, I

    2014-12-01

    The impact of venous resection (VR) in pancreatico-dudenectomy (PD) for pancreatic adenocarcinoma (PDAC) is controversial. The aim of the study is to comparatively assess the postoperative outcomes after PD with and without VR for PDAC and to identify predictors of morbidity and survival in the subgroup of PD with VR. The data of 51 PD with VR were compared with those of 183 PD without VR. Binary logistic regression and Cox survival analyses were performed. Both the operative time and estimated blood loss was significantly higher in the VR group (P<0.001). A trend towards an increased 90-day mortality (9.8% vs. 5.5%) and severe morbidity (20% vs. 13%) was observed when a VR was performed (P ≥0.264). The median overall survival time after the PD with and without VR was 13 months and 17 months, respectively (P=0.845). The absence of histological tumor invasion of the VR was found as the only independent predictor for a better survival (HR=0.359; 95% CI 0.161-0.803; P=0.013). A PD with VR can be safely incorporated in a pancreatic surgeon armamentarium. However, the trend towards increased mortality and severe morbidity rates should be expected, along with higher operative time and blood loss, compared with PD without VR. Associated VR does not appear to significantly impair the prognosis after PD for PDAC; however, histological tumor invasion of the VR has a negative impact on the survival.

  7. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis.

    Directory of Open Access Journals (Sweden)

    Richard Fristedt

    Full Text Available The polymeric immunoglobulin receptor (pIgR is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175 and paired lymph node metastases (n = 105. A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3% primary tumours and in 96/105 (91.4% lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018. Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001, perineural growth (p = 0.027, lymphatic invasion (p = 0.016, vascular invasion (p = 0.033 and infiltration of the peripancreatic fat (p = 0.039. In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI 1.71-5.25 and early recurrence (HR = 2.89, 95% CI 1.67-4.98. This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57. These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies

  8. RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells

    OpenAIRE

    Chow, Jimmy Y.C.; Quach, Khai T.; Cabrera, Betty L.; Cabral, Jennifer A.; Beck, Stayce E.; Carethers, John M.

    2007-01-01

    Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-β might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFβ and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFβ surface receptors. Cells were t...

  9. Susceptibility of ATM-deficient pancreatic cancer cells to radiation.

    Science.gov (United States)

    Ayars, Michael; Eshleman, James; Goggins, Michael

    2017-05-19

    Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Isogenic cell lines were tested for sensitivity to several chemotherapeutic agents and radiation. DNA repair kinetics were analyzed in irradiated cells using the comet assay. We find that while rendering pancreatic cancer cells ATM-deficient did not significantly change their sensitivity to several chemotherapeutics, it did render them exquisitely sensitized to radiation. Pancreatic cancer ATM status may help predict response to radiotherapy.

  10. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis

    NARCIS (Netherlands)

    Cahen, Djuna L.; Gouma, Dirk J.; Nio, Yung; Rauws, Erik A. J.; Boermeester, Marja A.; Busch, Olivier R.; Stoker, Jaap; Lameris, Johan S.; Dijkgraaf, Marcel G. W.; Huibregtse, Kees; Bruno, Marco J.

    2007-01-01

    BACKGROUND: For patients with chronic pancreatitis and a dilated pancreatic duct, ductal decompression is recommended. We conducted a randomized trial to compare endoscopic and surgical drainage of the pancreatic duct. METHODS: All symptomatic patients with chronic pancreatitis and a distal

  11. [Recommendations for the diagnosis, staging and treatment of pre-malignant lesions and pancreatic adenocarcinoma].

    Science.gov (United States)

    Martin-Richard, Marta; Ginès, Angels; Ayuso, Juan Ramón; Sabater, Luis; Fabregat, Joan; Mendez, Ramiro; Fernández-Esparrach, Glòria; Molero, Xavier; Vaquero, Eva C; Cuatrecasas, Miriam; Ferrández, Antonio; Maurel, Joan

    2016-11-18

    Clinical management of adenocarcinoma of the pancreas is complex, and requires a multidisciplinary approach. The same applies for the premalignant lesions that are increasingly being diagnosed. The current document is an update on the diagnosis and management of premalignant lesions and adenocarcinoma of the pancreas. A conference to establish the basis of the literature review and manuscript redaction was organized by the Grupo Español Multidisciplinar en Cáncer Digestivo. Experts in the field from different specialties (Gastroenterology, Surgery, Radiology, Pathology, Medical Oncology and Radiation Oncology) met to prepare the present document. The current literature was reviewed and discussed, with subsequent deliberation on the evidence. Final recommendations were established in view of all the above. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  12. Influence of Interferon-Alpha Combined with Chemo (Radio Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Svetlana Karakhanova

    2014-03-01

    Full Text Available Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

  13. Adenocarcinoma of the pancreatic head: preoperative helical CT. Criteria of resectability

    International Nuclear Information System (INIS)

    Kozima, Shigeru; Szelagowski, Carlos; Tisserand, Guy L.; Ocampo, Carlos; Zandalazini, Hugo; Silva, Walter; Oria, Alejandro; Vidovic, Gustavo; Varas, Pablo

    2001-01-01

    Objective: The purpose of this study is to determine the accuracy of biphasic helical CT scanning in predicting resectability of adenocarcinoma of the head of the pancreas by staying tumor involvement of the portal and superior mesenteric veins. Material and methods: 46 patients with proven adenocarcinoma of the head of the pancreas who underwent curative or palliative surgery were studied with preoperative biphasic helical CT scanning. Tumor involvement of the portal and mesenteric veins was graduated on a 1-3 scale based on circumferential contiguity of the tumor vessel. Grade 1: without contact; grade 2: tumor involvement of less than 50% of the vessel; grade 3: tumor involvement of more than 50%. Results: The total number of vessels evaluated was 92. In our series the preoperative biphasic helical CT was accurate in 77% for resectability and unresectability. Conclusion: Our experience of staging in 3 grades with biphasic helical CT, vessel involvement the portal and superior mesenteric veins of adenocarcinoma of the head of the pancreas is highly specific for unresectable tumor in patients who were graded 2 and 3. (author)

  14. Complex role for the immune system in initiation and progression of pancreatic cancer.

    Science.gov (United States)

    Inman, Kristin S; Francis, Amanda A; Murray, Nicole R

    2014-08-28

    The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.

  15. An Extremely Rapid Case of Pneumonitis with the Use of Nivolumab for Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Rubens Barros Costa

    2018-01-01

    Full Text Available Pancreatic cancer is the fourth most common cancer death in the United States despite comprising a small percentage of the total number of cancer cases. The estimated 5-year overall survival (OS for patients with distant metastatic disease is approximately 3%. New treatment options are an unmet need and remain an area of active investigation. A 53-year-old male with metastatic pancreatic cancer presented to the hospital with acute-on-chronic respiratory failure approximately 24 hours after receiving a novel therapeutic combination. Chest imaging showed marked changes as concerning for pneumonitis. Infectious workup was negative. The patient had initial clinical improvement after receiving initial intravenous steroids and oxygen support but eventually deteriorated later opting for supportive measures only. With infection ruled out, drug-induced pneumonitis was felt to be the likely cause of the radiologic and clinical changes. The rapidity of onset of symptoms is the aspect being highlighted in this case.

  16. Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Katarzyna A Ellsworth

    Full Text Available FKBP51, (FKBP5, is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies.In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 "A(T" SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR. The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing.This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

  17. Looking to the Future: Biomarkers in the Management of Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Karen E. Mulder

    2011-09-01

    Full Text Available The incidence and mortality of pancreas cancer converge. There has been little advancement in the treatment of pancreas cancer since the acceptance of gemcitabine as the standard therapy. Unfortunately, the efficacy of gemcitabine is dismal. While there is much discussion for the development of biomarkers to help direct therapy in this area, there is little action to move them into clinical practice. Herein, we review potential pancreatic cancer biomarkers and discuss the limitations in their implementation.

  18. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    Science.gov (United States)

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  19. Evaluation of the 8th AJCC staging system for pathologically versus clinically staged pancreatic adenocarcinoma: A time to revisit a dogma?

    Science.gov (United States)

    Abdel-Rahman, Omar

    2018-02-01

    The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic exocrine adenocarcinoma has been released. The current study seeks to assess the 7th and 8th editions among patients registered within the surveillance, epidemiology and end results (SEER) database. SEER database (2010-2013) has been accessed through SEER*Stat program and AJCC 8th edition stages were reconstructed utilizing the collaborative stage descriptions. Kaplan-Meier analysis of overall survival and pancreatic cancer-specific survival analyses (according to both 7th and 8th editions and according to whether pathological or clinical staging were conducted) has been performed. Multivariate analysis of factors affecting pancreatic cancer-specific survival was also conducted through a Cox proportional hazard model. A total of 18  948 patients with pancreatic adenocarcinoma were identified in the period from 2010-2013. Pancreatic cancer-specific survival among pathologically staged patients and according to the 8th edition showed significant differences for all pair wise comparisons among different stages (P < 0.0001) except for the comparison between stage IA and stage IB (P = 0.307) and the comparison between stage IB and stage IIA (P = 0.116). Moreover, P value for stage IA vs IIA was 0.014; while pancreatic cancer-specific survival according to the 7th edition among pathologically staged patients showed significant differences for all pair wise comparisons among different stages (P < 0.0001) except for the comparison between IA and IB (P = 0.072), the comparison between stage IIA and stage IIB (P = 0.065), the comparison between stage IIA and stage III (P = 0.059) and the comparison between IIB and III (P = 0.595). Among clinically staged patients (i.e. those who did not undergo initial radical surgery), the prognostic performance of both 7th and 8th stages for both overall survival and pancreatic cancer-specific survival was

  20. Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: report of two cases.

    Science.gov (United States)

    Vaquero, Eva C; Salcedo, Maria T; Cuatrecasas, Míriam; De León, Hannah; Merino, Xavier; Navarro, Salvador; Ginès, Angels; Abu-Suboh, Monder; Balsells, Joaquim; Fernández-Cruz, Laureano; Molero, Xavier

    2014-01-01

    Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation. Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  1. New markers of pancreatic cancer identified through differential gene expression analyses: claudin 18 and annexin A8.

    Science.gov (United States)

    Karanjawala, Zarir E; Illei, Peter B; Ashfaq, Raheela; Infante, Jeffrey R; Murphy, Kathleen; Pandey, Akhilesh; Schulick, Richard; Winter, Jordan; Sharma, Rajni; Maitra, Anirban; Goggins, Michael; Hruban, Ralph H

    2008-02-01

    New markers to distinguish benign reactive glands from infiltrating ductal adenocarcinoma of the pancreas are needed. The gene expression patterns of 24 surgically resected primary infiltrating ductal adenocarcinomas of the pancreas were compared with 18 non-neoplastic samples using the Affymetrix U133 Plus 2.0 Arrays and the Gene Logic GeneExpress Software System. Gene fragments from 4 genes (annexin A8, claudin 18, CXCL5, and S100 A2) were selected from the fragments found to be highly expressed in infiltrating adenocarcinomas when compared with normal tissues. The protein expression of these genes was examined using immunohistochemical labeling of tissue microarrays. Claudin 18 labeled infiltrating carcinomas in a membranous pattern. When compared with normal and reactive ducts, claudin 18 was overexpressed, at least focally, in 159 of 166 evaluable carcinomas (96%). Strong and diffuse claudin 18 overexpression was most often seen in well-differentiated carcinomas (P=0.02). Claudin 18 was overexpressed in 51 of 52 cases (98%) of pancreatic intraepithelial neoplasia. Annexin A8 was at least focally overexpressed in 149 of 154 evaluable infiltrating carcinomas (97%). S100 A2 was at least focally overexpressed in 118 of 154 evaluable infiltrating carcinomas (77%). Non-neoplastic glands also frequently expressed S100 A2 diminishing its potential diagnostic utility. Immunolabeling with antibodies directed against CXCL5 did not reveal any significant differences in protein expression between infiltrating adenocarcinomas and normal pancreatic ducts. Claudin 18 and annexin A8 are frequently highly overexpressed in infiltrating ductal adenocarcinomas when compared with normal reactive ducts, suggesting a role for these molecules in pancreatic ductal adenocarcinomas. Furthermore, these may serve as diagnostic markers, as screening tests and as therapeutic targets.

  2. Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome

    OpenAIRE

    Serracant Barrera, Anna; Serra Pla, Sheila; Blázquez Maña, Carmen María; Salas, Rubén Carrera; García Monforte, Neus; Bejarano González, Natalia; Romaguera Monzonis, Andreu; Andreu Navarro, Francisco Javier; Bella Cueto, Maria Rosa; Borobia, Francisco G.

    2017-01-01

    Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and seboma...

  3. pH-sensitive K+ channel TREK-1 is a novel target in pancreatic cancer

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter; Sørensen, Christiane Elisabeth; Rapedius, Markus

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and new therapeutic targets are urgently needed. One of the hallmarks of cancer is changed pH-homeostasis and potentially pH-sensors may play an important role in cancer cell behavior. Two-pore potassium channels (K2P) are p...... proliferation and migration indicating that hyperpolarization of Vm attenuates cancer cell behavior. TREK-1 may therefore be a promising novel target for PDAC therapy....

  4. In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis.

    Science.gov (United States)

    Qian, Jiaying; Niu, Jiangong; Li, Ming; Chiao, Paul J; Tsao, Ming-Sound

    2005-06-15

    Genetic analysis of pancreatic ductal adenocarcinomas and their putative precursor lesions, pancreatic intraepithelial neoplasias (PanIN), has shown a multistep molecular paradigm for duct cell carcinogenesis. Mutational activation or inactivation of the K-ras, p16(INK4A), Smad4, and p53 genes occur at progressive and high frequencies in these lesions. Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and is found early in the PanIN-carcinoma sequence, but its functional roles remain poorly understood. We show here that the expression of K-ras(G12V) oncogene in a near diploid HPV16-E6E7 gene immortalized human pancreatic duct epithelial cell line originally derived from normal pancreas induced the formation of carcinoma in 50% of severe combined immunodeficient mice implanted with these cells. A tumor cell line established from one of these tumors formed ductal cancer when implanted orthotopically. These cells also showed increased activation of the mitogen-activated protein kinase, AKT, and nuclear factor-kappaB pathways. Microarray expression profiling studies identified 584 genes whose expression seemed specifically up-regulated by the K-ras oncogene expression. Forty-two of these genes have been reported previously as differentially overexpressed in pancreatic cancer cell lines or primary tumors. Real-time PCR confirmed the overexpression of a large number of these genes. Immunohistochemistry done on tissue microarrays constructed from PanIN and pancreatic cancer samples showed laminin beta3 overexpression starting in high-grade PanINs and occurring in >90% of pancreatic ductal carcinoma. The in vitro modeling of human pancreatic duct epithelial cell transformation may provide mechanistic insights on gene expression changes that occur during multistage pancreatic duct cell carcinogenesis.

  5. High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

    International Nuclear Information System (INIS)

    Colbert, Lauren E.; Fisher, Sarah B.; Balci, Serdar; Saka, Burcu; Chen, Zhengjia; Kim, Sungjin; El-Rayes, Bassel F.; Adsay, N. Volkan; Maithel, Shishir K.; Landry, Jerome C.

    2015-01-01

    Purpose: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for

  6. Surgery of malignant pancreatic tumors

    International Nuclear Information System (INIS)

    Loos, M.; Friess, H.; Kleeff, J.

    2009-01-01

    Ductal adenocarcinoma is the most common malignant tumor of the pancreas. Despite great efforts in basic and clinical pancreatic cancer research, the prognosis remains poor with an overall 5-year survival rate of less than 5%. Complete surgical resection represents the only curative treatment option and 5-year survival rates of 20-25% can be achieved following curative resection and adjuvant chemotherapy. Although pancreatic surgery is considered one of the most technically demanding and challenging procedures, there has been constant progress in surgical techniques and advances in perioperative care with a modern interdisciplinary approach including anesthesiology, oncology, radiology and nursing. This has reduced morbidity and especially mortality rates in high-volume centers. Among extended resection procedures multivisceral and venous resections are technically feasible and should be considered if a complete tumor resection can be achieved. Multimodal regimens have shown promising results, however, only adjuvant chemotherapy is supported by solid evidence from randomized controlled trials. (orig.) [de

  7. Tumor Size on Abdominal MRI Versus Pathologic Specimen in Resected Pancreatic Adenocarcinoma: Implications for Radiation Treatment Planning

    Energy Technology Data Exchange (ETDEWEB)

    Hall, William A., E-mail: whall4@emory.edu [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Mikell, John L. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Mittal, Pardeep [Department of Radiology, Emory University, Atlanta, Georgia (United States); Colbert, Lauren [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Prabhu, Roshan S. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Kooby, David A. [Department of Surgery, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Nickleach, Dana [Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Hanley, Krisztina [Department of Pathology, Emory University, Atlanta, Georgia (United States); Sarmiento, Juan M. [Department of Surgery, Emory University, Atlanta, Georgia (United States); Ali, Arif N.; Landry, Jerome C. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

    2013-05-01

    Purpose: We assessed the accuracy of abdominal magnetic resonance imaging (MRI) for determining tumor size by comparing the preoperative contrast-enhanced T1-weighted gradient echo (3-dimensional [3D] volumetric interpolated breath-hold [VIBE]) MRI tumor size with pathologic specimen size. Methods and Materials: The records of 92 patients who had both preoperative contrast-enhanced 3D VIBE MRI images and detailed pathologic specimen measurements were available for review. Primary tumor size from the MRI was independently measured by a single diagnostic radiologist (P.M.) who was blinded to the pathology reports. Pathologic tumor measurements from gross specimens were obtained from the pathology reports. The maximum dimensions of tumor measured in any plane on the MRI and the gross specimen were compared. The median difference between the pathology sample and the MRI measurements was calculated. A paired t test was conducted to test for differences between the MRI and pathology measurements. The Pearson correlation coefficient was used to measure the association of disparity between the MRI and pathology sizes with the pathology size. Disparities relative to pathology size were also examined and tested for significance using a 1-sample t test. Results: The median patient age was 64.5 years. The primary site was pancreatic head in 81 patients, body in 4, and tail in 7. Three patients were American Joint Commission on Cancer stage IA, 7 stage IB, 21 stage IIA, 58 stage IIB, and 3 stage III. The 3D VIBE MRI underestimated tumor size by a median difference of 4 mm (range, −34-22 mm). The median largest tumor dimensions on MRI and pathology specimen were 2.65 cm (range, 1.5-9.5 cm) and 3.2 cm (range, 1.3-10 cm), respectively. Conclusions: Contrast-enhanced 3D VIBE MRI underestimates tumor size by 4 mm when compared with pathologic specimen. Advanced abdominal MRI sequences warrant further investigation for radiation therapy planning in pancreatic adenocarcinoma before

  8. Tumor Size on Abdominal MRI Versus Pathologic Specimen in Resected Pancreatic Adenocarcinoma: Implications for Radiation Treatment Planning

    International Nuclear Information System (INIS)

    Hall, William A.; Mikell, John L.; Mittal, Pardeep; Colbert, Lauren; Prabhu, Roshan S.; Kooby, David A.; Nickleach, Dana; Hanley, Krisztina; Sarmiento, Juan M.; Ali, Arif N.; Landry, Jerome C.

    2013-01-01

    Purpose: We assessed the accuracy of abdominal magnetic resonance imaging (MRI) for determining tumor size by comparing the preoperative contrast-enhanced T1-weighted gradient echo (3-dimensional [3D] volumetric interpolated breath-hold [VIBE]) MRI tumor size with pathologic specimen size. Methods and Materials: The records of 92 patients who had both preoperative contrast-enhanced 3D VIBE MRI images and detailed pathologic specimen measurements were available for review. Primary tumor size from the MRI was independently measured by a single diagnostic radiologist (P.M.) who was blinded to the pathology reports. Pathologic tumor measurements from gross specimens were obtained from the pathology reports. The maximum dimensions of tumor measured in any plane on the MRI and the gross specimen were compared. The median difference between the pathology sample and the MRI measurements was calculated. A paired t test was conducted to test for differences between the MRI and pathology measurements. The Pearson correlation coefficient was used to measure the association of disparity between the MRI and pathology sizes with the pathology size. Disparities relative to pathology size were also examined and tested for significance using a 1-sample t test. Results: The median patient age was 64.5 years. The primary site was pancreatic head in 81 patients, body in 4, and tail in 7. Three patients were American Joint Commission on Cancer stage IA, 7 stage IB, 21 stage IIA, 58 stage IIB, and 3 stage III. The 3D VIBE MRI underestimated tumor size by a median difference of 4 mm (range, −34-22 mm). The median largest tumor dimensions on MRI and pathology specimen were 2.65 cm (range, 1.5-9.5 cm) and 3.2 cm (range, 1.3-10 cm), respectively. Conclusions: Contrast-enhanced 3D VIBE MRI underestimates tumor size by 4 mm when compared with pathologic specimen. Advanced abdominal MRI sequences warrant further investigation for radiation therapy planning in pancreatic adenocarcinoma before

  9. Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine

    OpenAIRE

    Isayev, Orkhan; Rausch, Vanessa; Bauer, Nathalie; Liu, Li; Fan, Pei; Zhang, Yiyao; Gladkich, Jury; Nwaeburu, Clifford C.; Mattern, Jürgen; Mollenhauer, Martin; Rückert, Felix; Zach, Sebastian; Haberkorn, Uwe; Gross, Wolfgang; Schönsiegel, Frank

    2014-01-01

    According to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non-malignant cells, and 3 patien...

  10. Nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreatic cancer: utility and experience from the clinic

    OpenAIRE

    Dragovich, Tomislav; Kundranda,Madappa

    2016-01-01

    Madappa N Kundranda, Tomislav Dragovich Division of Hematology and Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Abstract: Pancreatic ductal adenocarcinoma remains one of the deadliest epithelial cancers, primarily due to late diagnosis, early metastasis and the lack of effective treatments. With recent advances in systemic therapies, the median survival for metastatic disease has essentially doubled to approximately 1 year, and a significant number of patients are receiving m...

  11. Impact of Hepatitis B Virus on Clinicopathological Features and Outcomes After Resection for Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Dumitrascu, Traian; Pineau, Pascal; Dima, Simona; Stroescu, Cezar; Brasoveanu, Vladislav; Herlea, Vlad; Ionescu, Mihnea; Popescu, Irinel

    2015-09-01

    Background/ Aim: Chronic hepatitis B virus (HBV) infection is sometimes considered a risk factor for pancreatic cancer (PDAC), but the prognostic value of its presence has only rarely been investigated. The present study aimed to explore the impact of HBV after resection for PDAC. According to HBV surface antigen seroreactivity, 343 patients were classified as having non-viral or HBV-related cases of PDAC. Clinicopathological data and outcomes were comparatively assessed between the groups. Chronic HBV infection was observed in 16 patients (4.5%). No significant differences between the HBV and non-viral cases of PDAC were observed. Tumor diameters (3.4 vs. 3.0, p=0.092) and stages at diagnosis (31 vs. 14% T1-T2, p=0.082) tended to differ between the groups, albeit without reaching significance. Completion of adjuvant therapy (63 vs. 54%, p=0.612), as well as median overall survival (15 vs. 17 months, p=0.346) was similar in the HBV and non-viral PDAC groups. HBV-positive and virus-free patients with PDAC generally shared the same demographic, clinical and pathological profiles. HBV did not appear to have a detrimental effect on either early or long-term outcomes after resection for PDAC. Future studies searching for occult infection might, however, shed a different light on the role of HBV in PDAC. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  12. Erlotinib-loaded albumin nanoparticles: A novel injectable form of erlotinib and its in vivo efficacy against pancreatic adenocarcinoma ASPC-1 and PANC-1 cell lines.

    Science.gov (United States)

    Noorani, M; Azarpira, N; Karimian, K; Heli, H

    2017-10-05

    Erlotinib was loaded on albumin nanoparticles for the first time and the cytotoxic effect of the resulting nanoparticles against ASPC-1 and PANC-1 pancreatic adenocarcinoma cell lines was evaluated. The carrier (albumin nanoparticles, ANPs) was synthesized by desolvation method using a mixed solvent followed by thermal crosslinking for stabilization. ANPs and the drug-loaded ANPs were characterized by field emission scanning and transmission electron microscopies, particle size analysis and Fourier transform infrared spectroscopy. The nanoformulation had a size of PANC-1 cell line). Values of IC 50 were obtained for both cell lines and indicated significant reduction in the erlotinib dose necessary for killing the cells, while, ANPs were completely safe. The results demonstrated that erlotinib-loaded ANPs had a remarkable potential for pancreatic cancer drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation.

    Science.gov (United States)

    Zhang, Qiang; Zhang, Yaqing; Parsels, Joshua D; Lohse, Ines; Lawrence, Theodore S; Pasca di Magliano, Marina; Sun, Yi; Morgan, Meredith A

    2016-11-01

    Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras G12D ;Fbxw7 fl/fl (KFC fl/fl ) compound mice. We found that KFC fl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC fl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC fl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras G12D -induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  14. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  15. Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: Implications for radiation therapy planning

    International Nuclear Information System (INIS)

    Qiu Haoming; Wild, Aaron T.; Wang Hao; Fishman, Elliot K.; Hruban, Ralph H.; Laheru, Daniel A.; Kumar, Rachit; Hacker-Prietz, Amy; Tuli, Richard; Tryggestad, Erik; Schulick, Richard D.; Cameron, John L.; Edil, Barish H.; Pawlik, Timothy M.; Wolfgang, Christopher L.; Herman, Joseph M.

    2012-01-01

    Background and purpose: This study seeks to: (a) quantify radiologic-pathologic discrepancy for pancreatic adenocarcinoma by comparing tumor size on conventional computed tomography (C-CT) and 3-dimensional CT (3D-CT) to corresponding pathologic specimens; and (b) to identify clinico-pathologic characteristics predictive of radiologic-pathologic discrepancy to assist radiotherapy planning. Materials and methods: Sixty-three patients with pancreatic adenocarcinoma and preoperative C-CT and volume-rendered 3D-CT imaging within 6 weeks of resection were identified. Maximum tumor diameter (MTD) was measured on pathology, C-CT, and 3D-CT and compared for each patient as well as among different clinico-pathologic subgroups. Results: There was a trend toward C-CT underestimation of MTD compared to final pathology (p = 0.08), but no significant difference between 3D-CT MTD and pathology (p = 0.54). Pathologic tumor size was significantly underestimated by C-CT in patients with larger pathologic tumor size (>3.0 cm, p = 0.0001), smaller tumor size on C-CT ( 90 U/mL, p = 0.008), and location in the pancreatic head (p = 0.015). A model for predicting pathologic MTD using C-CT MTD and CA19-9 level was generated. Conclusions: 3D-CT may allow for more accurate contouring of pancreatic tumors than C-CT. Patients with the above clinico-pathologic characteristics may require expanded margins relative to tumor size estimates on C-CT during radiotherapy planning.

  16. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  17. Management of pancreatic cancer in the elderly.

    Science.gov (United States)

    Higuera, Oliver; Ghanem, Ismael; Nasimi, Rula; Prieto, Isabel; Koren, Laura; Feliu, Jaime

    2016-01-14

    Currently, pancreatic adenocarcinoma mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. The aging of the population will result in a rise in the incidence of pancreatic adenocarcinoma within the next years. Thus, the management of pancreatic cancer in the elderly population is gaining increasing relevance. Older cancer patients represent a heterogeneous group with different biological, functional and psychosocial characteristics that can modify the usual management of this disease, including pharmacokinetic and pharmacodynamic changes, polypharmacy, performance status, comorbidities and organ dysfunction. However, the biological age, not the chronological age, of the patient should be the limiting factor in determining the most appropriate treatment for these patients. Unfortunately, despite the increased incidence of this pathology in older patients, there is an underrepresentation of these patients in clinical trials, and the management of older patients is thus determined by extrapolation from the results of studies performed in younger patients. In this review, the special characteristics of the elderly, the multidisciplinary management of localized and advanced ductal adenocarcinoma of the pancreas and the most recent advances in the management of this condition will be discussed, focusing on surgery, chemotherapy, radiation and palliative care.

  18. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Seung Min, E-mail: smjeong@catholic.ac.kr [Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Hwang, Sunsook; Seong, Rho Hyun [School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2016-03-11

    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. - Highlights: • Pancreatic ductal adenocarcinoma (PDAC) exhibits an elevated transferrin receptor (TfR1) expression in comparison with non-transformed pancreatic cells. • TfR1 is required for PDAC growth by regulating mitochondrial respiration and ROS production. • TfR1 functions as a determinant of cell viability to oxidative stress in PDAC cells.

  19. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation

    International Nuclear Information System (INIS)

    Jeong, Seung Min; Hwang, Sunsook; Seong, Rho Hyun

    2016-01-01

    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. - Highlights: • Pancreatic ductal adenocarcinoma (PDAC) exhibits an elevated transferrin receptor (TfR1) expression in comparison with non-transformed pancreatic cells. • TfR1 is required for PDAC growth by regulating mitochondrial respiration and ROS production. • TfR1 functions as a determinant of cell viability to oxidative stress in PDAC cells.

  20. Occupational exposures and risk of pancreatic cancer

    International Nuclear Information System (INIS)

    Santibanez, Miguel; Vioque, Jesus; Alguacil, Juan; Hera, Manuela Garcia de la; Moreno-Osset, Eduardo; Carrato, Alfredo; Porta, Miquel; Kauppinen, Timo

    2010-01-01

    The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated hydrocarbon solvents (OR = 4.1, 95% CI: 1.1-15.2, p-trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'hydrocarbon solvents'. Results support the hypothesis that occupational exposure to chlorinated hydrocarbon solvents is associated with exocrine pancreatic cancer.

  1. Compared With Elastin Stains, h-Caldesmon and Desmin Offer Superior Detection of Vessel Invasion in Gastric, Pancreatic, and Colorectal Adenocarcinomas.

    Science.gov (United States)

    Ekinci, Özgür; Öğüt, Betül; Çelik, Bülent; Dursun, Ayşe

    2018-06-01

    The presence of vessel invasion is considered indicative of a poor prognosis in many malignant tumors. We aimed to compare the sensitivity of elastin stains (van Gieson's and orcein methods) with 2 smooth muscle markers (h-caldesmon and desmin) in gastric, pancreatic, and colorectal adenocarcinoma specimens. We used 27 (29.3%) gastric, 35 (38.0%) pancreatic, and 30 (32.6%) colorectal resection specimens. We applied a provisional classification of vessel invasion patterns: type A, a focus with a nearby artery unaccompanied by a vein; type T, a focus at the invasive front without an unaccompanied artery; and type X, foci that only appeared by any of the 4 stains used. There were 369 foci. The smooth muscle markers were more sensitive than the elastin stains, and h-caldesmon more sensitive than desmin, in all types. Among the 139 type A foci, 33 (23.7%) were positive by desmin and h-caldesmon, whereas the elastin stains were not ( P = .001). h-Caldesmon was the only positive marker in 11 (7.9%; P = .011). Among the 78 type T foci, 21 (26.9%) were positive by desmin and h-caldesmon, when both elastin stains were negative ( P = .000). In 16 (20.5%) foci, h-caldesmon was the only positive marker ( P = .002). Among 152 type X foci, 91 (59.9%) were positive by all markers, 26 (17.1%) by both desmin and h-caldesmon, and 9 (5.9%) by only the 2 elastin stains ( P = .001). We recommend these stains for suspect foci in gastric, pancreatic, and colorectal adenocarcinoma specimens. They might highlight both predictable and unpredictable foci.

  2. Pancreatic cancer clinical trials and accrual in the United States.

    Science.gov (United States)

    Hoos, William A; James, Porsha M; Rahib, Lola; Talley, Anitra W; Fleshman, Julie M; Matrisian, Lynn M

    2013-09-20

    Pancreatic cancer clinical trials open in the United States and their accrual were examined to identify opportunities to accelerate progress in the treatment of pancreatic cancer. Pancreatic cancer-specific clinical trials open in the United States in the years 2011 and 2012 were obtained from the Pancreatic Cancer Action Network database. Accrual information was obtained from trial sponsors. The portfolio of pancreatic cancer clinical trials identified by type (adenocarcinoma or neuroendocrine), phase, disease stage, and treatment approach is reported. More than half of trials for patients with pancreatic ductal adenocarcinoma applied biologic insights to new therapeutic approaches, and 38% focused on optimization of radiation or chemotherapy delivery or regimens. In 2011, pancreatic cancer trials required total enrollment of 11,786 patients. Actual accrual to 93.2% of trials was 1,804 patients, an estimated 4.57% of the patients with pancreatic cancer alive in that year. The greatest need was for patients with resectable cancer. Trials open in 2011 enrolled an average of 15% of their total target accrual. Physician recommendations greatly influenced patients' decision to enroll or not enroll onto a clinical trial. Matching to a clinical trial within a 50-mile radius and identifying trials for recurrent/refractory disease were documented as challenges for patient accrual. Overall trial enrollment indicates that pancreatic cancer trials open in 2011 would require 6.7 years on average to complete accrual. These results suggest that harmonizing patient supply and demand for clinical trials is required to accelerate progress toward improving survival in pancreatic cancer.

  3. Diffusion-weighted MR imaging of pancreatic cancer: A comparison of mono-exponential, bi-exponential and non-Gaussian kurtosis models.

    Science.gov (United States)

    Kartalis, Nikolaos; Manikis, Georgios C; Loizou, Louiza; Albiin, Nils; Zöllner, Frank G; Del Chiaro, Marco; Marias, Kostas; Papanikolaou, Nikolaos

    2016-01-01

    To compare two Gaussian diffusion-weighted MRI (DWI) models including mono-exponential and bi-exponential, with the non-Gaussian kurtosis model in patients with pancreatic ductal adenocarcinoma. After written informed consent, 15 consecutive patients with pancreatic ductal adenocarcinoma underwent free-breathing DWI (1.5T, b-values: 0, 50, 150, 200, 300, 600 and 1000 s/mm 2 ). Mean values of DWI-derived metrics ADC, D, D*, f, K and D K were calculated from multiple regions of interest in all tumours and non-tumorous parenchyma and compared. Area under the curve was determined for all metrics. Mean ADC and D K showed significant differences between tumours and non-tumorous parenchyma (both P  < 0.001). Area under the curve for ADC, D, D*, f, K, and D K were 0.77, 0.52, 0.53, 0.62, 0.42, and 0.84, respectively. ADC and D K could differentiate tumours from non-tumorous parenchyma with the latter showing a higher diagnostic accuracy. Correction for kurtosis effects has the potential to increase the diagnostic accuracy of DWI in patients with pancreatic ductal adenocarcinoma.

  4. Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bournet, Barbara [Department of Gastroenterology, University Hospital Center Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9 (France); INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Pointreau, Adeline; Delpu, Yannick; Selves, Janick; Torrisani, Jerome [INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Buscail, Louis, E-mail: buscail.l@chu-toulouse.fr [Department of Gastroenterology, University Hospital Center Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9 (France); INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Cordelier, Pierre [INSERM U1037, University Hospital Center Rangueil, Toulouse (France)

    2011-02-24

    Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer.

  5. Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Bournet, Barbara; Pointreau, Adeline; Delpu, Yannick; Selves, Janick; Torrisani, Jerome; Buscail, Louis; Cordelier, Pierre

    2011-01-01

    Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer

  6. Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant

    Directory of Open Access Journals (Sweden)

    Jonathan R. Aspe

    2014-02-01

    Full Text Available Background: Current therapeutic options for advanced pancreatic cancer have been largely disappointing with modest results at best, and though adjuvant therapy remains controversial, most remain in agreement that Gemcitabine should stand as part of any combination study. The inhibitor of apoptosis (IAP protein Survivin is a key factor in maintaining apoptosis resistance, and its dominant-negative mutant (Survivin-T34A has been shown to block Survivin, inducing caspase activation and apoptosis. Methods: In this study, exosomes, collected from a melanoma cell line built to harbor a tetracycline-regulated Survivin-T34A, were plated on the pancreatic adenocarcinoma (MIA PaCa-2 cell line. Evaluation of the presence of Survivin-T34A in these exosomes followed by their ability to induce Gemcitabine-potentiative cell killing was the objective of this work. Results: Here we show that exosomes collected in the absence of tetracycline (tet-off from the engineered melanoma cell do contain Survivin-T34A and when used alone or in combination with Gemcitabine, induced a significant increase in apoptotic cell death when compared to Gemcitabine alone on a variety of pancreatic cancer cell lines. Conclusion: This exosomes/Survivin-T34A study shows that a new delivery method for anticancer proteins within the cancer microenvironment may prove useful in targeting cancers of the pancreas.

  7. Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

    NARCIS (Netherlands)

    Kuhlmann, K.F.D.; Geer, M.A. van; Bakker, C.T.; Dekker, J.E.M.; Havenga, M.J.E.; Oude Elferink, R.P.J.; Gouma, D.J.; Bosma, P.J.; Wesseling, J.G.

    2009-01-01

    Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved

  8. Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2015-03-01

    Full Text Available Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7 ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the MatrigelTM-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment.

  9. Single-source dual-energy spectral multidetector CT of pancreatic adenocarcinoma: Optimization of energy level viewing significantly increases lesion contrast

    International Nuclear Information System (INIS)

    Patel, B.N.; Thomas, J.V.; Lockhart, M.E.; Berland, L.L.; Morgan, D.E.

    2013-01-01

    Aim: To evaluate lesion contrast in pancreatic adenocarcinoma patients using spectral multidetector computed tomography (MDCT) analysis. Materials and methods: The present institutional review board-approved, Health Insurance Portability and Accountability Act of 1996 (HIPAA)-compliant retrospective study evaluated 64 consecutive adults with pancreatic adenocarcinoma examined using a standardized, multiphasic protocol on a single-source, dual-energy MDCT system. Pancreatic phase images (35 s) were acquired in dual-energy mode; unenhanced and portal venous phases used standard MDCT. Lesion contrast was evaluated on an independent workstation using dual-energy analysis software, comparing tumour to non-tumoural pancreas attenuation (HU) differences and tumour diameter at three energy levels: 70 keV; individual subject-optimized viewing energy level (based on the maximum contrast-to-noise ratio, CNR); and 45 keV. The image noise was measured for the same three energies. Differences in lesion contrast, diameter, and noise between the different energy levels were analysed using analysis of variance (ANOVA). Quantitative differences in contrast gain between 70 keV and CNR-optimized viewing energies, and between CNR-optimized and 45 keV were compared using the paired t-test. Results: Thirty-four women and 30 men (mean age 68 years) had a mean tumour diameter of 3.6 cm. The median optimized energy level was 50 keV (range 40–77). The mean ± SD lesion contrast values (non-tumoural pancreas – tumour attenuation) were: 57 ± 29, 115 ± 70, and 146 ± 74 HU (p = 0.0005); the lengths of the tumours were: 3.6, 3.3, and 3.1 cm, respectively (p = 0.026); and the contrast to noise ratios were: 24 ± 7, 39 ± 12, and 59 ± 17 (p = 0.0005) for 70 keV, the optimized energy level, and 45 keV, respectively. For individuals, the mean ± SD contrast gain from 70 keV to the optimized energy level was 59 ± 45 HU; and the mean ± SD contrast gain from the optimized energy level to 45 ke

  10. Single-source dual-energy spectral multidetector CT of pancreatic adenocarcinoma: optimization of energy level viewing significantly increases lesion contrast.

    Science.gov (United States)

    Patel, B N; Thomas, J V; Lockhart, M E; Berland, L L; Morgan, D E

    2013-02-01

    To evaluate lesion contrast in pancreatic adenocarcinoma patients using spectral multidetector computed tomography (MDCT) analysis. The present institutional review board-approved, Health Insurance Portability and Accountability Act of 1996 (HIPAA)-compliant retrospective study evaluated 64 consecutive adults with pancreatic adenocarcinoma examined using a standardized, multiphasic protocol on a single-source, dual-energy MDCT system. Pancreatic phase images (35 s) were acquired in dual-energy mode; unenhanced and portal venous phases used standard MDCT. Lesion contrast was evaluated on an independent workstation using dual-energy analysis software, comparing tumour to non-tumoural pancreas attenuation (HU) differences and tumour diameter at three energy levels: 70 keV; individual subject-optimized viewing energy level (based on the maximum contrast-to-noise ratio, CNR); and 45 keV. The image noise was measured for the same three energies. Differences in lesion contrast, diameter, and noise between the different energy levels were analysed using analysis of variance (ANOVA). Quantitative differences in contrast gain between 70 keV and CNR-optimized viewing energies, and between CNR-optimized and 45 keV were compared using the paired t-test. Thirty-four women and 30 men (mean age 68 years) had a mean tumour diameter of 3.6 cm. The median optimized energy level was 50 keV (range 40-77). The mean ± SD lesion contrast values (non-tumoural pancreas - tumour attenuation) were: 57 ± 29, 115 ± 70, and 146 ± 74 HU (p = 0.0005); the lengths of the tumours were: 3.6, 3.3, and 3.1 cm, respectively (p = 0.026); and the contrast to noise ratios were: 24 ± 7, 39 ± 12, and 59 ± 17 (p = 0.0005) for 70 keV, the optimized energy level, and 45 keV, respectively. For individuals, the mean ± SD contrast gain from 70 keV to the optimized energy level was 59 ± 45 HU; and the mean ± SD contrast gain from the optimized energy level to 45 keV was 31 ± 25 HU (p = 0

  11. Mixed acinar-neuroendocrine-ductal carcinoma of the pancreas: a tale of three lineages.

    Science.gov (United States)

    Anderson, Mark J; Kwong, Christina A; Atieh, Mohammed; Pappas, Sam G

    2016-06-02

    Most pancreatic cancers arise from a single cell type, although mixed pancreatic carcinomas represent a rare exception. The rarity of these aggressive malignancies and the limitations of fine-needle aspiration (FNA) pose significant barriers to diagnosis and appropriate management. We report a case of a 54-year-old man presenting with abdominal pain, jaundice and a hypodense lesion within the uncinate process on CT. FNA suggested poorly differentiated adenocarcinoma, which was subsequently resected via pancreaticoduodenectomy. Pathological analysis yielded diagnosis of invasive mixed acinar-neuroendocrine-ductal pancreatic carcinoma. Given the rare and deadly nature of these tumours, clinicians must be aware of their pathophysiology and do practice with a high degree of clinical suspicion, when appropriate. Surgical resection and thorough pathological analysis with immunohistochemical staining and electron microscopy remain the standards of care for mixed pancreatic tumours without gross evidence of metastasis. Diligent characterisation of the presentation and histological findings associated with these neoplasms should continue in order to promote optimal diagnostic and therapeutic strategies. 2016 BMJ Publishing Group Ltd.

  12. Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β--emitting 177Lu in human pancreatic adenocarcinoma cells

    International Nuclear Information System (INIS)

    Nayak, Tapan K.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Prossnitz, Eric R.; Stabin, Michael G.; Atcher, Robert W.

    2007-01-01

    Introduction: Advance clinical cancer therapy studies of patients treated with somatostatin receptor (sstr)-targeted [DOTA 0 -Tyr 3 ]octreotide (DOTATOC) labeled with low-linear-energy-transfer (LET) β - -emitters have shown overall response rates in the range of 15-33%. In order to improve outcomes, we sought to compare the therapeutic effectiveness of sstr-targeted high-LET α-emitting 213 Bi to that of low-LET β - -emitting 177 Lu by determining relative biological effectiveness (RBE) using the external γ-beam of 137 Cs as reference radiation. Methods: Sstr-expressing human pancreatic adenocarcinoma Capan-2 cells and A549 control cells were used for this study. The effects of different radiation doses of 213 Bi and 177 Lu labeled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and sstr-targeted DOTATOC were investigated with a clonogenic cell survival assay. Apoptosis was measured using the Cell Death Detection ELISA PLUS 10x kit. Results: Using equimolar DOTATOC treatment with concurrent irradiation with a 137 Cs source as reference radiation, the calculated RBE of [ 213 Bi]DOTATOC was 3.4, as compared to 1.0 for [ 177 Lu]DOTATOC. As measured in terms of absorbance units, [ 213 Bi]DOTATOC caused a 2.3-fold-greater release of apoptosis-specific mononucleosomes and oligonucleosomes than [ 177 Lu]DOTATOC at the final treatment time of 96 h (P 213 Bi]DOTATOC is therapeutically more effective in decreasing survival than is [ 177 Lu]DOTATOC in human pancreatic adenocarcinoma cells due to its comparatively higher RBE

  13. Complete Response after Treatment with Neoadjuvant Chemoradiation with Prolonged Chemotherapy for Locally Advanced, Unresectable Adenocarcinoma of the Pancreas

    Directory of Open Access Journals (Sweden)

    Tiffany A. Pompa

    2017-01-01

    Full Text Available Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC, the National Comprehensive Cancer Network (NCCN suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2×3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles, intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.

  14. Positron emission tomography (PET) and pancreatic tumours

    International Nuclear Information System (INIS)

    Montravers, F.; Kerrou, K.; Grahek, D.; Gutman, F.; Beco, V. de; Talbot, J.N.

    2005-01-01

    Neoplasms of the pancreas may originate front both exocrine and endocrine cells but in 90% of the cases, they correspond to ductal adenocarcinomas. For adenocarcinomas, the major indication of FDG-PET corresponds to the pre-operative staging because unexpected distant metastases can be detected by FDG-PET in about 20 to 40% of the cases, which results in avoidance of unnecessary surgical procedures. FDG PET is also useful in evaluation of the treatment effect, monitoring after the operation and detection of recurrent pancreatic cancers. For the characterisation of the pancreatic tumour, the performance of FDG-PET is sometimes limited due to poor cellularity, hyperglycemia or inflammatory processes. especially for large tumours and is indicated only in cases of doubtful results of CT or MRI. For endocrine pancreatic tumours, FDG-PET is useful only in case of poorly-differentiated and aggressive tumours. F-DOPA PET can he useful, complementary to pentetreotide scintigraphy, in well-differentiated endocrine tumours. (authors)

  15. LASP-06: Drug Efficacy in a Three-Arm Survival Study in Kras/p53 Pancreatic Ductal Adenocarcinoma (PDAC) Mice | FNLCR

    Science.gov (United States)

    The Laboratory Animal Sciences Program will induce breed 50 KPC animals with the intent of generating a cohort of 40 animals with confirmed tumor-load matching the following enrollment criteria:female mice are considered eligible for enrollment

  16. N0/N1, PNL, or LNR? The effect of lymph node number on accurate survival prediction in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Valsangkar, Nakul P; Bush, Devon M; Michaelson, James S; Ferrone, Cristina R; Wargo, Jennifer A; Lillemoe, Keith D; Fernández-del Castillo, Carlos; Warshaw, Andrew L; Thayer, Sarah P

    2013-02-01

    We evaluated the prognostic accuracy of LN variables (N0/N1), numbers of positive lymph nodes (PLN), and lymph node ratio (LNR) in the context of the total number of examined lymph nodes (ELN). Patients from SEER and a single institution (MGH) were reviewed and survival analyses performed in subgroups based on numbers of ELN to calculate excess risk of death (hazard ratio, HR). In SEER and MGH, higher numbers of ELN improved the overall survival for N0 patients. The prognostic significance (N0/N1) and PLN were too variable as the importance of a single PLN depended on the total number of LN dissected. LNR consistently correlated with survival once a certain number of lymph nodes were dissected (≥13 in SEER and ≥17 in the MGH dataset). Better survival for N0 patients with increasing ELN likely represents improved staging. PLN have some predictive value but the ELN strongly influence their impact on survival, suggesting the need for a ratio-based classification. LNR strongly correlates with outcome provided that a certain number of lymph nodes is evaluated, suggesting that the prognostic accuracy of any LN variable depends on the total number of ELN.

  17. SOX9 regulates ERBB signalling in pancreatic cancer development.

    Science.gov (United States)

    Grimont, Adrien; Pinho, Andreia V; Cowley, Mark J; Augereau, Cécile; Mawson, Amanda; Giry-Laterrière, Marc; Van den Steen, Géraldine; Waddell, Nicola; Pajic, Marina; Sempoux, Christine; Wu, Jianmin; Grimmond, Sean M; Biankin, Andrew V; Lemaigre, Frédéric P; Rooman, Ilse; Jacquemin, Patrick

    2015-11-01

    The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  18. Validation of full-field optical coherence tomography in distinguishing malignant and benign tissue in resected pancreatic cancer specimens.

    Directory of Open Access Journals (Sweden)

    Labrinus van Manen

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States. The minority of patients can undergo curative-intended surgical therapy due to progressive disease stage at time of diagnosis. Nonetheless, tumor involvement of surgical margins is seen in up to 70% of resections, being a strong negative prognostic factor. Real-time intraoperative imaging modalities may aid surgeons to obtain tumor-free resection margins. Full-field optical coherence tomography (FF-OCT is a promising diagnostic tool using high-resolution white-light interference microscopy without tissue processing. Therefore, we composed an atlas of FF-OCT images of malignant and benign pancreatic tissue, and investigated the accuracy with which the pathologists could distinguish these.One hundred FF-OCT images were collected from specimens of 29 patients who underwent pancreatic resection for various indications between 2014 and 2016. One experienced gastrointestinal pathologist and one pathologist in training scored independently the FF-OCT images as malignant or benign blinded to the final pathology conclusion. Results were compared to those obtained with standard hematoxylin and eosin (H&E slides.Overall, combined test characteristics of both pathologists showed a sensitivity of 72%, specificity of 74%, positive predictive value of 69%, negative predictive value of 79% and an overall accuracy of 73%. In the subset of pancreatic ductal adenocarcinoma patients, 97% of the FF-OCT images (n = 35 were interpreted as tumor by at least one pathologist. Moreover, normal pancreatic tissue was recognised in all cases by at least one pathologist. However, atrophy and fibrosis, serous cystadenoma and neuroendocrine tumors were more often wrongly scored, in 63%, 100% and 25% respectively.FF-OCT could distinguish normal pancreatic tissue from pathologic pancreatic tissue in both processed as non-processed specimens using architectural features. The accuracy in

  19. Genomic analyses identify molecular subtypes of pancreatic cancer.

    Science.gov (United States)

    Bailey, Peter; Chang, David K; Nones, Katia; Johns, Amber L; Patch, Ann-Marie; Gingras, Marie-Claude; Miller, David K; Christ, Angelika N; Bruxner, Tim J C; Quinn, Michael C; Nourse, Craig; Murtaugh, L Charles; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourbakhsh, Ehsan; Wani, Shivangi; Fink, Lynn; Holmes, Oliver; Chin, Venessa; Anderson, Matthew J; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Xu, Qinying; Wilson, Peter J; Cloonan, Nicole; Kassahn, Karin S; Taylor, Darrin; Quek, Kelly; Robertson, Alan; Pantano, Lorena; Mincarelli, Laura; Sanchez, Luis N; Evers, Lisa; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chantrill, Lorraine A; Mawson, Amanda; Humphris, Jeremy; Chou, Angela; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Moran-Jones, Kim; Jamieson, Nigel B; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Grützmann, Robert; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Rusev, Borislav; Capelli, Paola; Salvia, Roberto; Tortora, Giampaolo; Mukhopadhyay, Debabrata; Petersen, Gloria M; Munzy, Donna M; Fisher, William E; Karim, Saadia A; Eshleman, James R; Hruban, Ralph H; Pilarsky, Christian; Morton, Jennifer P; Sansom, Owen J; Scarpa, Aldo; Musgrove, Elizabeth A; Bailey, Ulla-Maja Hagbo; Hofmann, Oliver; Sutherland, Robert L; Wheeler, David A; Gill, Anthony J; Gibbs, Richard A; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M

    2016-03-03

    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.

  20. The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

    Directory of Open Access Journals (Sweden)

    Sunjida Ahmed

    2017-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target.

  1. Clinical Value of Dual-energy CT in Detection of Pancreatic Adenocarcinoma: Investigation of the Best Pancreatic Tumor Contrast to Noise Ratio.

    Science.gov (United States)

    He, Yong-Lan; Zhang, Da-Ming; Xue, Hua-Dan; Jin, Zheng-Yu

    2013-01-01

    Objective To quantitatively compare and determine the best pancreatic tumor contrast to noise ratio (CNR) in different dual-energy derived datasets. Methods In this retrospective, single center study, 16 patients (9 male, 7 female, average age 59.4±13.2 years) with pathologically diagnosed pancreatic cancer were enrolled. All patients received an abdominal scan using a dual source CT scanner 7 to 31 days before biopsy or surgery. After injection of iodine contrast agent, arterial and pancreatic parenchyma phase were scanned consequently, using a dual-energy scan mode (100 kVp/230 mAs and Sn 140 kVp/178 mAs) in the pancreatic parenchyma phase. A series of derived dual-energy datasets were evaluated including non-liner blending (non-linear blending width 0-500 HU; blending center -500 to 500 HU), mono-energetic (40-190 keV), 100 kVp and 140 kVp. On each datasets, mean CT values of the pancreatic parenchyma and tumor, as well as standard deviation CT values of subcutaneous fat and psoas muscle were measured. Regions of interest of cutaneous fat and major psoas muscle of 100 kVp and 140 kVp images were calculated. Best CNR of subcutaneous fat (CNRF) and CNR of the major psoas muscle (CNRM) of non-liner blending and mono-energetic datasets were calculated with the optimal mono-energetic keV setting and the optimal blending center/width setting for the best CNR. One Way ANOVA test was used for comparison of best CNR between different dual-energy derived datasets. Results The best CNRF (4.48±1.29) was obtained from the non-liner blending datasets at blending center -16.6±103.9 HU and blending width 12.3±10.6 HU. The best CNRF (3.28±0.97) was obtained from the mono-energetic datasets at 73.3±4.3 keV. CNRF in the 100 kVp and 140 kVp were 3.02±0.91 and 1.56±0.56 respectively. Using fat as the noise background, all of these images series showed significant differences (Pbest CNRF of mono-energetic image sets vs. CNRF of 100 kVp image (P=0.460). Similar results were

  2. Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

    Science.gov (United States)

    Lakatos, Gábor; Balázs, Anita; Kui, Balázs; Gódi, Szilárd; Szücs, Ákos; Szentesi, Andrea; Szentkereszty, Zsolt; Szmola, Richárd; Kelemen, Dezső; Papp, Róbert; Vincze, Áron; Czimmer, József; Pár, Gabriella; Bajor, Judit; Szabó, Imre; Izbéki, Ferenc; Halász, Adrienn; Leindler, László; Farkas, Gyula; Takács, Tamás; Czakó, László; Szepes, Zoltán; Hegyi, Péter; Kahán, Zsuzsanna

    2016-06-01

    Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.

  3. Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling.

    Science.gov (United States)

    Wen, Shi; Zhan, Bohan; Feng, Jianghua; Hu, Weize; Lin, Xianchao; Bai, Jianxi; Huang, Heguang

    2017-11-02

    The differentiation of pancreatic ductal adenocarcinoma (PDAC) could be associated with prognosis and may influence the choices of clinical management. No applicable methods could reliably predict the tumor differentiation preoperatively. Thus, the aim of this study was to compare the metabonomic profiling of pancreatic ductal adenocarcinoma with different differentiations and assess the feasibility of predicting tumor differentiations through metabonomic strategy based on nuclear magnetic resonance spectroscopy. By implanting pancreatic cancer cell strains Panc-1, Bxpc-3 and SW1990 in nude mice in situ, we successfully established the orthotopic xenograft models of PDAC with different differentiations. The metabonomic profiling of serum from different PDAC was achieved and analyzed by using 1 H nuclear magnetic resonance (NMR) spectroscopy combined with the multivariate statistical analysis. Then, the differential metabolites acquired were used for enrichment analysis of metabolic pathways to get a deep insight. An obvious metabonomic difference was demonstrated between all groups and the pattern recognition models were established successfully. The higher concentrations of amino acids, glycolytic and glutaminolytic participators in SW1990 and choline-contain metabolites in Panc-1 relative to other PDAC cells were demonstrated, which may be served as potential indicators for tumor differentiation. The metabolic pathways and differential metabolites identified in current study may be associated with specific pathways such as serine-glycine-one-carbon and glutaminolytic pathways, which can regulate tumorous proliferation and epigenetic regulation. The NMR-based metabonomic strategy may be served as a non-invasive detection method for predicting tumor differentiation preoperatively.

  4. CT findings of pancreatic carcinoma. Evaluation with the combined method of early enhancement CT and high dose enhancement CT

    International Nuclear Information System (INIS)

    Itoh, Shigeki; Endo, Tokiko; Isomura, Takayuki; Ishigaki, Takeo; Ikeda, Mitsuru; Senda, Kouhei.

    1995-01-01

    Computed tomographic (CT) findings of pancreatic ductal adenocarcinoma were studied with the combined method of early enhancement CT and high dose enhancement CT in 72 carcinomas. Common Findings were change in pancreatic contour, abnormal attenuation in a tumor and dilatation of the main pancreatic duct. The incidence of abnormal attenuation and dilatation of the main pancreatic duct and bile duct was constant regardless of tumor size. The finding of hypoattenuation at early enhancement CT was most useful for demonstrating a carcinoma. However, this finding was negative in ten cases, five of which showed inhomogenous hyperattenuation at high dose enhancement CT. The detection of change in pancreatic contour and dilatation of the main pancreatic duct was most frequent at high dose enhancement CT. The finding of change in pancreatic contour and/or abnormal attenuation in a tumor could be detected in 47 cases at plain CT, 66 at early enhancement CT and 65 at high dose enhancement CT. Since the four cases in which neither finding was detected by any CT method showed dilatated main pancreatic duct, there was no case without abnormal CT findings. This combined CT method will be a reliable diagnostic technique in the imaging of pancreatic carcinoma. (author)

  5. Pancreatic cancer accompanied by a moderate-sized pseudocyst with extrapancreatic growth

    International Nuclear Information System (INIS)

    Ohkura, Yu; Sasaki, Kazunari; Matsuda, Masamichi; Hashimoto, Masaji; Fujii, Takeshi; Watanabe, Goro

    2015-01-01

    Pancreatic cancer accompanied by a moderate-sized pseudocyst with extrapancreatic growth is extremely rare. Diagnosis of pancreatic cancer on preoperative imaging is difficult when the pancreatic parenchyma is compressed by a pseudocyst and becomes unclear. Despite advances in imaging techniques, accurate preoperative diagnosis of cystic lesions of the pancreas remains difficult. In this case, it was challenging to diagnose pancreatic cancer preoperatively as we could not accurately assess the pancreatic parenchyma, which had been compressed by a moderate-sized cystic lesion with extrapancreatic growth. A 63-year-old woman underwent investigations for epigastric abdominal pain. She had no history of pancreatitis. Although we suspected pancreatic ductal carcinoma with a pancreatic cyst, there was no mass lesion or low-density area suggestive of pancreatic cancer. We did not immediately suspect pancreatic cancer, as development of a moderate-sized cyst with extrapancreatic growth is extremely rare and known tumor markers were not elevated. Therefore, we initially suspected that a massive benign cyst (mucinous cyst neoplasm, serous cyst neoplasm, or intraductal papillary mucinous neoplasm) resulted in stenosis of the main pancreatic duct. We were unable to reach a definitive diagnosis prior to the operation. We had planned a pancreaticoduodenectomy to reach a definitive diagnosis. However, we could not remove the tumor because of significant invasion of the surrounding tissue (portal vein, superior mesenteric vein, etc.). The fluid content of the cyst was serous, and aspiration cytology from the pancreatic cyst was Class III (no malignancy), but the surrounding white connective tissue samples were positive for pancreatic adenocarcinoma on pathological examination during surgery. We repeated imaging (CT, MRI, endoscopic ultrasound, etc.) postoperatively, but there were neither mass lesions nor a low-density area suggestive of pancreatic cancer. In retrospect, we think

  6. Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer.

    Science.gov (United States)

    Gillard, Marc; Lack, Justin; Pontier, Andrea; Gandla, Divya; Hatcher, David; Sowalsky, Adam G; Rodriguez-Nieves, Jose; Vander Griend, Donald; Paner, Gladell; VanderWeele, David

    2017-12-08

    Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci

  7. A Contemporary Review of the Treatment Landscape and the Role of Predictive and Prognostic Biomarkers in Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Irene S. Yu

    2018-01-01

    Full Text Available Pancreatic cancer continues to represent one of the leading causes of cancer-related morbidity and mortality in the developed world. Over the past decade, novel systemic therapy combination regimens have contributed to clinically meaningful and statistically significant improvements in overall survival as compared to conventional monotherapy. However, the prognosis for most patients remains guarded secondary to the advanced stages of disease at presentation. There is growing consensus that outcomes can be further optimized with the use of predictive and prognostic biomarkers whereby the former can be enriching for patients who would benefit from therapies and the latter can inform decision-making regarding the need and timing of advanced care planning. One of the challenges of current biomarkers is the lack of standardization across clinical practices such that comparability between jurisdictions can be difficult or even impossible. This inconsistency can impede widespread implementation of their use. In this review article, we provide a comprehensive overview of the contemporary treatment options for pancreatic cancer and we offer some insights into the existing landscape and future directions of biomarker development for this disease.

  8. Obstructed pancreaticojejunostomy partly explains exocrine insufficiency after pancreatic head resection.

    Science.gov (United States)

    Nordback, Isto; Parviainen, Mickael; Piironen, Anneli; Räty, Sari; Sand, Juhani

    2007-02-01

    The majority of patients with long-term survival after pancreatic head resection suffer from pancreatic exocrine insufficiency. The objective of this study was to investigate whether this is due to glandular malfunction or obstructed pancreaticojejunal anastomosis. Twenty-six patients (10 M, 16 F, mean age 61 years, range 34-81 years) were re-examined a median of 52 months (range 3-76 months) after pancreatic head resection and end-to-end invaginated pancreaticojejunostomy. Pancreatic exocrine function was measured by fecal elastase-1 assay. The size of the pancreatic remnant, glandular secretion and the flow through the anastomosis were analyzed with secretin-stimulated dynamic magnetic resonance pancreatography (D-MRP). All patients had pancreatic exocrine insufficiency, 24 (92%) of them having severe insufficiency. Eighteen patients (69%) reported moderate to severe diarrhea. Lowest fecal elastase-1 concentrations were associated with the initial diagnosis of chronic pancreatitis or ductal adenocarcinoma, suggesting preoperative primary or secondary chronic pancreatitis as important determinants. The size of the remnant gland did not correlate with the fecal elastase-1 concentrations. D-MRP failed in three patients. Severe glandular malfunctions were found in 7 (30%) of the 23 successful D-MRP examinations. The anastomosis was totally obstructed in 5 patients (22%) or partially obstructed in 6 (26%) but remained perfectly open in 5 patients (22%). The five patients with perfect anastomoses had the highest measured median fecal elastase-1 activity. Although late diarrhea and pancreatic exocrine insufficiency may be partly induced already by the disease treated with resection, at least half may be explained by obstructed anastomosis. To obtain better late functional results, improvements may be required in the surgical techniques.

  9. Pancreatic duct abnormalities in focal autoimmune pancreatitis: MR/MRCP imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Negrelli, Riccardo; Manfredi, Riccardo; Pedrinolla, Beatrice; Boninsegna, Enrico; Ventriglia, Anna; Mehrabi, Sara; Pozzi Mucelli, Roberto [G.B. Rossi University Hospital, University of Verona, Department of Radiology, Verona (Italy); Frulloni, Luca [Universita di Verona, Department of Gastroenterology, Policlinico G.B. Rossi, Verona (Italy)

    2014-08-09

    To evaluate the magnetic resonance (MR) imaging-MR cholangiopancreatographic (MRCP) findings of focal forms of autoimmune pancreatitis (AIP) to describe ductal involvement at diagnosis. MR examinations of 123 patients affected by AIP were analysed. We included 26 patients who satisfied International Consensus Diagnostic Criteria and were suffering from focal AIP. Image analysis included: site of parenchymal enlargement, main pancreatic duct (MPD) diameter, MPD stenosis, stricture length, presence of upstream dilation within the stricture, signal intensity, and pancreatic enhancement. Signal intensity abnormalities were localized in the head in 10/26 (38.5 %) and in the body-tail in 16/26 (61.5 %) patients. MRCP showed a single MPD stenosis in 12/26 (46.1 %) and multiple MPD stenosis in 14/26 (53.8 %) patients, without a dilation of the upstream MPD (mean: 3.83 mm). Lesions showed hypointensity on T1-weighted images in all patients, and hyperintensity on T2-weighted images in 22/26 (84.6 %) patients. The affected parenchyma was hypovascular during the arterial phase in 25/26 (96.2 %) patients with contrast retention. MR-MRCP are effective techniques for the diagnosis of AIP showing the loss of the physiological lobulation and the typical contrastographic appearance. The presence of multiple, long stenoses without an upstream MPD dilation at MRCP suggests the diagnosis of AIP, and can be useful in differential diagnosis of pancreatic adenocarcinoma. (orig.)

  10. TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2012-01-01

    Full Text Available Transient receptor potential (TRP ion channels are essential for normal functions and health by acting as molecular sensors and transducing various stimuli into cellular and physiological responses. Growing evidence has revealed that TRP ion channels play important roles in a wide range of human diseases, including malignancies. In light of recent discoveries, it has been found that TRP melastatin-subfamily members, TRPM7 and TRPM8, are required for normal and cancerous development of exocrine pancreas. We are currently investigating the mechanisms which mediate the functional roles of TRPM7 and TRPM8 and attempting to develop these ion channels as clinical biomarkers and therapeutic targets for achieving the goal of personalized therapy in pancreatic cancer.

  11. Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, Kapil, E-mail: kmehta@mdanderson.org; Han, Amy [Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 (United States); Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030 (United States)

    2011-02-25

    Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer.

  12. Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications.

    Science.gov (United States)

    Reid, Michelle D; Saka, Burcu; Balci, Serdar; Goldblum, Andrew S; Adsay, N Volkan

    2014-02-01

    To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation. Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis. Mutations in KRAS, P16/CDKN2A, TP53, and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics. When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

  13. Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor.

    Science.gov (United States)

    Eguchi, Daiki; Ikenaga, Naoki; Ohuchida, Kenoki; Kozono, Shingo; Cui, Lin; Fujiwara, Kenji; Fujino, Minoru; Ohtsuka, Takao; Mizumoto, Kazuhiro; Tanaka, Masao

    2013-05-01

    Pancreatic cancer (PC), a hypovascular tumor, thrives under hypoxic conditions. Pancreatic stellate cells (PSCs) promote PC progression by secreting soluble factors, but their functions in hypoxia are poorly understood. This study aimed to clarify the effects of hypoxic conditions on the interaction between PC cells and PSCs. We isolated human PSCs from fresh pancreatic ductal adenocarcinomas and analyzed functional differences in PSCs between normoxia (21% O2) and hypoxia (1% O2), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule-connective tissue growth factor (CTGF)-in PSCs under hypoxic conditions, using RNA interference techniques. Conditioned media from hypoxic PSCs enhanced PC cell invasiveness more intensely than that from normoxic PSCs (P cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. KRAS Mutation and Epithelial-Macrophage Interplay in Pancreatic Neoplastic Transformation.

    Science.gov (United States)

    Bishehsari, Faraz; Zhang, Lijuan; Barlass, Usman; Preite, Nailliw; Turturro, Sanja; Najor, Matthew S; Shetuni, Brandon B; Zayas, Janet P; Mahdavinia, Mahboobeh; Abukhdeir, Abde M; Keshavarzian, Ali

    2018-05-14

    Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased i) ductal to acinar gene expression ratios, ii) epithelial cells proliferation, and iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a pro-tumorigenic phenotype in macrophages. Altered macrophages decreased epithelial Pigment Epithelial Derived Factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) as well as in our human PDA specimens. Epithelium-macrophage cross talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a pro-tumorigenic phenotype in macrophages, in turn augmenting neoplastic growth. This article is protected by copyright. All rights reserved. © 2018 UICC.

  15. Preoperative Serum Thymidine Kinase Activity as Novel Monitoring, Prognostic, and Predictive Biomarker in Pancreatic Cancer.

    Science.gov (United States)

    Felix, Klaus; Hinz, Ulf; Dobiasch, Sophie; Hackert, Thilo; Bergmann, Frank; Neumüller, Magnus; Gronowitz, Simon; Bergqvist, Mattias; Strobel, Oliver

    2018-01-01

    The aim of the study was to investigate serum thymidine kinase 1 (S-TK) activity as a diagnostic and prognostic marker for patients with pancreatic ductal adenocarcinoma (PDAC). Using the sensitive TK activity assay DiviTum, preoperative serum samples from 404 PDAC, 28 chronic pancreatitis, and 25 autoimmune pancreatitis patients and 83 healthy volunteers were analyzed. The preoperative S-TK activities of 54 PDAC patients who received neoadjuvant therapy (nTx) were also compared with those of 258 PDAC patients who did not receive nTx. The preoperative S-TK activities of PDAC patients were significantly higher and discriminatory from autoimmune and chronic pancreatitis patients and control groups. The S-TK activity in PDAC patients was associated with overall survival. Patients with S-TK activity of less than 80 Du (DiviTum units)/L demonstrated median survival of 20.3 months with an estimated 18.0% 5-year survival rate; for S-TK activity of 80 Du/L or greater, median survival was 15.1 months with a 6.8% 5-year survival rate. For early-stage PDAC, these differences were even more pronounced. The S-TK activity in the nTx group was significantly higher than that in the group not receiving nTx. Pancreatic ductal adenocarcinomas reveal a significant increase in S-TK activity, which is associated with overall survival, especially in early tumor stages. Serum thymidine kinase 1 activity may be a useful parameter for monitoring nTx efficacy.

  16. SU-E-J-154: Image Quality Assessment of Contrast-Enhanced 4D-CT for Pancreatic Adenocarcinoma in Radiotherapy Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Choi, W; Xue, M; Patel, K; Regine, W; Wang, J; D’Souza, W; Lu, W [University of Maryland School of Medicine, Baltimore, MD (United States); Kang, M [University of Maryland School of Medicine, Baltimore, MD (United States); Yeungnam University Medical Center, Daegu, Daegu (Korea, Republic of); Klahr, P [Philips Healthcare, Highland Heights, OH (United States)

    2015-06-15

    Purpose: This study presents quantitative and qualitative assessment of the image qualities in contrast-enhanced (CE) 3D-CT, 4D-CT and CE 4D-CT to identify feasibility for replacing the clinical standard simulation with a single CE 4D-CT for pancreatic adenocarcinoma (PDA) in radiotherapy simulation. Methods: Ten PDA patients were enrolled and underwent three CT scans: a clinical standard pair of CE 3D-CT immediately followed by a 4D-CT, and a CE 4D-CT one week later. Physicians qualitatively evaluated the general image quality and regional vessel definitions and gave a score from 1 to 5. Next, physicians delineated the contours of the tumor (T) and the normal pancreatic parenchyma (P) on the three CTs (CE 3D-CT, 50% phase for 4D-CT and CE 4D-CT), then high density areas were automatically removed by thresholding at 500 HU and morphological operations. The pancreatic tumor contrast-to-noise ratio (CNR), signal-tonoise ratio (SNR) and conspicuity (C, absolute difference of mean enhancement levels in P and T) were computed to quantitatively assess image quality. The Wilcoxon rank sum test was used to compare these quantities. Results: In qualitative evaluations, CE 3D-CT and CE 4D-CT scored equivalently (4.4±0.4 and 4.3±0.4) and both were significantly better than 4D-CT (3.1±0.6). In quantitative evaluations, the C values were higher in CE 4D-CT (28±19 HU, p=0.19 and 0.17) than the clinical standard pair of CE 3D-CT and 4D-CT (17±12 and 16±17 HU, p=0.65). In CE 3D-CT and CE 4D-CT, mean CNR (1.8±1.4 and 1.8±1.7, p=0.94) and mean SNR (5.8±2.6 and 5.5±3.2, p=0.71) both were higher than 4D-CT (CNR: 1.1±1.3, p<0.3; SNR: 3.3±2.1, p<0.1). The absolute enhancement levels for T and P were higher in CE 4D-CT (87, 82 HU) than in CE 3D-CT (60, 56) and 4DCT (53, 70). Conclusions: The individually optimized CE 4D-CT is feasible and achieved comparable image qualities to the clinical standard simulation. This study was supported in part by Philips Healthcare.

  17. Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression

    International Nuclear Information System (INIS)

    Xu, Xiulong; Rao, Geetha S; Groh, Veronika; Spies, Thomas; Gattuso, Paolo; Kaufman, Howard L; Plate, Janet; Prinz, Richard A

    2011-01-01

    Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51 Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively. Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production

  18. Major histocompatibility complex class I-related chain A/B (MICA/B expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression

    Directory of Open Access Journals (Sweden)

    Kaufman Howard L

    2011-05-01

    Full Text Available Abstract Background Major histocompatibility complex class I-related chain A and B (MICA/B are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. Methods Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC and ELISA, respectively. Results Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68% pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. Conclusions The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.

  19. Studies of diagnostic imaging and surgical treatment on patients with pancreatic cysts

    International Nuclear Information System (INIS)

    Koh, Koichi; Yamamoto, Masahiro; Okumura, Shuichi

    1987-01-01

    A retrospective study of 36 cases of pancreatic cyst treated during the recent 13 years was performed from the aspects of imaging and treatment. Visualization of the internal structure by abdominal echography and CT was rare in inflammatory cysts, but frequent in neoplastic cysts. Differentiation between mucous and serous cystadenoma on the basis of properties was possible. Retrograde pancreatography, which disclosed the entire pancreatic ductal system, was important in determining surgical procedure. Angiography was effective for differentiating between benign and malignant cysts, even though some of the inflammatory cysts suggested malignant findings. The most frequent therapy in cases of inflammatory cyst was internal fistulization, with additional side-to-side pancreaticojejunostomy as a procedure for underlying chronic pancreatitis. Neoplastic cysts were resected in all cases, and the procedure for pancreatic cancer was modified for use in the cases of cystic adenocarcinoma. The remote postoperative results in the cases of inflammatory cyst were satisfactory: symptomatic improvement was found in 83.1 % of patients and occupational rehabilitation in 70.6 %. All of the three patients with cystic adenocarcinoma are well, including the one surviving a maximum period of 4 years and 10 months. (author)

  20. Studies of diagnostic imaging and surgical treatment on patients with pancreatic cysts

    Energy Technology Data Exchange (ETDEWEB)

    Koh, K.; Yamamoto, M.; Okumura, S.

    1987-04-01

    A retrospective study of 36 cases of pancreatic cyst treated during the recent 13 years was performed from the aspects of imaging and treatment. Visualization of the internal structure by abdominal echography and CT was rare in inflammatory cysts, but frequent in neoplastic cysts. Differentiation between mucous and serous cystadenoma on the basis of properties was possible. Retrograde pancreatography, which disclosed the entire pancreatic ductal system, was important in determining surgical procedure. Angiography was effective for differentiating between benign and malignant cysts, even though some of the inflammatory cysts suggested malignant findings. The most frequent therapy in cases of inflammatory cyst was internal fistulization, with additional side-to-side pancreaticojejunostomy as a procedure for underlying chronic pancreatitis. Neoplastic cysts were resected in all cases, and the procedure for pancreatic cancer was modified for use in the cases of cystic adenocarcinoma. The remote postoperative results in the cases of inflammatory cyst were satisfactory: symptomatic improvement was found in 83.1 % of patients and occupational rehabilitation in 70.6 %. All of the three patients with cystic adenocarcinoma are well, including the one surviving a maximum period of 4 years and 10 months.

  1. Pancreatic Pseudocyst Pleural Fistula in Gallstone Pancreatitis

    Directory of Open Access Journals (Sweden)

    Sala Abdalla

    2016-01-01

    Full Text Available Extra-abdominal complications of pancreatitis such as pancreaticopleural fistulae are rare. A pancreaticopleural fistula occurs when inflammation of the pancreas and pancreatic ductal disruption lead to leakage of secretions through a fistulous tract into the thorax. The underlying aetiology in the majority of cases is alcohol-induced chronic pancreatitis. The diagnosis is often delayed given that the majority of patients present with pulmonary symptoms and frequently have large, persistent pleural effusions. The diagnosis is confirmed through imaging and the detection of significantly elevated amylase levels in the pleural exudate. Treatment options include somatostatin analogues, thoracocentesis, endoscopic retrograde cholangiopancreatography (ERCP with pancreatic duct stenting, and surgery. The authors present a case of pancreatic pseudocyst pleural fistula in a woman with gallstone pancreatitis presenting with recurrent pneumonias and bilateral pleural effusions.

  2. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

    Science.gov (United States)

    Ochi, Atsuo; Graffeo, Christopher S.; Zambirinis, Constantinos P.; Rehman, Adeel; Hackman, Michael; Fallon, Nina; Barilla, Rocky M.; Henning, Justin R.; Jamal, Mohsin; Rao, Raghavendra; Greco, Stephanie; Deutsch, Michael; Medina-Zea, Marco V.; Saeed, Usama Bin; Ego-Osuala, Melvin O.; Hajdu, Cristina; Miller, George

    2012-01-01

    Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 an