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Sample records for advanced pancreatic adenocarcinoma

  1. 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.

  2. Synchronous gastric adenocarcinoma and pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Mirko Muroni; Francesco D'Angelo; Massimo Pezzatini; Simone Sebastiani; Samantha Noto; Emanuela Pilozzi; Giovanni Ramacciato

    2010-01-01

    BACKGROUND: The association between gastric and pancreatic carcinoma is a relatively rare condition. In gastric carcinoma patients, the prevalence of second tumors varies 2.8% to 6.8% according to the reported statistics. Gastric cancer associated with pancreatic cancer is uncommon. METHODS: We report a case of a 73-year-old patient hospitalized for vomiting and weight loss. Esophagogastro-duodenoscopy demonstrated an ulcerative lesion of the gastric antrum. Computed tomography and magnetic resonance showed a gastric thickening in the antral and pyloric portion and a nodular mass (3×1.7 cm) in the uncinate portion of the pancreas. RESULTS: The patient underwent pancreaticoduoden-ectomy according to Whipple regional typeⅠFortner. Histological examination of the specimen demonstrated a moderately differentiated adenocarcinoma of the stomach and a poorly differentiated ductal adenocarcinoma of the pancreas. CONCLUSIONS: Long survival is rare in patients with associated gastric and pancreatic cancer. Surgical resection remains the only potentially curative treatment.

  3. Locally advanced pancreatic adenocarcinoma. Chemoradiotherapy, reevaluation and secondary resection; Adenocarcinomes pancreatiques localement evolues. Chimioradiotherapie, reevaluation et resection secondaire?

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    Delpero, J.R.; Turrini, O. [Institut Paoli-Calmettes, Dept. de chirurgie, 13 - Marseille (France)

    2006-11-15

    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

  4. Pancreatic adenocarcinoma pathology : changing "landscape"

    NARCIS (Netherlands)

    Brosens, Lodewijk A A; Hackeng, Wenzel M; Offerhaus, G Johan; Hruban, Ralph H; Wood, Laura D

    2015-01-01

    Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improv

  5. Current Standards and Novel Treatment Options for Metastatic Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Weinberg, Benjamin A; Yabar, Cinthya S; Brody, Jonathan R; Pishvaian, Michael J

    2015-11-01

    Pancreatic cancer is one of the most lethal solid tumors. The prognosis of metastatic pancreatic adenocarcinoma remains dismal, with a median survival of less than 1 year, due in large part to the fact that pancreatic adenocarcinoma is notoriously refractory to chemotherapy. However, there recently have been significant improvements in outcomes for patients with pancreatic adenocarcinoma: ongoing trials have shown promise, and these may lead to still further progress. Here we review the current treatment paradigms for metastatic disease, focusing on ways to ameliorate symptoms and lengthen survival. We then summarize recent advances in our understanding of the molecular and cellular aspects of pancreatic cancer. Finally, we outline new approaches currently under development for the treatment of metastatic disease, arising from our improved understanding of the genetic and nongenetic alterations within pancreatic cancer cells-and of interactions between cancer cells, the tumor microenvironment, and the immune system.

  6. THE SUBTYPES OF PANCREATIC DUCTAL ADENOCARCINOMAS

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    Apeksha Kakkar

    2016-12-01

    Full Text Available Being the 4th leading cause of cancer deaths in the U.S. and with a global increase in incidence, above 80% of pancreatic cancers are locally advanced or metastatic at the time of diagnosis. As surgical resection is the only hope for a cure, the answer is probably in early screening, proper classification and right therapy. The advancing research will likely lead to a better understanding of Pancreatic Ductal Adenocarcinoma (PDAC as well as enhance the techniques for screening, diagnosis, accurate subtyping and enable the use of targeted therapy. Thus, instead of clubbing together various subtypes of PDAC for trials, improving the subcategorization will ensure statistical significance for the academicians, and the clinicians would avoid administration of placebo drug to a vast number of patients.

  7. Updates on Treatment of Gemcitabine-Refractory Pancreatic Adenocarcinoma

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    Nektaria Makrilia

    2011-07-01

    Full Text Available Gemcitabine monotherapy and gemcitabine-based regimens are the current standard of care for locally advanced or metastatic pancreatic adenocarcinoma. However, there is still great controversy over the role of salvage chemotherapy after failure of gemcitabine. This review is an update on the 2011 American Society of Clinical Oncology (ASCO Annual Meeting regarding the most important developments in the treatment of refractory pancreatic cancer, as they were reported in Abstracts #e14542 and #e14588.

  8. Pancreatic ductal adenocarcinoma screening: New perspectives

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli; Dario Fabbri; Andrea Imbrogno

    2012-01-01

    Pancreatic ductal adenocarcinoma accounts for more than 90% of all pancreatic cancers and its incidence has increased significantly worldwide.Patients with pancreatic ductal adenocarcinoma have a poor outcome and more than 95% of the people affected die from the disease within 12 mo after diagnosis.Surgery is the first-line treatment in the case of resectable neoplasm,but only 20% of patients are candidates for this approach.One of the reasons there are few candidates for surgery is that,during the early phases of the disease,the symptoms are poor or non-specific.Early diagnosis is of crucial importance to improve patient outcome; therefore,we are looking for a good screening test.The screening test must identify the disease in an early stage in order to be effective; having said this,a need exists to introduce the concept of "early" ductal adenocarcinoma.It has been reported that at least five additional years after the occurrence of the initiating mutation are required for the acquisition of metastatic ability of pancreatic adenocarcinoma and patients die an average of two years thereafter.We have reviewed the most recent literature in order to evaluate the present and future perspectives of screening programs of this deadly disease.

  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......, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced......-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis...

  10. Pancreatic ductal adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia:repor t of a case

    Institute of Scientific and Technical Information of China (English)

    Rajkumar Krishnasamy; Shaleen Agarwal; Shivendra Singh; Sunil Puri; Puja Sakhuja; Anil K Agarwal

    2007-01-01

    BACKGROUND:The presence of pancreatic ductal intraepithelial neoplasia in patients with chronic pancreatitis is a risk factor for development of pancreatic adenocarcinoma. METHOD: A case of pancreatic ductal adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia was diagnosed in the setting of chronic pancreatitis. RESULTS:Distal pancreatectomy combined with splenec-tomy was performed with a diagnosis of pancreatic body carcinoma. Histopathological examination suggested adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia. The tumor was detected in the remaining head of the pancreas, for which a total pancreatectomy was done. CONCLUSIONS: When a patient with pancreatic ductal intraepithelial neoplasia associated with adenocarcinoma of the pancreas in the setting of chronic pancreatitis is at an increased risk of recurrence in the remaining pancreatic parenchyma, total pancreatectomy may be feasible.

  11. Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma

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    Abelson, Jonathan A.; Murphy, James D.; Minn, Ann Yuriko; Chung, Melody [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Fisher, George A.; Ford, James M.; Kunz, Pamela [Department of Medical Oncology, Stanford University, Stanford, CA (United States); Norton, Jeffrey A.; Visser, Brendan C.; Poultsides, George A. [Department of Surgical Oncology, Stanford University, Stanford, CA (United States); Koong, Albert C. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Chang, Daniel T., E-mail: dtchang@stanford.edu [Department of Radiation Oncology, Stanford University, Stanford, CA (United States)

    2012-03-15

    Purpose: To report the outcomes and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for pancreatic adenocarcinoma. Methods and Materials: Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively. Results: The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%). Conclusions: Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity.

  12. MicroRNA Expression Analyses in Preoperative Pancreatic Juice Samples of Pancreatic Ductal Adenocarcinoma

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    Yoshihiko Sadakari

    2010-11-01

    Full Text Available Context Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. Objective The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine whether specific microRNAs in pancreatic juice could be used for detecting pancreatic ductal adenocarcinoma. Methods Relative expression levels of microRNA-21 and microRNA-155 in formalin-fixed paraffin-embedded tissues of resected specimens (no. 13 and pancreatic juice samples collected using preoperative endoscopic retrograde cholangiopancreatography (no. 21 were quantified and their expression levels were then compared to pancreatic ductal adenocarcinoma and chronic pancreatitis. Results Relative expression levels of microRNA-21 in tissue and pancreatic juice samples were significantly higher in pancreatic ductal adenocarcinoma than those in chronic pancreatitis (P=0.009 and P=0.021, respectively. The same results were obtained in the expression levels of microRNA-155 in tissue and pancreatic juice between pancreatic ductal adenocarcinoma and chronic pancreatitis (P=0.014 and P=0.021, respectively. Expression levels of microRNA-21 and microRNA-155 did not correlate with the preoperative cytological results of pancreatic juice. Conclusion MicroRNA-21 and microRNA-155 in pancreatic juice have the potential of becoming biomarkers for diagnosing pancreatic ductal adenocarcinoma.

  13. CT and MRI Findings of Autoimmune Polymorph Bifocal Pancreatitis Mimicking Pancreatic Adenocarcinoma

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    Roman Rotzinger MD

    2015-03-01

    Full Text Available Autoimmune pancreatitis is a rare type of chronic pancreatitis. It is supposed to be a pancreatic manifestation of an immune-complex modulated systemic disorder. In contrast, pancreatic adenocarcinoma is the most frequent malignant neoplasm of the pancreas. Within the rare type of focal autoimmune pancreatitis, only few presentations with multifocal pancreatic lesions have been described. Herein we report a case of a 58-year-old patient with autoimmune pancreatitis presenting with bifocal manifestations of the pancreatic head and tail, mimicking pancreatic adenocarcinoma clinically, on computed tomography and magnetic resonance imaging. Typical imaging findings of autoimmune pancreatitis are compared with typical findings in pancreatic carcinoma. The diagnostic dilemma of differentiating between both entities is discussed. A review of the present literature regarding multifocal presence of autoimmune pancreatitis is performed.

  14. MicroRNA Expression Analyses in Preoperative Pancreatic Juice Samples of Pancreatic Ductal Adenocarcinoma

    OpenAIRE

    Yoshihiko Sadakari; Takao Ohtsuka; Kenoki Ohuchida; Kosuke Tsutsumi; Shunichi Takahata; Masafumi Nakamura; Kazuhiro Mizumoto; Masao Tanaka

    2010-01-01

    Context Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. Objective The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine w...

  15. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

    Science.gov (United States)

    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.

  16. Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma

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    Kapp Daniel S

    2010-11-01

    Full Text Available Abstract Purpose To analyze the outcomes of patients from a single institution treated with surgery and orthovoltage intraoperative radiotherapy (IORT for pancreatic adenocarcinoma. Methods We retrospectively reviewed 23 consecutive patients from 1990-2001 treated with IORT to 23 discrete sites with median and mean follow up of 6.5 and 21 months, respectively. Most tumors were located in the head of the pancreas (83% and sites irradiated included: tumor bed (57%, vessels (26%, both the tumor bed/vessels (13% and other (4%. The majority of patients (83% had IORT at the time of their definitive surgery. Three patients had preoperative chemoradiation (13%. Orthovoltage X-rays (200-250 kVp were employed via individually sized and beveled cone applicators. Additional mean clinical characteristics include: age 64 (range 41-81; tumor size 4 cm (range 1.4-11; and IORT dose 1106 cGy (range 600-1500. Post-operative external beam radiation (EBRT or chemotherapy was given to 65% and 76% of the assessable patients, respectively. Outcomes measured were infield control (IFC, loco-regional control (LRC, distant metastasis free survival (DMFS, overall survival (OS and treatment-related complications. Results Kaplan-Meier (KM 2-year IFC, LRC, DMFS and OS probabilities for the whole group were 83%, 61%, 26%, and 27%, respectively. Our cohort had three grade 3-5 complications associated with treatment (surgery and IORT. Conclusions Orthovoltage IORT following tumor reductive surgery is reasonably well tolerated and seems to confer in-field control in carefully selected patients. However, distant metastases remain the major problem for patients with pancreatic adenocarcinoma.

  17. MicroRNA in pancreatic ductal adenocarcinoma and itsprecursor lesions

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the 4thdeadliest cancer in the United States, due to its aggressivenature, late detection, and resistance tochemotherapy. The majority of PDAC develops from3 precursor lesions, pancreatic intraepithelial lesions(PanIN), intraductual papillary mucinous neoplasm(IPMN), and mucinous cystic neoplasm. Early detectionand surgical resection can increase PDAC 5-year survivalrate from 6% for Stage Ⅳ to 50% for Stage Ⅰ. To date,there are no reliable biomarkers that can detect PDAC.MicroRNAs (miRNA) are small noncoding RNAs (18-25nucleotides) that regulate gene expression by affectingtranslation of messenger RNA (mRNA). A large bodyof evidence suggests that miRNAs are dysregulated invarious types of cancers. MiRNA has been profiled as apotential biomarker in pancreatic tumor tissue, blood,cyst fluid, stool, and saliva. Four miRNA biomarkers(miR-21, miR-155, miR-196, and miR-210) have beenconsistently dysregulated in PDAC. MiR-21, miR-155, andmiR-196 have also been dysregulated in IPMN and PanINlesions suggesting their use as early biomarkers of thisdisease. In this review, we explore current knowledge ofmiRNA sampling, miRNA dysregulation in PDAC and itsprecursor lesions, and advances that have been made inusing miRNA as a biomarker for PDAC and its precursorlesions.

  18. MicroRNAs in pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Jong Y Park; James Helm; Domenico Coppola; Donghwa Kim; Mokenge Malafa; Seung Joon Kim

    2011-01-01

    Ductal adenocarcinoma of the pancreas is a lethal cancer for which the only chance of long-term survival belongs to the patient with localized disease in whom a potentially curative resection can be done.Therefore,biomarkers for early detection and new therapeutic strategies are urgently needed.miRNAs are a recently discovered class of small endogenous non-coding RNAs of about 22 nucleotides that have gained attention for their role in downregulation of mRNA expression at the posttranscriptional level.miRNAs regulate proteins involved in critical cellular processes such as differentiation,proliferation,and apoptosis.Evidence suggests that deregulated miRNA expression is involved in carcinogenesis at many sites,including the pancreas.Aberrant expression of miRNAs may upregulate the expression of oncogenes or downregulate the expression of tumor suppressor genes,as well as play a role in other mechanisms of carcinogenesis.The purpose of this review is to summarize our knowledge of deregulated miRNA expression in pancreatic cancer and discuss the implication for potential translation of this knowledge into clinical practice.

  19. Dose-Volume Analysis of Predictors for Gastrointestinal Toxicity After Concurrent Full-Dose Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma

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    Huang Jiayi [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Robertson, John M., E-mail: jrobertson@beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Ye Hong [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Margolis, Jeffrey; Nadeau, Laura [Division of Medical Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Yan Di [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States)

    2012-07-15

    Purpose: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT). Methods and Materials: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity. Results: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V{sub 20Gy} to V{sub 35Gy} of duodenum were significantly associated with GI toxicity (all p {<=} 0.05). On MVA, the V{sub 25Gy} of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V{sub 25Gy} of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V{sub 25Gy} {<=} 45% and V{sub 25Gy} > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V{sub 35Gy} is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V{sub 35Gy} {<=} 20% and V{sub 35Gy} > 20%, respectively (p = 0.04). Conclusions: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI

  20. Isolated Supraclavicular Lymph Node Metastasis in Pancreatic Adenocarcinoma: A Report of Three Cases and Review of the Literature

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    Arundhati D Soman

    2010-11-01

    Full Text Available Context Supraclavicular lymph nodes represent a rare site of metastasis in pancreatic cancer. We report three cases of pancreatic adenocarcinoma with metastases to supraclavicular lymph nodes. Case report A 51-year-old male was diagnosed with locally advanced pancreatic adenocarcinoma on computed tomography (CT scan. He was recommended neoadjuvant chemotherapy followed by chemoradiation therapy. However, positron emission tomography (PET/CT scans and subsequent fine needle aspiration cytology showed supraclavicular lymph node metastasis. The patient received systemic chemotherapy for metastatic pancreatic adenocarcinoma. The second patient, a 66-year-old female with pancreatic adenocarcinoma, underwent pancreaticoduodenectomy and was found to have peripancreatic lymph node involvement. She received adjuvant chemotherapy and was followed-up with surveillance CT scans, which did not reveal any metastasis. However, the patient complained of neck swelling. PET/CT scan and biopsy revealed supraclavicular lymph node metastasis from a pancreatic adenocarcinoma primary. The third patient, a 79-year-old male with a past history of thyroid carcinoma who was treated with partial thyroidectomy, developed neck swelling 4 years after his surgery. Fine needle aspiration cytology was consistent with known papillary thyroid carcinoma. Staging evaluations revealed a pancreatic mass for which he underwent subtotal pancreatectomy and splenectomy. Histopathology revealed grade 3 pancreatic adenocarcinoma. Excisional biopsy of a supraclavicular lymph node showed metastatic pancreatic adenocarcinoma. PET/CT results were consistent with these findings. Conclusion In patients with pancreatic adenocarcinoma, supraclavicular lymph node metastasis represents an uncommon, but clinically significant finding that can lead to changes in treatment planning. PET imaging represents a valuable tool in the detection and follow up of these patients.

  1. Prognostic role of sex steroid receptors in pancreatic adenocarcinoma.

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    Georgiadou, Despoina; Sergentanis, Theodoros N; Sakellariou, Stratigoula; Vlachodimitropoulos, Dimitris; Psaltopoulou, Theodora; Lazaris, Andreas C; Gounaris, Antonia; Zografos, George C

    2016-01-01

    From the available literature, it is unclear what proportion of pancreatic adenocarcinomas express estrogen receptors (ERα, ERβ), progesterone receptors (PR), and androgen receptors (AR), and if any of these markers have prognostic significance. We aimed to assess (1) the expression and (2) the correlation of the aforementioned markers with clinicopathological parameters and prognosis in patients with pancreatic adenocarcinoma. During a five-year period, 60 patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution. Immunohistochemical stains of the studied markers were quantified by Image analysis system. ERα expression was positively associated with PR expression. Moreover, ERβ was inversely associated with the presence of metastases, whereas no significant associations implicated AR. As far as the prognostic significance of the studied receptors is concerned, higher ERα expression correlated with poorer survival at the univariate analysis, but the finding dissipated at the multivariate approach. No significant associations with overall survival were noted regarding the other receptors. The role of sex hormone receptors in the survival from pancreatic adenocarcinoma seems rather limited. Further prospective studies assessing those receptors should ideally be designed in order to confirm our results and possibly outline additional correlations between other steroid receptors and features of pancreatic adenocarcinoma.

  2. 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

  3. Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy.

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    Sohal, Davendra P S; Walsh, R Matthew; Ramanathan, Ramesh K; Khorana, Alok A

    2014-03-01

    Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic cancer resection. Preclinical studies using genomics and mouse models reveal evidence of metastatic spread even before histopathologic evidence of a pancreatic tumor. Analogous to breast cancer, we propose that the Halstedian approach of treating pancreatic cancer as a local, surgical problem should be replaced by Fisher's alternative hypothesis of cancer as a systemic disease. Newer multiagent chemotherapy regimens have shown meaningful response rates and improvement in overall survival in the metastatic setting and, for the first time, offer investigators an opportunity to use effective systemic therapy. We emphasize that a surgery-first approach is not resonant with our current understanding of pancreatic adenocarcinoma biology and that an upfront systemic approach for even resectable pancreatic cancer warrants testing in clinical trials.

  4. Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

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    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.

  5. 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.

  6. Small Undifferentiated Pancreatic Adenocarcinoma which Mimics IPMN at Imaging

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    Mirko D’Onofrio

    2009-07-01

    Full Text Available Context To present the case of an unusual presentation at imaging of a very small solid undifferentiated pancreatic adenocarcinoma which mimics a side-branch intraductal papillary mucinous neoplasm. Case report The patient came to our hospital for a revaluation of a cystic pancreatic lesion. Ultrasound (US and contrast-enhanced ultrasound (CEUS examinations were carried out. A small cystic lesion of about 1.5 cm in diameter was seen in the posterior aspect of the pancreatic uncinate process A very small, solid, vascularized nodule was detected at CEUS within the lesion. Consequently, the patient underwent CT and MRI. MRI confirmed the presence of an intralesional nodule and communication with the main pancreatic duct was demonstrated, suggesting the diagnosis of intraductal papillary mucinous neoplasm with solid intralesional tissue. A pylorus preserving pancreaticoduodenectomy was carried out. An undifferentiated adenocarcinoma having a notable peripheral inflammatory reaction and dilated branch duct was finally diagnosed. Conclusion To our knowledge, we present for the first time, the case of a very small solid undifferentiated pancreatic adenocarcinoma of the uncinate process which mimicked a side-branch intraductal papillary mucinous neoplasm at imaging. The cystic appearance may be an epiphenomenon of a solid lesion and this possibility has to be considered when one encounters incidental cystic lesions at imaging.

  7. Primary Pancreatic Head Tuberculosis: Great Masquerader of Pancreatic Adenocarcinoma

    Science.gov (United States)

    Gupta, Dhaval; Patel, Jatin; Rathi, Chetan; Ingle, Meghraj; Sawant, Prabha

    2015-01-01

    Isolated pancreatic tuberculosis (TB) is considered an extremely rare condition, even in the developing countries. Most reported cases of pancreatic TB are diagnosed after exploratory laparotomy or autopsy. Pancreatic TB is a potential mimic of invasive pancreatic malignancy and the presence of vascular invasion does not distinguish one condition from the other. Every effort should be made for the earliest diagnosis of this condition as TB is a treatable condition and it avoids unnecessary management of pancreatic carcinoma. Here we report a rare case of primary pancreatic head TB in a 58-year-old male who presented with hypodense lesion in head of pancreas with double duct sign and portal vein invasion mimicking non-resectable pancreatic carcinoma. PMID:27785295

  8. Second Primary Pancreatic Adenocarcinoma Three Years After Successfully Treated Index Esophageal Cancer

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    Nina Nandy

    2014-01-01

    Full Text Available Context Development of a second primary malignancy after an index esophageal cancer is a rare event, primarily due to short survival of patients with esophageal cancer. However, the number of long-term esophageal cancer survivors has been increasing due to advances in early detection and therapy. Case report We report herein a case of pancreatic adenocarcinoma that developed three years after a successfully treated early-stage adenocarcinoma of the esophagus. A 70-year-old Caucasian male presented with vague complaints of nausea, vomiting and abdominal distention, with subsequent development of jaundice. A computed tomography scan of abdomen revealed a 2.9 cm soft tissue mass in the head of the pancreas and the patient underwent a Whipple’s procedure, with pathology confirming the diagnosis of pancreatic adenocarcinoma. Three years previously, the patient was successfully treated for adenocarcinoma of the esophagus via minimally invasive esophagogastrectomy. Despite chemoradiotherapy for localized disease and subsequent systemic chemotherapy for metastatic pancreatic cancer, the patient eventually succumbed to his illness. Conclusion We discuss the association between esophageal cancer and subsequent second malignancies, along with implications for surveillance and therapy.

  9. Therapeutic Endoscopic Ultrasonography: Intratumoral Injection for Pancreatic Adenocarcinoma

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    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.

  10. What is the origin of pancreatic adenocarcinoma?

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    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. Activation of Raf-1 in human pancreatic adenocarcinoma.

    Science.gov (United States)

    Berger, D H; Jardines, L A; Chang, H; Ruggeri, B

    1997-04-01

    Point mutations in the Ras oncogene cause Ras to remain in its active GTP-bound state sending signals downstream continuously. Since 75 to 90% of all human pancreatic ductal adenocarcinomas harbor activating mutations at codon 12 of the K-ras oncogene it was our belief that Raf-1-MEK-MAPK will be activated in the majority of human pancreatic cancers. The aim of this study was to confirm activation of Raf-1 in K-ras mutant human pancreatic cancer. Additionally, we sought to determine if Raf-1 activation differed in K-ras mutant and nonmutant pancreatic cancer. Furthermore, we were interested in determining if Raf-1 activation in pancreatic cancer led to subsequent activation of downstream effectors such as MAP kinase. The presence of mutations in codon 12 of the K-ras oncogene in 14 human pancreatic adenocarcinoma cell lines was determined by use of mutant allele-specific PCR restriction fragment length polymorphism analysis. Raf-1 expression of quiescent cells was determined by immunoblotting using a rabbit anti-human polyclonal antibody and enhanced chemiluminescence. MAP kinase activity was determined by measuring the incorporation of phosphate into Myelin Basic Protein. Seven cell lines were noted to have mutations in codon 12 of K-ras while seven cell lines did not. There was no difference in expression of the 74 kDa-activated form of Raf-1 in K-ras mutant vs K-ras nonmutant cell lines. However, there was a significant increase in MAP kinase activity in the nonmutant cell lines compared to the cell lines with Ras mutations (P = 0.026). We conclude that Raf-1 is expressed in its active form in human pancreatic cancer regardless of K-ras status. However, signalling downstream of Raf-1 differs in cell lines with K-ras mutations compared to those cell lines without K-ras mutations.

  12. Role of surgical resection in treatment of pancreatic adenocarcinoma

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    Milošević Pavle

    2011-01-01

    Full Text Available Introduction. Pancreatic adenocarcinoma is the fifth leading cause of death from malignant diseases. The total five-year rate is bellow 5%, but in patients who underwent pancreatic resection, the fiveyear rate may be up to 20%. Surgical resection is still the only therapeutic option that offers the possibility of cure. In recent decades, the perioperative mortality rate has been significantly reduced in the institutions performing a number of these operations per year and has become less than 5%. Postoperative morbidity remains high. Material and Methods. The results of surgical resection in the treatment of pancreatic adenocarcinoma have been analyzed. A retrospective study included the patients operated at the Department for Abdominal, Endocrine and Transplantation surgery, Clinical Center of Vojvodina. Results. In the period from February 1st 1998 to February 1st 2007 a total of 67 patients with pancreatic adenocarcinoma underwent resection. The average age of patients was 58.81±1.42 years. There were 44 (65.7% male and 23 (34.3% female patients. The most common locations of cancer were the head, then the body and the tail of the pancreas and they were found in 57 (85.1% cases, 7 (10,4% cases and 3 (4,47% cases, respectively. The postoperative mortality appeared in 3 (4.47% cases and postoperative morbidity in 21 (31.3% cases. The average survival was 22.89± 3.87 months, the median being 9.0±2.18 months. The five-year survival rate was 13.5%. Conclusion. For patients with pancreatic cancer, surgical resection still remains the only chance of cure. These procedures are performed with acceptable postoperative mortality and morbidity rate. The percentage of cured patients is still unsatisfactorily low.

  13. Systematic review of the value of chemoradiotherapy in the management of locally advanced pancreatic adenocarcinoma; Interet de la chimioradiotherapie dans la prise en charge des denocarcinomes du pancreas localement avances: revue systematique

    Energy Technology Data Exchange (ETDEWEB)

    Azria, D. [Centre de Lutte Contre le Cancer Val d' Aurelle, 34 Montpellier (France); Seblain-El Guerche, C. [Institut National du Cancer, 92 - Boulogne-Billancourt (France); Girard, N. [Centre Hospitalier Lyon-Sud, 69 - Pierre-Benite (France); Hennequin, C. [Hopital Saint-Louis, 75 - Paris (France); Huguet, F. [Hopital Tenon, 75 - Paris (France)

    2009-06-15

    Introduction: At the request of the National Thesaurus of Gastrointestinal Cancer (T.N.C.D.), the S.O.R. program, led by the French National Cancer Institute (I.N.Ca), completed a systematic review to evaluate the value of chemoradiotherapy (C.R.T.) in the management of locally advanced pancreatic adenocarcinoma in collaboration with clinician experts. Methods: Results of a systematic literature search using Medline (from 1980 to 2008) were completed by a consult of evidence-based medicine web sites. All phase III randomized trials and systematic reviews concerning non-resectable locally advanced pancreatic adenocarcinoma and non-metastatic (stage III) were included in the study. Some phase II trials were also included if no phase III trials were retrieved. The following interventions were compared: C.R.T. versus best supportive care, C.R.T. versus radiotherapy, and C.R.T. versus chemotherapy. The modalities of C.R.T. regimens and the sequences of chemotherapy-C.R.T. versus C.R.T. were also studied. The quality and clinical relevance of the trials were evaluated using validated checklists, allowing associating each result with a level of evidence. Data synthesis was performed considering both efficacy and toxicity outcomes for each intervention. Results: Nineteen references were included in this systematic review: two meta-analyses, 11 randomized trials, five non-randomized trials and one randomized trial only published in abstract form. After a clinical and methodological critical appraisal, compared to the alternative best supportive care, concomitant C.R.T. increases overall survival (C). Concomitant C.R.T. compared to the radiotherapy alone increases the overall survival (B1) but is more toxic (B1). Concomitant C.R.T. compared to chemotherapy alone is not superior in terms of survival (B1) and increases toxicity (A). Concerning administration modalities of radiotherapy, recent data are in favour to a limited irradiation to the tumoral volume (C) and to a total

  14. Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go?

    Institute of Scientific and Technical Information of China (English)

    Dimitra; Grapsa; Muhammad; Wasif; Saif; Konstantinos; Syrigos

    2015-01-01

    Pancreatic adenocarcinoma(usually referred to aspancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field.

  15. Stellate Cell Activation in Tropical Calcific Pancreatitis Compared to Alcoholic Pancreatitis, Adenocarcinoma of Pancreas and Normal Pancreas

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    Johny Cyriac

    2012-07-01

    Full Text Available ContextPancreatic stellate cell (PSC is known to be the source of fibrosis in pancreatic pathology of various etiologies. However, there is no published data on activation of PSCs in tropical calcific pancreatitis. ObjectivesThe present study was undertaken to estimate the proportion of activated stellate cells, in a semi-quantitative manner, in normal pancreas and pancreatic fibrosis due to, tropical calcific pancreatitis, alcoholic chronic pancreatitis and pancreatic adenocarcinoma. PatientsSurgically resected specimen from patients with tropical calcific pancreatitis (n=22, alcoholic chronic pancreatitis(n=16, adenocarcinoma of pancreas (n=20 and normal pancreas (n=20 were included. Main outcome measuresExpression of CD34, and alpha-smooth muscle actin (α-SMA was assessed by immunohistochemistry. Morphometry was performed by a pointcounting procedure and CD34 positive areas were excluded from α-SMA positive areas for estimating activated PSCs. StatisticsThe one-way ANOVA and the Tukey multiple comparison test were used to compare the proportion ofactivated stellate cells among the four categories. ResultsIn all the disease conditions studied, namely, tropical calcific pancreatitis (16.7±14.5%, mean±SD, alcoholic chronic pancreatitis (13.6±12.4% and pancreatic adenocarcinoma (22.8±14.4%, there was highly significant (P<0.001 increased percentage of activated PSCs compared to normal pancreas (-0.9±6.4%. Proportion of activated PSCs in tropical calcific pancreatitis was similar to that in cases of alcoholic chronic pancreatitis and pancreatic adenocarcinoma. Such activation is documented for the first time in tropical calcific pancreatitis while it is known for the other causes. ConclusionsThe present study suggests that a final common pathway of PSC activation leads to fibrogenesis in tropical calcific pancreatitis just as in other pancreatic pathologies.

  16. A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

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    Ozhan Ocal

    2015-10-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR signaling activates Kras. Regulators of G-protein signaling (RGS proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC transgenic mice with KIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane plus inhibitors of Axl signaling

  17. Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas

    DEFF Research Database (Denmark)

    Schultz, Nicolai Aagaard; Roslind, Anne; Christensen, Ib J

    2012-01-01

    The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied.......The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied....

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca2+-activated Cl- channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological f...... intracellular calcium concentration. Functional studies on PDAC behavior showed that surprisingly inhibition of ANO1 did not influence cellular proliferation. On the other hand, we found ANO1 channel to be pivotal in PDAC cell migration as assessed in wound healing experiments....

  19. Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

    DEFF Research Database (Denmark)

    Henriksen, Stine Dam; Madsen, Poul Henning; Larsen, Anders Christian;

    2016-01-01

    analysis using backward stepwise elimination. RESULTS: Patients with pancreatic adenocarcinoma (n = 95), chronic pancreatitis (n = 97) and acute pancreatitis (n = 59) and patients screened, but negative for pancreatic adenocarcinoma (n = 27), were included. The difference in mean number of methylated genes...... with chronic/acute pancreatitis were included as additional benign control groups. Based on an optimized accelerated bisulfite treatment protocol, methylation-specific PCR of a 28 gene panel was performed on plasma samples. A diagnostic prediction model was developed by multivariable logistic regression...

  20. Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine.

    Science.gov (United States)

    Knudsen, Erik S; O'Reilly, Eileen M; Brody, Jonathan R; Witkiewicz, Agnieszka K

    2016-01-01

    Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy.

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca2+-activated Cl- channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological...... 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...... PaCa 2, Capan-1, AsPC-1, BxPC-3) and compared the results to those obtained in a human pancreatic ductal epithelium (HPDE) cell line. All cancer cell lines showed an upregulation of ANO1 on mRNA and protein levels. Whole-cell patch-clamp recordings identified large Ca2+ and voltage-dependent Cl...

  2. Novel Drug Targets Based on Association between Inflammation and Pancreatic Ductal Adenocarcinoma

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    Muhammad Wasif Saif

    2010-07-01

    Full Text Available Dear Sir We read with great interest the editorial published by Uomo et al. in the 2010 May issue of JOP. J Pancreas (Online titled: “Inflammation and Pancreatic Ductal Adenocarcinoma: A Potential Scenario for Novel Drug Targets” [1]. There is a growing amount of evidence that inflammation plays a contributory role in the pathogenesis of cancer, including pancreatic carcinogenesis. Inflammatory states are characterized by the formation of reactive oxygen species and the induction of cell cycling for tissue growth and repair [1, 2, 3]. The initiation, promotion and expansion of tumors may be influenced by numerous components that also function in the inflammatory response. Recognized risk factors for pancreatic cancer include cigarette smoking, chronic/hereditary pancreatitis, obesity and type II diabetes. Each risk factor is linked by the fact that the inflammatory state significantly drives its pathology. We agree with the authors that multiple links between inflammation and pancreatic adenocarcinoma has led to development of novel targeted therapy which is under evaluation both in vivo and in vitro studies to fight against pancreatic adenocarcinoma. Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. Therefore, developments of novel agents, in particular based on the pathogenesis of pancreatic adenocarcinoma are urgently indicated.

  3. Discovery and analysis of pancreatic adenocarcinoma genes using cDNA microarrays

    Institute of Scientific and Technical Information of China (English)

    Gang Jin; Xian-Gui Hu; Kang Ying; Yan Tang; Rui Liu; Yi-Jie Zhang; Zai-Ping Jing; Yi Xie; Yu-Min Mao

    2005-01-01

    AIM: To study the pathogenetic processes and the role of gene expression by microarray analyses in expediting our understanding of the molecular pathophysiology of pancreatic adenocarcinoma, and to identify the novel cancer-associated genes.METHODS: Nine histologically defined pancreatic head adenocarcinoma specimens associated with clinical data were studied. Total RNA and mRNA were isolated and labeled by reverse transcription reaction with Cy5 and Cy3 for cDNA probe. The cDNA microarrays that represent a set of 4 096 human genes were hybridized with labeled cDNA probe and screened for molecular profiling analyses.RESULTS: Using this methodology, 184 genes were screened out for differences in gene expression level after nine couples of hybridizations. Of the 184 genes,87 were upregulated and 97 downregulated, including 11 novel human genes. In pancreatic adenocarcinoma tissue, several invasion and metastasis related genes showed their high expression levels, suggesting that poor prognosis of pancreatic adenocarcinoma might have a solid molecular biological basis.CONCLUSION: The application of cDNA microarray technique for analysis of gene expression patterns is a powerful strategy to identify novel cancer-associated genes, and to rapidly explore their role in clinical pancreatic adenocarcinoma. Microarray profiles provide us new insights into the carcinogenesis and invasive process of pancreatic adenocarcinoma. Our results suggest that a highly organized and structured process of tumor invasion exists in the pancreas.

  4. Photodynamic therapy for locally advanced pancreatic cancer: early clinical results

    Science.gov (United States)

    Sandanayake, N. S.; Huggett, M. T.; Bown, S. G.; Pogue, B. W.; Hasan, T.; Pereira, S. P.

    2010-02-01

    Pancreatic adenocarcinoma ranks as the fourth most common cause of cancer death in the USA. Patients usually present late with advanced disease, limiting attempted curative surgery to 10% of cases. Overall prognosis is poor with one-year survival rates of less than 10% with palliative chemotherapy and/or radiotherapy. Given these dismal results, a minimally invasive treatment capable of local destruction of tumor tissue with low morbidity may have a place in the treatment of this disease. In this paper we review the preclinical photodynamic therapy (PDT) studies which have shown that it is possible to achieve a zone of necrosis in normal pancreas and implanted tumour tissue. Side effects of treatment and evidence of a potential survival advantage are discussed. We describe the only published clinical study of pancreatic interstitial PDT, which was carried out by our group (Bown et al Gut 2002), in 16 patients with unresectable locally advanced pancreatic adenocarcinoma. All patients had evidence of tumor necrosis on follow-up imaging, with a median survival from diagnosis of 12.5 months. Finally, we outline a phase I dose-escalation study of verteporfin single fibre PDT followed by standard gemcitabine chemotherapy which our group is currently undertaking in patients with locally advanced pancreatic cancer. Randomized controlled studies are also planned.

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

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    Kalogeraki Alexandra

    2016-03-01

    Full Text Available Solid masses of the pancreas represent a variety of benign and malignant neoplasms of the exocrine and endocrine tissues of the pancreas. A tissue diagnosis is often required to direct therapy in the face of uncertain diagnosis or if the patient is not a surgical candidate either due to advanced disease or comorbidities. Endoscopic ultrasound (EUS is a relatively new technology that employs endoscopy and high-frequency ultrasound (US. EUS involves imaging of the pancreatic head and the uncinate from the duodenum and imaging of the body and tail from the stomach. It has been shown to be a highly sensitive method for the detection of pancreatic masses. It is superior to extracorporeal US and computed tomographic (CT scans, especially when the pancreatic tumor is smaller than 2-3 cm. Although EUS is highly sensitive in detecting pancreatic solid masses, its ability to differentiate between inflammatory masses and malignant disease is limited. Endoscopic retrograde cholangiopancreatography (ERCP brushing, CT-guided biopsies, and transabdominal ultrasound (US have been the standard nonsurgical methods for obtaining a tissue diagnosis of pancreatic lesions, but a substantial false-negative rate has been reported. Transabdominal US-guided fine-needle aspiration biopsy (US-FNAB has been used for tissue diagnosis in patients with suspected pancreatic carcinoma. It has been shown to be highly specific, with no false-positive diagnoses. With the advent of curvilinear echoendoscopes, transgastric and transduodenal EUS-FNAB of the pancreas have become a reality EUS with FNAB has revolutionized the ability to diagnose and stage cancers of the gastrointestinal tract and assess the pancreas. Gastrointestinal cancers can be looked at with EUS and their depth of penetration into the intestinal wall can be determined. Any suspicious appearing lymph nodes can be biopsied using EUS/FNAB. The pancreas is another organ that is well visualized with EUS. Abnormalities

  6. Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: applications in diagnosis and therapy.

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    María P Torres

    Full Text Available Pancreatic cancer (PC remains one of the most lethal human malignancies with poor prognosis. Despite all advances in preclinical research, there have not been significant translation of novel therapies into the clinics. The development of genetically engineered mouse (GEM models that produce spontaneous pancreatic adenocarcinoma (PDAC have increased our understanding of the pathogenesis of the disease. Although these PDAC mouse models are ideal for studying potential therapies and specific genetic mutations, there is a need for developing syngeneic cell lines from these models. In this study, we describe the successful establishment and characterization of three cell lines derived from two (PDAC mouse models. The cell line UN-KC-6141 was derived from a pancreatic tumor of a Kras(G12D;Pdx1-Cre (KC mouse at 50 weeks of age, whereas UN-KPC-960 and UN-KPC-961 cell lines were derived from pancreatic tumors of Kras(G12D;Trp53(R172H;Pdx1-Cre (KPC mice at 17 weeks of age. The cancer mutations of these parent mice carried over to the daughter cell lines (i.e. Kras(G12D mutation was observed in all three cell lines while Trp53 mutation was observed only in KPC cell lines. The cell lines showed typical cobblestone epithelial morphology in culture, and unlike the previously established mouse PDAC cell line Panc02, expressed the ductal marker CK19. Furthermore, these cell lines expressed the epithelial-mesenchymal markers E-cadherin and N-cadherin, and also, Muc1 and Muc4 mucins. In addition, these cell lines were resistant to the chemotherapeutic drug Gemcitabine. Their implantation in vivo produced subcutaneous as well as tumors in the pancreas (orthotopic. The genetic mutations in these cell lines mimic the genetic compendium of human PDAC, which make them valuable models with a high potential of translational relevance for examining diagnostic markers and therapeutic drugs.

  7. Pancreatic adenocarcinomas without secondary signs on multiphasic multidetector CT: association with clinical and histopathologic features

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Tsutomu; Ito, Katsuyoshi; Sone, Teruki; Kanki, Akihiko; Higaki, Atsushi; Hayashida, Minoru; Yamamoto, Akira [Kawasaki Medical School, Departments of Radiology, Kurashiki City, Okayama (Japan); Kanomata, Naoki [Kawasaki Medical School, Department of Pathology, Kurashiki City, Okayama (Japan)

    2016-03-15

    To determine the clinical, histopathologic and imaging features of pancreatic adenocarcinomas without secondary signs on dynamic CT. Seventy patients (mean age 70 years) with histologically proven pancreatic adenocarcinoma underwent preoperative contrast material-enhanced multiphasic multidetector CT before pancreatic resection. In each patient, clinical data including carbohydrate antigen 19-9, frequency of isoattenuating tumours, and presence of secondary signs and histopathologic findings such as tumour location, tumour stage, and microscopic infiltrative growth grade were evaluated. Ten tumours (14 %) were without secondary signs, and 60 (86 %) were with secondary signs. Tumours without and with secondary signs were located in the uncinate process in 5 (50 %) and 3 (5 %), head in 3 (30 %) and 29 (48 %), body in 2 (20 %) and 22 (37 %), and tail in 0 (0 %) and 6 (10 %), respectively (p =.001). The frequency of isoattenuating pancreatic adenocarcinomas without secondary signs was significantly higher than those with secondary signs (p = 0.034). The tumour stage of pancreatic adenocarcinomas without secondary signs was earlier than that in tumours with secondary signs (p = 0.041). Pancreatic adenocarcinomas without secondary signs is characterized by the presence of uncinate and isoattenuating tumours and earlier tumour stage compared to tumours with secondary signs. (orig.)

  8. Lysosomal exoglycosidases in serum and urine of patients with pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Anna Stypułkowska

    2010-11-01

    Full Text Available Lysosomal exoglycosidases: N-acetyl-β-D-hexosaminidase (HEX, β-D-galactosidase (GAL, ι-L-fucosidase (FUC and ι-D-mannosidase (MAN modify oligosaccharide chains of glycoconjugates in endoplasmatic reticulum and/or Golgi apparatus and degrade them in lysosomes. In acid environment of lysosome, exoglycosidases degrade oligosaccharide chains of glycoproteins, glycolipids and glycosaminoglycans by eliminating single sugars from the edges of oligosaccharide chains. Neoplasms change biochemical processes in tissues and may significantly change the activity of many enzymes including the activity of lysosomal exoglycosidasses in serum and urine of persons with neoplasmatic diseases. The aim of the present paper was evaluation the activity of HEX, GAL, FUC and MAN in serum and urine of patients with pancreatic adenocarcinoma. Serum and urine samples were collected from 15 patients with adenocarcinoma of the pancreas and 15 healthy persons. The activity of lysosomal exoglycosidases was determined by the method of Marciniak et al. adapted to serum and urine of patients with adenocarcinoma of the pancreas. Our results indicate significant decrease in activity of GAL (p=0.037 in serum of patients with pancreatic adenocarcinoma, significant increase in activity of HEX (p<0.001 and FUC (p=0.027 in serum, and HEX (p=0.003 in urine, as well as significant decrease of FUC (p=0.016 and MAN (p=0.029 in urine o patients with adenocarcinoma of the pancreas, in comparison to the control group. Increase in activity of some lysosomal enzymes in serum and urine of pancreatic adenocarcinoma patients, may indicate on destruction of pancreatic tissue by pancreatic adenocarcinoma. Determination of the HEX, GAL, FUC and MAN in serum and urine may be useful in diagnostics of pancreatic adenocarcinoma.

  9. Stem cells as the root of pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Balic, Anamaria; Dorado, Jorge; Alonso-Gomez, Mercedes; Heeschen, Christopher, E-mail: christopher.heeschen@cnio.es

    2012-04-01

    Emerging evidence suggests that stem cells play a crucial role not only in the generation and maintenance of different tissues, but also in the development and progression of malignancies. For the many solid cancers, it has now been shown that they harbor a distinct subpopulation of cancer cells that bear stem cell features and therefore, these cells are termed cancer stem cells (CSC) or tumor-propagating cells. CSC are exclusively tumorigenic and essential drivers for tumor progression and metastasis. Moreover, it has been shown that pancreatic ductal adenocarcinoma does not only contain one homogeneous population of CSC rather than diverse subpopulations that may have evolved during tumor progression. One of these populations is called migrating CSC and can be characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumor and traveling to distant sites such as the liver as the preferred site of metastatic spread. Clinically even more important, however, is the observation that CSC are highly resistant to chemo- and radiotherapy resulting in their relative enrichment during treatment and rapid relapse of disease. Many laboratories are now working on the further in-depth characterization of these cells, which may eventually allow for the identification of their Achilles heal and lead to novel treatment modalities for fighting this deadly disease.

  10. Circulating IL-35 in pancreatic ductal adenocarcinoma patients.

    Science.gov (United States)

    Jin, Peng; Ren, He; Sun, Wei; Xin, Wen; Zhang, Huan; Hao, Jihui

    2014-01-01

    IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, pIL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (pIL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.

  11. Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation.

    Science.gov (United States)

    Vyas, Ojas; Leung, Keith; Ledbetter, Leslie; Kaley, Kristin; Rodriguez, Teresa; Garcon, Marie C; Saif, Muhammad W

    2015-02-01

    Patients with BRCA-1 and BRCA-2 germ line mutations are at an increased risk of developing pancreatic adenocarcinoma (PAC). In particular, the BRCA-2 mutation has been associated with a relative risk of developing PAC of 3.51. The BRCA-2 protein is involved in repair of double-stranded DNA breaks. Recent reports have suggested that in the setting of impaired DNA repair, chemotherapeutic agents that induce DNA damage, such as platinum-based antineoplastic drugs (platins) and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors), have improved efficacy. However, because of the relative rarity of BRCA-related PAC, studies evaluating such agents in this setting are scarce. Patients with a known BRCA-2 mutation and PAC were retrospectively reviewed. Ten patients with PAC and BRCA-2 mutation were identified. Four patients (40%) were of Ashkenazi Jewish descent. Seven patients (70%) received platinum agents, two (20%) received mitomycin-C, one (10%) received a PARP inhibitor, and seven (70%) received a topoisomerase-I inhibitor. Overall, chemotherapy was well tolerated with expected side effects. Patients with a BRCA-2 mutation and PAC represent a group with a unique biology underlying their cancer. Chemotherapies such as platinum derivatives, mitomycin-C, topoisomerase-I inhibitors, and PARP inhibitors targeting DNA require further investigation in this population. Genetic testing may guide therapy in the future.

  12. Challenges in pancreatic adenocarcinoma surgery - National survey and current practice guidelines

    Science.gov (United States)

    Dhayat, Sameer A.; Mirgorod, Philip; Lenschow, Christina; Senninger, Norbert

    2017-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers in Europe and the USA. There is consensus that radical tumor surgery is the only viable option for any long-term survival in patients with PDAC. So far, limited data are available regarding the routine surgical management of patients with advanced PDAC in the light of surgical guidelines. Methods A national survey on perioperative management of patients with PDAC and currently applied criteria on their tumor resectability in German university and community hospitals was carried out. Results With a response rate of 81.6% (231/283) a total of 95 (41.1%) participating departments practicing pancreatic surgery in Germany are certified as competence and reference centers for surgical diseases of the pancreas in 2016. More than 95% of them indicate to carry out structured and interdisciplinary therapies along with an interdisciplinary pre- and postoperative tumor board. The majority of survey respondents prefer the pylorus-preserving partial pancreatoduodenectomy (93.1%) with standard lymphadenectomy for cancer of the pancreatic head. Intraoperative histological evaluation of the resection margins is used regularly by 99% of the survey respondents. 98.7% of survey respondents carry out partial or complete vein resection, 126 respondents (54.5%) would resect tumor adjacent arteries, and 102 respondents (44.2%) would perform metastasectomy if complete PDAC resection (R0) is possible. Conclusion Evidence-based and standardized pancreatic surgery is practiced by a large number of hospitals in Germany. However, a significant number of survey respondents support an extended radical tumor resection in patients with advanced PDAC even when not indicated by current clinical guidelines. PMID:28267771

  13. Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Zhou, G; Yu, J; Wang, A; Liu, S-H; Sinnett-Smith, J; Wu, J; Sanchez, R; Nemunaitis, J; Ricordi, C; Rozengurt, E; Brunicardi, F C

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

  14. Analysis of 300 consecutive cases of pancreatic adenocarcinoma in a single-center in China

    Institute of Scientific and Technical Information of China (English)

    Han Lin; Yong Ma; Ji-Zhou Wang; Hua-Yang Pan; Lian-Xin Liu; Hai-Quan Qiao; Bei Sun; Hong-Chi Jiang

    2016-01-01

    BACKGROUND: Most of the reports on the prognostic indi-cators of patients with pancreatic adenocarcinoma are from developed countries. The present study focused on the prog-nostic indicators of Chinese patients with pancreatic adeno-carcinoma. METHODS: A total of 300 patients with pancreatic adenocar-cinoma who had undergone curative resection were included. The resection and R0/R1 resection rates for adenocarcinomas from different parts of the pancreas were calculated and clini-cal characteristics were analyzed. RESULTS: In 3427 patients diagnosed with pancreatic adeno-carcinomas, only 300 (8.8%) were eligible for radical resection. The total median survival of these patients was 19 months, and their 1-, 3-, and 5-year survival rates were 72.5%, 28.0%and 23.4%, respectively. The prognostic factors included so-cioeconomic status, smoking history, symptoms, high blood glucose, and various tumor characteristics, including perineu-ral and vascular invasion, lymph node metastases, and CA19-9 levels before and after operation. Operation-associated prog-nostic indicators included operation time, blood loss and transfusions, pancreatic ifstula, and complications. Indepen-dent predictors of mortality included poor socioeconomic sta-tus, smoking history, symptoms, CA19-9, perineural invasion and lymph node metastasis, grade of ifstula and complications. Patient survival was not correlated with either resection mar-gin or adjuvant chemotherapy in multivariate analysis. CONCLUSIONS: The survival rates of patients with curative resection for pancreatic adenocarcinoma in China are close to those in developed countries, but curative resection rate is far below. Socioeconomic status, symptoms, and CA19-9 are the three most prominent prognostic factors, which are helpful in patient selection and perioperative care.

  15. Controlled clinical study on pancreatic stenting in the relief of pain of advanced pancreatic cancer with dilated pancreatic duct

    Institute of Scientific and Technical Information of China (English)

    高飞

    2014-01-01

    Objective To explore the efficacy of pancreatic stenting in the relief of abdominal pain of advanced pancreatic cancer with dilated pancreatic duct.Methods A tolal of 61 patients with advanced pancreatic carcinoma companied with dilated pancreatic duct were divided into two groups.Twenty-eight cases(two cases were excluded because of stent loss)in stent group treated with

  16. Precision medicine in the treatment of pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Jianlin Chen; Yunmian Chu; Jin He; Lei Zheng; Xu Che

    2016-01-01

     Abstract Pancreatic cancer has a poor prognosis. Current therapies for pancreatic cancer have limited efects. In the past decade, precision medicine has shown great potential for clinical applications. In this review, diferent strategies for applying precision medicine to the treatment of pancreatic cancer are described.

  17. 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.

  18. Small nuclear ribonucleoprotein associated polypeptide N accelerates cell proliferation in pancreatic adenocarcinoma.

    Science.gov (United States)

    Ma, Jin; Zhang, Zhuo; Wang, Jiancheng

    2015-10-01

    The spliceosome, the large RNA‑protein molecular complex, is crucial for pre‑mRNA splicing. Several antitumor drugs have been found to tightly bind to the components of the spliceosome and mutations in the spliceosome have been reported in several types of cancer. However, the involvement of the spliceosome in pancreatic adenocarcinoma remains unclear. In the present study, small nuclear ribonucleoprotein associated polypeptide N (SNRPN), a key constituent of spliceosomes, was disrupted in BxPC‑3 pancreatic adenocarcinoma cells using lentivirus‑mediated RNA interference (RNAi). It was found that knockdown of SNRPN reduced the proliferation ability of BxPC‑3 cells, as determined by an MTT assay. Furthermore, cell colony formation was impaired in SNRPN depleted adenocarcinoma cells and cell cycle analysis showed that depletion of SNRPN led to S phase cell cycle arrest and apoptosis. These results suggest that SNRPN is a key player in pancreatic adenocarcinoma cell growth, and targeted loss of SNRPN may be a potential therapeutic method for pancreatic cancer.

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

    NARCIS (Netherlands)

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

  20. Cell-free plasma microRNA in pancreatic ductal adenocarcinoma and disease controls

    DEFF Research Database (Denmark)

    Carlsen, Anting Liu; Joergensen, Maiken Thyregod; Knudsen, Steen;

    2013-01-01

    There are no tumor-specific biochemical markers for pancreatic ductal adenocarcinoma (PDAC). Tissue-specific gene expression including microRNA (miRNA) profiling, however, identifies specific PDAC signatures. This study evaluates associations between circulating, cell-free plasma-miRNA profiles...

  1. Gemcitabine in elderly patients with advanced pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Olivia Hentic; Chantal Dreyer; Vinciane Rebours; Magaly Zappa; Philippe Lévy; Eric Raymond; Philippe Ruszniewski; Pascal Hammel

    2011-01-01

    AIM: To assess feasibility, tolerability and efficacy of gemcitabine-based chemotherapy in patients ≥ 75 years old with advanced pancreatic cancer. METHODS: All consecutive patients ≥ 75 years old with advanced pancreatic adenocarcinoma were included in this retrospective study. Necessary criteria to receive chemotherapy were: performance status 0-2, adequate biological parameters and no serious comorbidities. Other patients received best supportive care (BSC). RESULTS: Thirty-eight patients (53% women, median age 78 years, range 75-84) with pancreatic cancer (metastatic: n = 20, locally advanced: n = 18) were studied. Among them, 30 (79%) were able to receive chemotherapy [median number: 9 infusions (1-45)]. Six patients (23%) had at least one episode of grade 3 neutropenia and one patient developed a grade 3 hemolytic-uremic syndrome. No toxic death occurred. Three patients (11%) had a partial tumor response, 13 (46%) had a stable disease and 12 (43%) had a tumor progression. Median survival was 9.1 mo (metastatic: 6.9 mo, locally advanced: 11.4 mo). CONCLUSION: Tolerance and efficacy of gemcitabinebased chemotherapy is acceptable in elderly patients in good condition, with similar results to younger patients.

  2. Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    O'Connor, Kate; Li-Chang, Hector H; Kalloger, Steven E; Peixoto, Renata D; Webber, Douglas L; Owen, David A; Driman, David K; Kirsch, Richard; Serra, Stefano; Scudamore, Charles H; Renouf, Daniel J; Schaeffer, David F

    2015-04-01

    Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...... of intensity of the contrast signal through time-intensity curve analysis. Thus, contrast harmonic imaging-EUS has been used to differentiate pancreatic adenocarcinoma based on lower values of the peak enhancement. Future applications of CE-EUS in pancreatic adenocarcinoma include not only use of targeted...... 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...

  4. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.

    Science.gov (United States)

    Mann, Karen M; Ward, Jerrold M; Yew, Christopher Chin Kuan; Kovochich, Anne; Dawson, David W; Black, Michael A; Brett, Benjamin T; Sheetz, Todd E; Dupuy, Adam J; Chang, David K; Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Grimmond, Sean M; Rust, Alistair G; Adams, David J; Jenkins, Nancy A; Copeland, Neal G

    2012-04-17

    Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.

  5. Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives.

    Science.gov (United States)

    Dalla Pozza, Elisa; Donadelli, Massimo; Costanzo, Chiara; Zaniboni, Tatyana; Dando, Ilaria; Franchini, Marta; Arpicco, Silvia; Scarpa, Aldo; Palmieri, Marta

    2011-04-15

    Pancreatic adenocarcinoma is a common malignancy that remains refractory to all available therapies, including the gold standard drug gemcitabine (GEM). We investigated the effect of the combination of GEM and each of the ionophore compounds pyrrolidine dithiocarbamate (PDTC) and disulfiram [DSF; 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethylmethanethioamide] on p53(-/-) pancreatic adenocarcinoma cell growth. PDTC or DSF synergistically inhibited cell proliferation when used in combination with GEM by inducing apoptotic cell death. This effect was associated with an increased mitochondrial O(2)(•-) production and was further enhanced by zinc ions. Basal levels of mitochondrial O(2)(•-) or manganese superoxide dismutase (MnSOD) strictly correlated with the IC(50) for GEM or the percentage of synergism. Thus, the most relevant values of the antiproliferative synergism were obtained in GEM-resistant pancreatic adenocarcinoma cell lines. Interestingly, the GEM-sensitive T3M4 cells transfected with MnSOD expression vector showed mitochondrial O(2)(•-) and IC(50) for GEM similar to those of resistant cell lines. In vivo experiments performed on nude mice xenotransplanted with the GEM-resistant PaCa44 cell line showed that only the combined treatment with GEM and DSF/Zn completely inhibited the growth of the tumoral masses. These results and the consideration that DSF is already used in clinics strongly support the GEM and DSF/Zn combination as a new approach to overcoming pancreatic cancer resistance to standard chemotherapy.

  6. Strategies for screening for pancreatic adenocarcinoma in high-risk patients.

    Science.gov (United States)

    Canto, Marcia Irene

    2007-08-01

    Identification of high-risk individuals, genetic counseling, and informed consent are important components of a screening program for familial pancreatic cancer. Screening high-risk individuals with imaging tests, such endoscopic ultrasound (EUS) and computed tomography (CT), can lead to the detection and treatment of predominantly asymptomatic early pancreatic neoplasms, as well as extra-pancreatic tumors. These pancreatic neoplasms consist of resectable, mostly branch-type non-invasive intraductal papillary mucinous neoplasms (IPMNs). EUS can visualize these very early IPMNs as focal duct ectasias or cysts. EUS features of chronic pancreatitis are highly prevalent in high-risk individuals and these directly correlate with multifocal lobulocentric parenchymal atrophy due to multifocal pancreatic intraepithelial neoplasia (PanIN). No one molecular marker is ready for "prime time" screening of high-risk individuals. Translational studies are underway to discover novel biomarkers for IPMNs, PanIN-3 lesions, or microinvasive adenocarcinoma, which are likely to be cured by timely intervention. Long-term, multi-prospective studies are needed to determine if screening for early pancreatic neoplasia and timely intervention results in decreased pancreatic cancer incidence and mortality in high-risk individuals.

  7. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

    Science.gov (United States)

    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I; Pandol, Stephen J; Wang, Qiang

    2015-11-16

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis.

  8. Advances in Management of Acute Pancreatitis.

    Science.gov (United States)

    Janisch, Nigeen H; Gardner, Timothy B

    2016-03-01

    This article reviews advances in the management of acute pancreatitis. Medical treatment has been primarily supportive for this diagnosis, and despite extensive research efforts, there are no pharmacologic therapies that improve prognosis. The current mainstay of management, notwithstanding the ongoing debate regarding the volume, fluid type, and rate of administration, is aggressive intravenous fluid resuscitation. Although antibiotics were used consistently for prophylaxis in severe acute pancreatitis to prevent infection, they are no longer used unless infection is documented. Enteral nutrition, especially in patients with severe acute pancreatitis, is considered a cornerstone in management of this disease.

  9. Assessment of the stromal contribution to Sonic Hedgehog-dependent pancreatic adenocarcinoma.

    Science.gov (United States)

    Damhofer, Helene; Medema, Jan Paul; Veenstra, Veronique L; Badea, Liviu; Popescu, Irinel; Roelink, Henk; Bijlsma, Maarten F

    2013-12-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. It is typically detected at an advanced stage, at which the therapeutic options are very limited. One remarkable feature of PDAC that contributes to its resilience to treatment is the extreme stromal activation seen in these tumors. Often, the vast majority of tumor bulk consists of non-tumor cells that together provide a tumor-promoting environment. One of the signals that maintains and activates the stroma is the developmental protein Sonic Hedgehog (SHH). As the disease progresses, tumor cells produce increasing amounts of SHH, which activates the surrounding stroma to aid in tumor progression. To better understand this response and identify targets for inhibition, we aimed to elucidate the proteins that mediate the SHH-driven stromal response in PDAC. For this a novel mixed-species coculture model was set up in which the cancer cells are human, and the stroma is modeled by mouse fibroblasts. In conjunction with next-generation sequencing we were able to use the sequence difference between these species to genetically distinguish between the epithelial and stromal responses to SHH. The stromal SHH-dependent genes from this analysis were validated and their relevance for human disease was subsequently determined in two independent patient cohorts. In non-microdissected tissue from PDAC patients, in which a large amount of stroma is present, the targets were confirmed to associate with tumor stroma versus normal pancreatic tissue. Patient survival analysis and immunohistochemistry identified CDA, EDIL3, ITGB4, PLAUR and SPOCK1 as SHH-dependent stromal factors that are associated with poor prognosis in PDAC patients. Summarizing, the presented data provide insight into the role of the activated stroma in PDAC, and how SHH acts to mediate this response. In addition, the study has yielded several candidates that are interesting therapeutic targets for a disease for which treatment

  10. 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.

  11. QUILT-2.014: Gemcitabine and AMG 479 in Metastatic Adenocarcinoma of the Pancreas

    Science.gov (United States)

    2016-10-26

    Adenocarcinoma of the Pancreas; Advanced Solid Tumors; Cancer; Cancer of Pancreas; Cancer of the Pancreas; Metastases; Metastatic Cancer; Metastatic Pancreatic Cancer; Pancreas Cancer; Pancreatic Cancer; Bone Metastases; Endocrine Cancer; Oncology; Oncology Patients; Solid Tumors; Advanced Malignancy

  12. Resection of Late Pulmonary Metastases from Pancreatic Adenocarcinoma: Is Surgery an Option?

    Science.gov (United States)

    Brieau, Bertrand; Barret, Maximilien; Rouquette, Alexandre; Dréanic, Johann; Brezault, Catherine; Regnard, Jean François; Coriat, Romain

    2015-01-01

    Patients with recurrences from pancreas adenocarcinoma have a poor survival rate despite new chemotherapy treatment options. Recurrences are mainly hepatic metastases or peritoneal dissemination and surgical treatment is not recommended. Late and single metachronous pulmonary recurrences are uncommon and may mimic primary lung carcinoma. We report two patients with late and unique pulmonary metastasis from pancreatic cancer. These two patients underwent surgical resection; three and five years later, they did not experience recurrences. Cases called for a surgical approach in late and unique pulmonary metastases from pancreatic cancer, and paved the way for a prolonged chemotherapy free period.

  13. Novel Agents for the Treatment of Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Haiying Cheng

    2011-07-01

    Full Text Available There are urgent needs to develop novel and more effective regimens to improve outcomes of pancreatic cancer given its dismal prognosis and limited treatment options. Several phase I clinical trials involving novel agents were recently presented at the 2011 American Society of Clinical Oncology (ASCO Annual Meeting. It appears that hedgehog inhibition with IPI-926 was welltolerated and might be effective in treating pancreatic cancer when combined with gemcitabine. The survival benefits will be tested in the following randomized phase II trial. The new combination of gemcitabine and blockade of checkpoint kinases with AZD7762 showed an acceptable safety profile. Furthermore, inhibition of PI3K by BAY80-6946 was well tolerated with PET-CT suggesting reduction in FDG uptake in some pancreatic cancer. The benefits of above novel agents/regimens need to be further tested in phase II trials.

  14. Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Wu, Yanhua; Wei, Youheng; Fang, Yuan; Han, Xu; Li, Jianang; Zhou, Ping; Yi, Qing; Maitra, Anirban; Liu, Jun O; Tuveson, David A.; Lou, Wenhui; Yu, Long

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor, hypoperfused tumor, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using an adapted thick tumor section immunostaining and 3-dimensional (3D) construction imaging method in human tissue samples, we identified an undiscovered feature of the mature and angiostatic microvasculature in advanced PDAC tumors; long, “hairy”-like projections on the basal surface of microvessels that we refer to as “basal microvilli”. Functionally, these basal microvilli have an actin-rich cytoskeleton, endocytic and exocytic properties, and they contain glucose transporter-1 (GLUT-1) positive vesicles. Clinically, as was demonstrated by PET-CT, the tumor microvasculature with the longest and the most abundant basal microvilli positively correlated with the high glucose uptake of the PDAC tumor itself. In addition, these basal microvilli were found in regions of the tumor with low GLUT-1 expression, suggesting their presence could be dependent upon the glucose concentrations in the tumor milieu. Altogether, these basal microvilli mark a novel, pathological feature of the PDAC tumor microvasculature. Because these basal microvilli are pathological features with endo- and exocytic properties, they may provide a non-conventional method for cellular trafficking in PDAC tumors. PMID:25561062

  15. Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Sabine Kersting

    2012-05-01

    Full Text Available Context Rare solid tumors of the pancreas can be misinterpreted as primary pancreatic cancer. Objective The aim of this study was to report our experience in the treatment of patients with rare tumor lesions of the pancreas and to discuss clinical and pathological characteristics in the context of the role of surgery. Design Data from patients of our prospective data-base with rare benign and malignant tumors of the pancreas, treated in our division from January 2004 to August 2010, were analyzed retrospectively. Results One-thousand and ninety-eight patients with solid tumors of the pancreas underwent pancreatic surgery. In 19 patients (10 women, 9 men with a mean age of 57 years (range: 20-74 years rare pancreatic tumors (metastasis, solid pseudopapillary tumor, teratoma, hemangioma, accessory spleen, lymphoepithelial cyst, hamartoma, sarcoidosis, yolk sac tumor were the reason for surgical intervention. Conclusion If rare benign and malignant pancreatic tumors, intrapancreatic metastasis, as well as pancreatic malformations or other abnormalities, present themselves as solid masses of the pancreas, they constitute an important differential diagnosis to primary pancreatic neoplasia, e.g. pancreatic ductal adenocarcinoma. Clinical imaging techniques cannot always rule out malignancy, thus operative exploration often remains the treatment of choice to provide the correct diagnosis and initiate adequate surgical therapy.

  16. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Riazy, Maziar; Kalloger, Steve E; Sheffield, Brandon S; Peixoto, Renata D; Li-Chang, Hector H; Scudamore, Charles H; Renouf, Daniel J; Schaeffer, David F

    2015-10-01

    Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective

  17. Dual-energy perfusion-CT of pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Klauß, M., E-mail: miriam.klauss@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Stiller, W., E-mail: wolfram.stiller@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Pahn, G., E-mail: gregor.pahn@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Fritz, F., E-mail: franzi.fritz@cegug.org [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Kieser, M., E-mail: meinhard.kieser@med.uni-heidelberg.de [University of Heidelberg, Inst. of Medical Biometry and Informatics, Im Neuenheimer Feld 305, 69120 Heidelberg (Germany); Werner, J., E-mail: jens.werner@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Surgery, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Kauczor, H.U., E-mail: hans-ulrich.kauczor@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany); Grenacher, L., E-mail: lars.grenacher@med.uni-heidelberg.de [University of Heidelberg, Dpt. of Diagnostic and Interventional Radiology, Im Neuenheimer Feld 110, 69120 Heidelberg (Germany)

    2013-02-15

    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{sub p}, 140 kV{sub p}, and weighted average (linearly blended M0.3) 120 kV{sub 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{sub p}-equivalent perfusion-, permeability- and blood volume-values determined from DE image data were 0.27 ± 0.04 min{sup −1} vs. 0.91 ± 0.04 min{sup −1} (p < 0.0001), 0.5 ± 0.07 *0.5 min{sup −1} vs. 0.67 ± 0.05 *0.5 min{sup −1} (p = 0.06) and 0.49 ± 0.07 min{sup −1} vs. 1.28 ± 0.11 min{sup −1} (p < 0.0001). Compared with 80 and 140 kV{sub p} the standard deviations of the kV{sub p}120 kV{sub 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{sub p} in combination with the noise reduction at 140 kV{sub p}. Therefore using dual-energy perfusion data could improve the delineation

  18. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3 overexpression in pancreatic ductal adenocarcinoma correlates with poor survival

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    Scudamore Charles H

    2010-02-01

    Full Text Available Abstract Background Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more agrressive tumors could aid in managment decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2 and ACTB (beta-actin. Methods We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression. Results IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38% patient samples of tumor grade 1 (n = 24 and 27 (44% of tumor grade 2 (n = 61 showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42 with 26 (62% positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8. Conclusions Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

  19. KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

    Science.gov (United States)

    Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-...

  20. Systemic treatment for inoperable pancreatic adenocarcinoma: review and update

    Science.gov (United States)

    Chan, Stephen L.; Chan, Sin T.; Chan, Eric H.; He, Zhe-Xi

    2014-01-01

    There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents. PMID:24472302

  1. Recent Advances in Autoimmune Pancreatitis.

    Science.gov (United States)

    Hart, Phil A; Zen, Yoh; Chari, Suresh T

    2015-07-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term "AIP" with what is now called "type 1 AIP," we suggest using "AIP" solely for type 1 AIP and to acknowledge its own distinct disease status by using "idiopathic duct-centric chronic pancreatitis" (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ~25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP.

  2. Autoimmune pancreatitis--recent advances.

    Science.gov (United States)

    Novotný, I; Díte, P; Lata, J; Nechutová, H; Kianicka, B

    2010-01-01

    Autoimmune pancreatitis (AIP) is recognized as a distinct clinical entity, identified as a chronic inflammatory process of the pancreas in which the autoimmune mechanism is involved. Clinically and histologically, AIP has two subsets: type 1--lymphoplasmatic sclerosing pancreatitis with abundant infiltration of the pancreas and other affected organs with immunoglobulin G4-positive plasma cells, and type 2--duct centric fibrosis, characterized by granulocyte epithelial lesions in the pancreas without systemic involvement. In the diagnosis of AIP, two diagnostic criterions are used--the HISORt criteria and Asian Diagnostic Criteria. In the differential diagnosis, the pancreatic cancer must be excluded by endosonographically guided pancreatic biopsy. Typical signs of AIP are concomitant disorders in other organs (kidney, liver, biliary tract, salivary glands, colon, retroperitoneum, prostate). Novel clinicopathological entity was proposed as an 'IgG4-related sclerosing disease' (IgG4-RSC). Extensive IgG4-positive plasma cells and T lymphocyte infiltration is a common characteristics of this disease. Recently, IgG4-RSC syndrome was extended to a new entity, characterized by IgG4 hypergammaglobulinemia and IgG4-positive plasma cell infiltration, this being considered an expression of a lymphoproliferative disease, 'IgG4-positive multiorgan lymphoproliferative syndrome'. This syndrome includes Mikulicz's disease, mediastinal fibrosis, autoimmune hypophysitis, and inflammatory pseudotumor--lung, liver, breast. In the therapy of AIP, steroids constitute first-choice treatment. High response to the corticosteroid therapy is an important diagnostic criterion. In the literature, there are no case-control studies that determine if AIP predisposes to pancreatic cancer. Undoubtedly, AIP is currently a hot topic in pancreatology.

  3. MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Kennichi eSatoh

    2012-11-01

    Full Text Available MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC and intraductal papillary-mucinous neoplasia (IPMN harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level.

  4. Expression of Ki-67, p53, and K-ras in chronic pancreatitis and pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Seok Jeong; Young Bae Kim; Don Haeng Lee; Jung Il Lee; Jin-Woo Lee; Kye Sook Kwon; Pum-Soo Kim; Hyung Gil Kim; Yong Woon Shin; Young Soo Kim

    2005-01-01

    AIM: To examine surgical specimens of pancreas with either chronic pancreatitis or pancreatic cancer in order to study whether ductal hyperplasia and dysplasia in pancreas represent precursor lesions for pancreatic cancer.METHODS: We examined expression of Ki-67, CEA,p53, and K-ras, in the surgical specimens of pancreas with adenocarcinomas (n = 11) and chronic pancreatitis (n = 12). Cellular proliferation was assessed by Ki-67proliferation index using the proliferation marker Ki-67.In specimens with pancreas cancer, we divided pancreas epithelium into normal (n=7), ductal hyperplasia (n=3), dysplasia (n=4), and cancerous lesion (n=11) after hematoxylin and eosin staining, Ki-67, and CEA immunohistochemical staining. In cases with chronic pancreatitis, the specimen was pathologically examined as in cases with pancreas cancer, and they were also determined as normal (n=10), ductal hyperplasia (n=4), or dysplasia (n= 5). p53 and K-ras expression were also studied by immunohistochemical staining.RESULTS: In pancreatic cancer, the Ki-67 index was 3.73±3.58 in normal site, 6.62±4.39 in ductalhyperplasia, 13.47±4.02 in dysplasia and 37.03±10.05in cancer tissue, respectively. Overall, p53 was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 14 (0%), 0 of 7 (0%), 7 of 9 (78%),and 10 of 11 (91%), respectively, and K-ras was positive in 0 of 8 (0%), 1 of 3 (33%), 4 of 6 (67%), 4 of 5 (80%),respectively.CONCLUSION: Our results favorably support the hypothesis that ductal hyperplasia and dysplasia of the pancreas might be precursor lesions for pancreas cancer.Further evaluation of oncogenes by the molecular study is needed.

  5. Dynamic Contrast Enhanced MRI in Patients With Advanced Breast or Pancreatic Cancer With Metastases to the Liver or Lung

    Science.gov (United States)

    2014-05-28

    Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Liver Metastases; Lung Metastases; Recurrent Breast Cancer; Recurrent Pancreatic Cancer; Stage IV Breast Cancer; Stage IV Pancreatic Cancer

  6. Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

    Science.gov (United States)

    Laeseke, Paul F; Chen, Ru; Jeffrey, R Brooke; Brentnall, Teresa A; Willmann, Jürgen K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.

  7. The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas.

    Science.gov (United States)

    Liang, Shan; Yang, Zhulin; Li, Daiqiang; Miao, Xiongying; Yang, Leping; Zou, Qiong; Yuan, Yuan

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, but the genetic basis of PDAC is still unclear. In this study, Nectin-2 and DDX3 expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues were measured by immunohistochemical methods. Results showed that the percentage of positive Nectin-2 and DDX3 expression was significantly higher in PDAC tumors than in peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P DDX3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion and having TNM stage I/II disease than in patients with lymph node metastasis, invasion, and TNM stage III/IV disease (P DDX3 expression is associated with poor differentiation of PDAC. Kaplan-Meier survival analysis showed that positive Nectin-2 and DDX3 expression were significantly associated with survival in PDAC patients (P DDX3 expression were independent poor prognosis factors in PDAC patients. In conclusion, positive Nectin-2 and DDX3 expression are associated with the progression and poor prognosis in PDAC patients.

  8. The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Shan Liang

    2015-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a highly malignant disease, but the genetic basis of PDAC is still unclear. In this study, Nectin-2 and DDX3 expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues were measured by immunohistochemical methods. Results showed that the percentage of positive Nectin-2 and DDX3 expression was significantly higher in PDAC tumors than in peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P<0.01. The percentage of cases with positive Nectin-2 and DDX3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion and having TNM stage I/II disease than in patients with lymph node metastasis, invasion, and TNM stage III/IV disease (P<0.05 or P<0.01. Positive DDX3 expression is associated with poor differentiation of PDAC. Kaplan-Meier survival analysis showed that positive Nectin-2 and DDX3 expression were significantly associated with survival in PDAC patients (P<0.001. Cox multivariate analysis revealed that positive Nectin-2 and DDX3 expression were independent poor prognosis factors in PDAC patients. In conclusion, positive Nectin-2 and DDX3 expression are associated with the progression and poor prognosis in PDAC patients.

  9. Pancreatic adenocarcinoma presenting with sudden onset bilateral deafness secondary to metastatic leptomeningeal infiltration.

    Science.gov (United States)

    Blows, Samuel Joseph; Morgan, Richard; Dhariwal, Umeet; Petts, Gemma; Roncaroli, Frederico

    2012-11-01

    Deafness is a very common problem in older persons. We present a case of metastatic adenocarcinoma of the pancreas with deafness being the patient's only reason for seeking medical attention. The patient had bilateral vestibulocochlear nerve palsies with associated lower motor neurone facial nerve palsies and a bulbar palsy. Magnetic resonance imaging of his brain was unremarkable. It was only on post-mortem histology that tumour infiltrating the leptomeninges was demonstrated. Leptomeningeal metastases are rarely associated with adenocarcinoma of the pancreas. A review of the literature reveals only two other case reports of mestatic pancreatic carcinoma presenting with deafness but both had demonstrable temporal bone lesions on MRI as opposed to the meninges.

  10. Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between

    Institute of Scientific and Technical Information of China (English)

    Natalia JURA; Herbert ARCHER; Dafna BAR-SAGI

    2005-01-01

    Pancreatic cancer is a challenging disease for patients, doctors and researchers who for decades have searched for a cure for this deadly malignancy. Although existing mouse models of pancreatic cancer have shed light on the mechanistic basis of the neoplastic conversion of the pancreas, their impact in terms of offering new diagnostics and therapeutic modalities remains limited. Chronic pancreatitis is an inflammatory disease of the pancreas that is associated with a gradual damage of the organ and an increased risk of developing neoplastic lesions. In this review, we propose that detailed studies of chronic inflammatory processes in the pancreas will provide insights into the evolution of pancreatic cancer. This information may prove useful in the design of effective therapeutic strategies to battle the disease.

  11. Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment.

    Science.gov (United States)

    Singh, Puneet; Srinivasan, Radhika; Wig, Jai Dev

    2011-07-01

    Pancreatic cancer is notorious for its late presentation, early and aggressive local invasion, metastatic potential, and poor outcome. It presents at a clinically advanced stage that precludes the possibility of surgical resection in most cases and shows constitutive resistance to chemotherapy and radiotherapy in others. As a result, mortality from this disease parallels its incidence rates.Recent breakthroughs in the molecular biology of pancreatic cancer have assisted in translational research, giving hope for individualized therapy and better disease management. Molecular biology tools are guiding early diagnosis, the assessment of prognosis, and isolation of novel, more effective therapeutic targets.This review discusses the signature mutations of pancreatic cancer, implications of these mutations to pancreatic cancer biology, their linked pathways, and recent advances in their understanding as biomarkers as diagnostic, prognostic, and therapeutic tools in dealing with this disease.

  12. Laparoscopic distal pancreatectomy with preservation of the spleen and splenic vessels for pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Yan-Guo Zheng

    2009-06-01

    Full Text Available Background: A laparoscopic surgery can be beneficial in a spleen-preserving distal pancreatectomy. Aims: This report shows a 60-year-old woman who presented to her persistent upper abdominal and bilateral lumbodorsal distending pain for one year. A computed tomography scan demonstrated a 4cm×5cm×5cm solid space-occupying mass in the distal pancreas. The patient was referred to minimally invasive surgery service for resection of the pancreatic lesion. Methods: A laparoscopic spleen-preserving distal pancreatectomy was performed. Results: The mass was completely excised, the pathological examination revealed pancreatic adenocarcinoma with grade II. The postoperative advantages of this approach were the early return of bowel function, minimal complications, and early resumption of normal activities. Conclusions: This case illustrates that minimally invasive surgery in the performance of a spleen-and-splenic-vessel preserving distal pancreatectomy is a feasible procedure without compromising the splenic function.

  13. Novel Agents in the Management of Pancreatic Adenocarcinoma: Phase I Studies

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    Anastasios T Dimou

    2011-03-01

    Full Text Available Pancreatic adenocarcinoma has repetitively proved refractory to chemotherapy and biologic compounds with only a few drugs offering limited benefit. A number of novel regimens has been tested in phase I trials and reported recently in the 2011 American Society of Clinical Oncology (ASCO Gastrointestinal Cancers Symposium. Specifically, a novel mitogen-activated protein kinase kinase (MEK inhibitor, a connective tissue growth factor inhibitor, a coagulase factor VIIa inhibitor, as well as adenovirus delivery of herpes simplex virus thymidine synthase gene followed by anti-herpetic treatment have all proven to be safe in pancreatic cancer patients. Phase II trials will provide further evidence whether they can become clinically relevant in the future.

  14. Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists.

    Science.gov (United States)

    Brandi, Jessica; Dando, Ilaria; Palmieri, Marta; Donadelli, Massimo; Cecconi, Daniela

    2013-05-01

    The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down-regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.

  15. Detection of Pancreatic Ductal Adenocarcinoma in Mice by Ultrasound Imaging of Thymocyte Differentiation Antigen 1

    Science.gov (United States)

    Foygel, Kira; Wang, Huaijun; Machtaler, Steven; Lutz, Amelie M.; Chen, Ru; Pysz, Marybeth; Lowe, Anson W.; Tian, Lu; Carrigan, Tricia; Brentnall, Teresa A.; Willmann, Jürgen K.

    2013-01-01

    BACKGROUND & AIMS Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging. METHODS Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC. RESULTS Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC. CONCLUSION We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients. PMID:23791701

  16. 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.

  17. Expression of the "stem cell marker" CD133 in pancreas and pancreatic ductal adenocarcinomas

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    Sakariassen Per

    2008-02-01

    Full Text Available Abstract Background It has been suggested that a small population of cells with unique self-renewal properties and malignant potential exists in solid tumors. Such "cancer stem cells" have been isolated by flow cytometry, followed by xenograft studies of their tumor-initiating properties. A frequently used sorting marker in these experiments is the cell surface protein CD133 (prominin-1. The aim of this work was to examine the distribution of CD133 in pancreatic exocrine cancer. Methods Fifty-one cases of pancreatic ductal adenocarcinomas were clinically and histopathologically evaluated, and immunohistochemically investigated for expression of CD133, cytokeratin 19 and chromogranin A. The results were interpreted on the background of CD133 expression in normal pancreas and other normal and malignant human tissues. Results CD133 positivity could not be related to a specific embryonic layer of organ origin and was seen mainly at the apical/endoluminal surface of non-squamous, glandular epithelia and of malignant cells in ductal arrangement. Cytoplasmic CD133 staining was observed in some non-epithelial malignancies. In the pancreas, we found CD133 expressed on the apical membrane of ductal cells. In a small subset of ductal cells and in cells in centroacinar position, we also observed expression in the cytoplasm. Pancreatic ductal adenocarcinomas showed a varying degree of apical cell surface CD133 expression, and cytoplasmic staining in a few tumor cells was noted. There was no correlation between the level of CD133 expression and patient survival. Conclusion Neither in the pancreas nor in the other investigated organs can CD133 membrane expression alone be a criterion for "stemness". However, there was an interesting difference in subcellular localization with a minor cell population in normal and malignant pancreatic tissue showing cytoplasmic expression. Moreover, since CD133 was expressed in shed ductal cells of pancreatic tumors and was

  18. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Peng Huang; Chun-You Wang; Shan-Miao Gou; He-Shui Wu; Tap Liu; Jiang-Xin Xiong

    2008-01-01

    AIM: To explore the method of isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma cell line PANC-1.METHODS: The PANC-1 cells were cultured in Dulbecco modified eagle medium F12 (1:1 volume)(DMEM-F12) supplemented with 20% fetal bovine serum (FBS).Subpopulation cells with properties of tumor stem cells were isolated from pancreatic adenocarcinoma cell line PANC-1 according to the cell surface markers CD44 and CD24 by flow cytometry.The proliferative capability of these cells in vitro were estimated by 3-[4,5-dimehyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) method.And the tumor growth of different subpopulation cells which were injected into the hypodermisof right and left armpit of nude mice was studied,and expression of CD44 and CD24 of the CD44+CD24+ cell-formed nodules and PANC-1 cells were detected by avidin-biotin-peroxidase complex (ABC) immunohistochemical staining.RESULTS: The 5.1%-17.5% of sorted PANC-1 cells expressed the cell surface marker CD44,57.8% -70.1% expressed CD24,only 2.1%-3.5% of cells were CD44+ CD24+.Compared with CD44-CD24- cells,CD44+CD24+ cells had a lower growth rate in vitro.Implantation of 104 CD44 CD24- cells in nude mice showed no evident tumor growth at wk 12.In contrast,large tumors were found in nude mice implanted with 103 CD44+CD24+ cells at wk 4 (2/8),a 20-fold increase in tumorigenic potential (P<0.05 or P<0.01).There was no obvious histological difference between the cells of the CD44+CD24+ cell-formed nodules and PANC-1 cells.CONCLUSION: CD44 and CD24 may be used as the cell surface markers for isolation of pancreatic cancer stem cells from pancreatic adenocarcinoma cell line PANC-1.Subpopulation cells CD44+CD24+ have properties of tumor stem cells.Because cancer stem cells are thought to be responsible for tumor initiation and its recurrence after an initial response to chemotherapy,it may be a very promising target for new drug development.

  19. Role of anti-stromal polypharmacy in increasing survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Samuel; J; Tingle; John; A; Moir; Steven; A; White

    2015-01-01

    AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma(PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors(ACEI)/angiotensin Ⅱ receptor blockers(ARB), calcium channel blockers(CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects.RESULTS: No survival benefit was observed with respect to ACEI/ARB(n = 41), aspirin or statins on individual drug analysis(n = 39). However, the entire CCB group(n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio(HR) of 0.475(CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group(n = 15) compared with the group taking neither drug(n = 98); 1414 d vs 601 d(P = 0.029, logrank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332(CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination.CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.

  20. 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.

  1. The incremental benefit of EUS for identifying unresectable disease among adults with pancreatic adenocarcinoma: A meta-analysis

    Science.gov (United States)

    James, Paul D.; Zhang, Mei; Belletrutti, Paul J.; Mohamed, Rachid; Ghali, William; Roberts, Derek J.; Martel, Guillaume; Heitman, Steven J.

    2017-01-01

    Background and study aims It is unclear to what extent EUS influences the surgical management of patients with pancreatic adenocarcinoma. This systematic review sought to determine if EUS evaluation improves the identification of unresectable disease among adults with pancreatic adenocarcinoma. Patients and methods We searched MEDLINE, EMBASE, bibliographies of included articles and conference proceedings for studies reporting original data regarding surgical management and/or survival among patients with pancreatic adenocarcinoma, from inception to January 7th 2017. Our main outcome was the incremental benefit of EUS for the identification of unresectable disease (IBEUS). The pooled IBEUS were calculated using random effects models. Heterogeneity was explored using stratified meta-analysis and meta-regression. Results Among 4,903 citations identified, we included 8 cohort studies (study periods from 1992 to 2007) that examined the identification of unresectable disease (n = 795). Random effects meta-analysis suggested that EUS alone identified unresectable disease in 19% of patients (95% confidence interval [CI], 10–33%). Among those studies that considered portal or mesenteric vein invasion as potentially resectable, EUS alone was able to identify unresectable disease in 14% of patients (95% CI 8–24%) after a CT scan was performed. Limitations The majority of the included studies were retrospective. Conclusions EUS evaluation is associated with increased identification of unresectable disease among adults with pancreatic adenocarcinoma. PMID:28319148

  2. 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

  3. 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.

  4. Total Pancreatectomy and Islet Auto-Transplantation as Treatment for Ampullary Adenocarcinoma in the Setting of Pancreatic Ductal Disruption Secondary to Acute Necrotizing Pancreatitis. A Case Report

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    Uroghupatei P Iyegha

    2012-03-01

    Full Text Available Context Ampullary adenocarcinoma is the third most common periampullary malignancy. Obstruction of the main pancreatic duct is linked with an increased incidence of acute pancreatitis. Acute necrotizing pancreatitis leading to pancreatic duct disruption carries significant morbidity. When these conditions occur in combination, the treatment can be drastically limited as pancreaticoduodenectomy is not a viable option in the setting of friable ductal tissue, which precludes pancreatic ductal anastomosis and can lead to the complications of leak or stricture. Case report Our patient is a 72-year-old woman who developed pancreatic ductal disruption and splenic vein thrombosis as a result of acute necrotizing pancreatitis. Concurrently, she was found to have an ampullary adenoma with high-grade dysplasia. Her treatment options were limited, as she was neither a candidate for pancreaticoduodenectomy given the ductal disruption nor total pancreatectomy, which would render her a brittle diabetic. She was successfully treated with total pancreatectomy and islet auto-transplantation thereby resecting her ampullary lesion while both avoiding a pancreatic anastomosis and preserving pancreatic endocrine beta-cell function. Conclusion We report a case where total pancreatectomy and islet auto-transplantation can be considered as a viable option for treatment of ampullary lesions in a setting where standard surgical options are suboptimal.

  5. ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.

    Science.gov (United States)

    Rath, Nicola; Morton, Jennifer P; Julian, Linda; Helbig, Lena; Kadir, Shereen; McGhee, Ewan J; Anderson, Kurt I; Kalna, Gabriela; Mullin, Margaret; Pinho, Andreia V; Rooman, Ilse; Samuel, Michael S; Olson, Michael F

    2017-02-01

    Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras(G12D)/p53(R172H) mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK-induced genes that facilitate extracellular matrix remodeling, with greatest fold-changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13 MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three-dimensional contexts. Treatment of Kras(G12D)/p53(R172H) PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor-associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

  6. Proteomic identification of potential prognostic biomarkers in resectable pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Iuga, Cristina; Seicean, Andrada; Iancu, Cornel; Buiga, Rareş; Sappa, Praveen K; Völker, Uwe; Hammer, Elke

    2014-04-01

    Pancreatic cancer is a devastating disease with a mortality rate almost identical with its incidence. In this context, the investigation of the pancreatic cancer proteome has gained considerable attention because profiles of proteins may be able to identify disease states and progression more accurately. Therefore, our objective was to investigate the changes in the proteome of patients suffering from pancreatic ductal adenocarcinoma (PDAC) by a comprehensive quantitative approach. Comparative proteomic profiling by label-free LC-MS/MS analysis of nine matched pairs of tumor and nontumor pancreas samples was used to identify differences in protein levels characteristic for PDAC. In this analysis, 488 proteins were quantified by at least two peptides of which 99 proteins displayed altered levels in PDAC (p 1.3). Screening of data revealed a number of molecules that had already been related to PDAC such as galectin-1 (LEG1), major vault protein, adenylyl cyclase-associated protein 1 (CAP1), but also a potential new prognostic biomarker prolargin (PRELP). The Kaplan-Meier survival analysis revealed a significant correlation of protein abundance of PRELP with postoperative survival of patients with PDAC. For selected proteins the findings were verified by targeted proteomics (SRM), validated by immunohistochemistry and Western blotting and their value as candidate biomarkers is discussed.

  7. Neurotensin is a Versatile Modulator of In Vitro Human Pancreatic Ductal Adenocarcinoma Cell (PDAC Migration

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    Tatjana Mijatovic

    2007-01-01

    Full Text Available Background: While the neurotensin (NT roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.

  8. Prognostic analysis of patients with pancreatic head adenocarcinoma less than 2 cm undergoing resection

    Institute of Scientific and Technical Information of China (English)

    Kun-Chun Chiang; Chun-Nan Yeh; Wei-Chen Lee; Yi-Yin Jan; Tsann-Long Hwang

    2009-01-01

    AIM: To investigate the differences in clinicopathological features between patients with pancreatic cancer greater or less than 2 cm situated over the pancreatic head and the prognostic factors for survival of patients with pancreatic cancer < 2 cm over the pancreatic head. METHODS: From 1983 to 2006, 159 patients with histologically proven pancreatic adenocarcinoma (PAC) at the pancreatic head undergoing curative resection at the Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan were reviewed, comprising 123 cases of large (L)-PAC (tumor > 2 cm) and 36 cases of small (S)-PAC (tumor ≤ 2 cm). We compared the clinicopathological characteristics and prognosis of L-PAC and S-PAC patients. The clinicopathological characteristics of S-PAC were investigated to clarify the prognosis predictive factors of S-PAC. RESULTS: One hundred and fifty-nine PAC patients, aged 16-93 years (median, 59.0 years) with a tumor at the pancreatic head undergoing intentional curative resection were investigated. The S-PAC and L-PAC patients had similar demographic data, clinical features, and tumor markers (a similar positive rate of carcinoembryonic antigen and carbohydrate antigen 19-9). There were also similar rates of lymph node metastasis, portal vein invasion, stage distribution, tumor differentiation, positive resection margin, surgical morbidity and mortality observed between the two groups. During a follow-up period ranging from 1.0 to 122.7 mo (median, 10.9 mo), S-PAC and L-PAC patients had a similar prognosis after resection (P = 0.4805). Among the S-PAC patients group, patients with higher albumin level (> 3.5 g/dL) had more favorable survival than those with lower albumin levels, which was the only favorable predictive prognostic factor. Meanwhile, early-staged (stage Ⅰ, Ⅱ) S-PAC patients tended to have a more favorable outcome than late-stage (stage Ⅲ, Ⅳ) S-PAC patients, but this was not statistically significant. CONCLUSION: S-PAC patients

  9. The Impact on Clinical Practice of Endoscopic Ultrasonography Used for the Diagnosis and Staging of Pancreatic Adenocarcinoma

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    Queneau PE

    2001-05-01

    Full Text Available CONTEXT: Endoscopic ultrasonography is considered a highly accurate procedure for diagnosing small pancreatic tumors and assessing their locoregional extension. OBJECTIVE: To evaluate the impact of endoscopic ultrasonography on the management of pancreatic adenocarcinoma in clinical practice. PATIENTS: Sixty-four consecutive patients (mean age 70.5 plus/minus 11.9 years hospitalized for staging or diagnosis of pancreatic adenocarcinoma were retrospectively (from January 1995 to November 1997 or prospectively studied (from December 1997 to August 1999. SETTING: Group 1 consisted of 52 patients with pancreatic adenocarcinoma which was discovered using computerized tomography scanning and/or ultrasound. Endoscopic ultrasonography was utilized for staging purposes only in patients who were considered to be operable and the tumor to be resectable based on computerized tomography scanning criteria. Group 2 consisted of 12 patients who were diagnosed as having a pancreatic adenocarcinoma using endoscopic ultrasonography whereas computerized tomography scanning and ultrasound was negative. MAIN OUTCOME MEASURES: The impact of endoscopic ultrasonography was analyzed on the basis of the number of patients requiring endoscopic ultrasonography as a staging procedure (Group 1 and by evaluating the performance of endoscopic ultrasonography in determining resectability (Groups 1 and 2 based on the surgical and anatomopathological results. RESULTS: Endoscopic ultrasonography was performed in 20 out of 64 patients (31.3%: 8/52 in Group 1 (15.4% and all 12 patients of Group 2. Endoscopic ultrasonography correctly assessed an absolute contraindication to resection in 11 cases. Resection was confirmed in 8 of the 9 cases selected by endoscopic ultrasonography. The positive predictive value, negative predictive value and overall accuracy of endoscopic ultrasonography for determining resection were 89%, 100%, and 95%, respectively. CONCLUSIONS: The impact of

  10. Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Vaz, Arokia Priyanka; Deb, Shonali; Rachagani, Satyanarayana; Dey, Parama; Muniyan, Sakthivel; Lakshmanan, Imayavaramban; Karmakar, Saswati; Smith, Lynette; Johansson, Sonny; Lele, Subodh; Ouellette, Michel; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value < 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo. Interestingly, PD2 overexpression also resulted in enrichment of cancer stem cells (CSCs) and upregulation of oncogenes such as c-Myc and cell cycle progression marker, cyclin D1. Taken together, our results support that PD2 is overexpressed in the ducts of PDAC tissues, and results in tumorigenesis and metastasis via upregulation of oncogenes such as c-Myc and cyclin hence D1 implicating PD2 upregulation in pancreatic oncogenesis with targeted therapeutic potential. PMID:26689992

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

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    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.

  12. Complete Response after Treatment with Neoadjuvant Chemoradiation with Prolonged Chemotherapy for Locally Advanced, Unresectable Adenocarcinoma of the Pancreas

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    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.

  13. 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

    2015-01-01

    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 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. PMID:26522614

  14. Pancreatic Cancer Early Detection Program

    Science.gov (United States)

    2014-07-30

    Pancreatic Cancer; Pancreas Cancer; Pancreatic Adenocarcinoma; Familial Pancreatic Cancer; BRCA 1/2; HNPCC; Lynch Syndrome; Hereditary Pancreatitis; FAMMM; Familial Atypical Multiple Mole Melanoma; Peutz Jeghers Syndrome

  15. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

    Institute of Scientific and Technical Information of China (English)

    Hans U. Kasper; Hella Wolf; Uta Drebber; Helmut K. Wolf; Michael A. Kern

    2004-01-01

    AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide.Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas.METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ducal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data.RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2.The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density.However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data.CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.

  16. Hepatic Artery Chemotherapy for Advanced Adenocarcinoma of the Pancreas

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    Robert Levin

    2016-08-01

    Full Text Available Context Seventy patients with adenocarcinoma of the pancreas with liver metastases, received chemotherapy every four weeks and their outcomes are reported in this retrospective series. Objective Advanced adenocarcinoma of the pancreas has a poor prognosis with only 2% 5-year survival reported by SEER (Surveillance, Epidemiology and End Results of the NCI. Chemotherapy given as intra-arterial perfusions is more intense than intravenous chemotherapy. Responses in perfused tumor is expected to be better than that obtained with only intravenous chemotherapy. Design Hepatic artery therapy is given monthly as a 5 hour perfusion of the hepatic artery using DDP and MIC. Also given is monthy Intravenous (IV therapy with four hours of Leucovorin (LV, with an injection of FUDR during the last hour of LV, daily x 5 days. Setting all therapy was given at Midwestern Regional Medical Center. Patients Thirty seven patients had no prior chemotherapy, while 33 patients had progressed after prior IV chemotherapy. Intervention Hepatic artery therapy with IV LV-FUDR was given for up to six months depending upon marrow tolerance and response. At that point, if response was ongoing or improving, therapy was continued monthly with only IV LV-FUDR; all therapy was stopped whenever progressive disease was evident. Results of those without prior chemotherapy, the mean overall survival (OS was 17.3 ± 30.2 months (mean±SD, ranging up to 13 years. Six patients survived more than three years with four are living in continuing complete remission for more than five years. Conclusion This therapy offers the opportunity for long term survival in a subset of patients with metastatic adenocarcinoma of the pancreas who have liver metastases, and some patients can be cured.

  17. A Multicenter Trial Defining a Serum Protein Signature Associated with Pancreatic Ductal Adenocarcinoma

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    Anna S. Gerdtsson

    2015-01-01

    Full Text Available Background. Pancreatic ductal adenocarcinoma (PDAC is an aggressive disease with rapid tumor progression and poor prognosis. This study was motivated by the lack of sensitive and specific PDAC biomarkers and aimed to identify a diagnostic, serum protein signature for PDAC. Methods. To mimic a real life test situation, a multicenter trial comprising a serum sample cohort, including 338 patients with either PDAC or other pancreatic diseases (OPD and controls with nonpancreatic conditions (NPC, was analyzed on 293-plex recombinant antibody microarrays targeting immunoregulatory and cancer-associated antigens. Results. Serum samples collected from different hospitals were analyzed and showed that (i sampling from five different hospitals could not be identified as a preanalytical variable and (ii a multiplexed biomarker signature could be identified, utilizing up to 10 serum markers that could discriminate PDAC from controls, with sensitivities and specificities in the 91–100% range. The first protein profiles associated with the location of the primary tumor in the pancreas could also be identified. Conclusions. The results demonstrate that robust enough serum signatures could be identified in a multicenter trial, potentially contributing to the development of a multiplexed biomarker immunoassay for improved PDAC diagnosis.

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

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    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.

  19. ROCK signalling induced gene expression changes in mouse pancreatic ductal adenocarcinoma cells

    Science.gov (United States)

    Rath, Nicola; Kalna, Gabriela; Clark, William; Olson, Michael F.

    2016-01-01

    The RhoA and RhoC GTPases act via the ROCK1 and ROCK2 kinases to promote actomyosin contraction, resulting in directly induced changes in cytoskeleton structures and altered gene transcription via several possible indirect routes. Elevated activation of the Rho/ROCK pathway has been reported in several diseases and pathological conditions, including disorders of the central nervous system, cardiovascular dysfunctions and cancer. To determine how increased ROCK signalling affected gene expression in pancreatic ductal adenocarcinoma (PDAC) cells, we transduced mouse PDAC cell lines with retroviral constructs encoding fusion proteins that enable conditional activation of ROCK1 or ROCK2, and subsequently performed RNA sequencing (RNA-Seq) using the Illumina NextSeq 500 platform. We describe how gene expression datasets were generated and validated by comparing data obtained by RNA-Seq with RT-qPCR results. Activation of ROCK1 or ROCK2 signalling induced significant changes in gene expression that could be used to determine how actomyosin contractility influences gene transcription in pancreatic cancer. PMID:27824338

  20. CYP1B1 polymorphisms and k-ras mutations in patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Crous-Bou, Marta; De Vivo, Immaculata; Porta, Miquel; Pumarega, José A; López, Tomàs; Alguacil, Joan; Morales, Eva; Malats, Núria; Rifà, Juli; Hunter, David J; Real, Francisco X

    2008-05-01

    The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways.

  1. Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt/planar cell polarity signaling.

    Science.gov (United States)

    He, Ping; Jiang, Shuheng; Ma, Mingze; Wang, Yang; Li, Rongkun; Fang, Fang; Tian, Guangang; Zhang, Zhigang

    2015-07-01

    Trophoblast glycoprotein (TPBG), a 72 kDa glycoprotein was identified using a monoclonal antibody, which specifically binds human trophoblast. The expression of TPBG in normal tissues is limited; however, it is upregulated in numerous types of cancer. When TPBG is expressed at a high level, this usually indicates a poor clinical outcome. In the present study, it was demonstrated that TPBG was more commonly observed in human pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue. Immunohistochemical analysis of PDAC tissue microarrays indicated that the expression of TPBG in PDAC tissues was closely correlated with the tumor-node-metastasis stage of the tumor. Silencing of TPBG in PDAC cell lines resulted in a decreased ability of cancer cell migration and invasion. Further investigation demonstrated that the Wnt/planar cell polarity signaling pathway was suppressed, as the expression of Wnt5a and the activation of c-Jun N-terminal kinase was inhibited following TPBG knockdown. In conclusion, the present study provided evidence that TPBG is involved in PDAC metastasis, and that TPBG and its associated signaling pathways may be a suitable target for PDAC therapy.

  2. 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.

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

    Science.gov (United States)

    Ricci, Claudio; Mota, Carlos; Moscato, Stefania; D'Alessandro, Delfo; Ugel, Stefano; Sartoris, Silvia; Bronte, Vincenzo; Boggi, Ugo; Campani, Daniela; Funel, Niccola; Moroni, Lorenzo; Danti, Serena

    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 alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.

  4. 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.

  5. Single- versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Pollom, Erqi L.; Alagappan, Muthuraman; Eyben, Rie von [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Kunz, Pamela L.; Fisher, George A.; Ford, James A. [Department of Medicine, Stanford University School of Medicine, Stanford, California (United States); Poultsides, George A.; Visser, Brendan C.; Norton, Jeffrey A. [Department of Surgery, Stanford University School of Medicine, Stanford, California (United States); Kamaya, Aya; Cox, Veronica L. [Department of Radiology, Stanford University School of Medicine, Stanford, California (United States); Columbo, Laurie A.; Koong, Albert C. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Chang, Daniel T., E-mail: dtchang@stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States)

    2014-11-15

    Purpose: We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma. Methods and Materials: We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy. Results: Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival. Conclusions: Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

  6. 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.)

  7. Effect of CCR7, CXCR4 and VEGF-C on the lymph node metastasis of human pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Guo, Jinghui; Lou, Wenhui; Ji, Yuan; Zhang, Shuncai

    2013-05-01

    The aim of the present study was to investigate the association between the expression of chemokine receptors CCR7 and CXCR4 and vascular endothelial growth factor (VEGF)-C and the lymph node metastasis of pancreatic ductal adenocarcinoma (PDAC). The mRNA transcription levels of CCR7, CXCR4 and VEGF-C were measured in 24 specimens by real-time reverse transcription (RT)-PCR, while the protein expression levels were measured in 65 specimens by immuohistochemistry. Professional software for pathological image manipulation (Image Pro Plus 6.0) was used to quantitate the results of the immunohistochemical staining. The mRNA and protein expression levels of CCR7, CXCR4 and VEGF-C were all significantly higher in the cancer samples compared with those in the adjacent normal tissue. The CCR7 and VEGF-C mRNA and protein expression levels were significantly higher in the patients with cancer types exhibiting lymph node metastasis and an advanced International Union Against Cancer (UICC) stage (PCCR7 expression (PCCR7 and VEGF-C (P0.05), however the strong positive expression of CCR7 and VEGF-C was significantly associated with the lymph node metastasis of PDAC.

  8. ADH-1, Gemcitabine Hydrochloride and Cisplatin in Treating Patients With Metastatic Pancreatic or Biliary Tract Cancer That Cannot Be Removed By Surgery

    Science.gov (United States)

    2013-05-07

    Acinar Cell Adenocarcinoma of the Pancreas; Adenocarcinoma of the Gallbladder; Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Gallbladder; Duct Cell Adenocarcinoma of the Pancreas; Localized Unresectable Adult Primary Liver Cancer; Periampullary Adenocarcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Gallbladder Cancer; Recurrent Pancreatic Cancer; Stage II Gallbladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IV Pancreatic Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer

  9. 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.)

  10. Pancreatic Resections for Advanced M1-Pancreatic Carcinoma: The Value of Synchronous Metastasectomy

    Directory of Open Access Journals (Sweden)

    S. K. Seelig

    2010-01-01

    Materials and Methods. From January 1, 2004 to December, 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic, adjacent organ, or peritoneal metastases for proven UICC stage IV periampullary cancer of the pancreas. Perioperative as well as clinicopathological parameters were evaluated. Results. There were 20 patients (9 men, 11 women; mean age 58 years identified. The primary tumor was located in the pancreatic head (n=9, 45%, in pancreatic tail (n=9, 45%, and in the papilla Vateri (n=2, 10%. Metastases were located in the liver (n=14, 70%, peritoneum (n=5, 25%, and omentum majus (n=2, 10%. Lymphnode metastases were present in 16 patients (80%. All patients received resection of their tumors together with metastasectomy. Pylorus preserving duodenopancreatectomy was performed in 8 patients, distal pancreatectomy in 8, duodenopancreatectomy in 2, and total pancreatectomy in 2. Morbidity was 45% and there was no perioperative mortality. Median postoperative survival was 10.7 months (2.6–37.7 months which was not significantly different from a matched-pair group of patients who underwent pancreatic resection for UICC adenocarcinoma of the pancreas (median survival 15.6 months; P=.1. Conclusion. Pancreatic resection for M1 periampullary cancer of the pancreas can be performed safely in well-selected patients. However, indication for surgery has to be made on an individual basis.

  11. Relationship between clinicopathological features and mucin phenotypes of advanced gastric adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Fumiaki; Toki; Atsushi; Takahashi; Ryusuke; Aihara; Kyoichi; Ogata; Hiroyuki; Ando; Tetsuro; Ohno; Erito; Mochiki; Hiroyuki; Kuwano

    2010-01-01

    AIM: To investigate a relationship between the clinicopathological features and mucin phenotypes in advanced gastric adenocarcinoma (AGA). METHODS: Immunohistochemical staining was performed to determine the mucin phenotypes in 38 patients with differentiated adenocarcinomas (DACs), 9 with signet-ring cell carcinomas (SIGs), and 48 with other diffuse-type adenocarcinomas (non-SIGs) of AGA. The mucin phenotypes were classified into 4 types: gastric (G), gastrointestinal (GI), intestinal, and unclassified. RE...

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

    Science.gov (United States)

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

    2015-04-01

    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.

  13. Synchronous advanced gastric adenocarcinoma and advanced esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Fernando Augusto Mardiros Herbella

    2002-01-01

    Full Text Available CONTEXT: Synchronous associations of esophageal and gastric cancers are not a common finding, especially with differing histological types and both tumors in advanced forms. A case with such an association is presented, in which an unusual therapy was proposed: palliative gastrectomy and esophageal intubation. CASE REPORT: A 75-year-old white man was referred to our service complaining of malaise and weight loss for one year and dysphagia and vomiting for 2 months. The patient had sought out medical consultation as a result of the latter two complaints.

  14. 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.

  15. Treatment of advanced pancreatic cancer with opioid growth factor: phase I.

    Science.gov (United States)

    Smith, Jill P; Conter, Robert L; Bingaman, Sandra I; Harvey, Harold A; Mauger, David T; Ahmad, Mejdi; Demers, Lawrence M; Stanley, Wayne B; McLaughlin, Patricia J; Zagon, Ian S

    2004-03-01

    Opioid growth factor (OGF) is an endogenous pentapeptide that inhibits growth of human pancreatic cancer cells in culture, as well as xenografts in nude mice. To establish the maximum tolerated dose (MTD), and determine safety and toxicity of OGF, a phase I trial was performed in patients with advanced unresectable pancreatic cancer. Patients with unresectable pancreatic adenocarcinoma were treated with escalating doses of OGF for 30 min i.v. to determine the MTD. The s.c. route of administration also was evaluated. Once the MTD was established, a group of patients was treated chronically, and monitored for safety and toxicity. Hypotension was the dose-limiting toxicity, resulting in a MTD of 250 microg/kg i.v. Due to limited solubility of OGF in small volumes, a maximum dose of 50 microg/kg twice daily was determined by the s.c. route of administration. No adverse events were reported for oxygen saturation, cardiac rhythm, laboratory values or neurological status in either the acute or chronic parts of the study with the i.v. or s.c. routes. During the chronic i.v. phase, two subjects had resolution of liver metastases and one showed regression of the pancreatic tumor. Mean survival from the time of diagnosis was 8.7 months (range 2-23 months) in the i.v. group and 9.5 months (range 1-18 months) in the s.c. group. We conclude that OGF can be safely administered to patients with advanced pancreatic cancer. Further studies are needed to determine the efficacy of OGF alone or in combination with present modes of therapy for the treatment of pancreatic cancer.

  16. 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.

  17. Effect of Diabetes on Survival after Resection of Pancreatic Adenocarcinoma. A Prospective, Observational Study

    Science.gov (United States)

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

    2016-01-01

    Aim To investigate the effect of diabetes mellitus (DM) on disease-free and overall post-resection survival of patients with pancreatic ductal adenocarcinoma (PDAC) Methods Prospective observational study on patients admitted for pancreatic disease from January 2008 to October 2012. DM was classified as recent-onset (<48 months before PDAC diagnosis), longstanding (≥48 months before PDAC) or new onset (after surgery). Results Of 296 patients, 140 had a diagnosis of DM prior to surgery (26 longstanding, 99 recent-onset, 15 with unknown duration). Median follow-up time was 5.4 ± 0.22 years. Patients with recent onset DM had poorer postoperative survival than patients without DM: disease-free survival and overall survival were 1.14±0.13 years and 1.52±0.12 years in recent onset DM, versus 1.3±0.15 years and 1.87±0.15 years in non-diabetic patients (p = 0.013 and p = 0.025, respectively). Longstanding DM and postoperative new onset DM had no impact on prognosis. Compared to cases without DM, patients with recent onset DM were more likely to have residual disease after surgery and to develop liver metastases during follow-up. Multivariate analysis confirmed recent onset DM was independently associated with PDAC relapse (hazard ratio 1.45 [1.06–1.99]). Conclusion Preoperative recent onset DM has an impact on survival after the resection of PDAC. PMID:27814399

  18. Metabolites of purine nucleoside phosphorylase (NP in serum have the potential to delineate pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Shaiju K Vareed

    Full Text Available Pancreatic Adenocarcinoma (PDAC, the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX. A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7 and Alpha Synuclein (aSyn, both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC.

  19. Biologic therapies for advanced pancreatic cancer.

    Science.gov (United States)

    He, Aiwu Ruth; Lindenberg, Andreas Peter; Marshall, John Lindsay

    2008-08-01

    Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers. Therefore, inhibitors that target EGF receptor, K-RAS, RAF, MEK, mTOR, VEGF and PDGF, for example, have been evaluated in patients with pancreatic cancer. Although significant activities of these inhibitors have not been observed in the majority of pancreatic cancer patients, an enormous amount of experience and knowledge has been obtained from recent clinical trials. With a better inhibitor or combination of inhibitors, and improvement in the selection of patients for available inhibitors, better therapy for pancreatic cancer is on the horizon.

  20. Patient Derived Cancer Cell Lines in Identifying Molecular Changes in Patients With Previously Untreated Pancreatic Cancer Receiving Gemcitabine Hydrochloride-Based Chemotherapy

    Science.gov (United States)

    2016-10-18

    Pancreatic Ductal Adenocarcinoma; Stage IA Pancreatic Cancer; Stage IB Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

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

    Directory of Open Access Journals (Sweden)

    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

  2. Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

    Science.gov (United States)

    Neira, José L.; Bintz, Jennifer; Arruebo, María; Rizzuti, Bruno; Bonacci, Thomas; Vega, Sonia; Lanas, Angel; Velázquez-Campoy, Adrián; Iovanna, Juan L.; Abián, Olga

    2017-01-01

    Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

  3. Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Vizio, Barbara; Mauri, Francesco A; Prati, Adriana; Trivedi, Pritesh; Giacobino, Alice; Novarino, Anna; Satolli, Maria Antonietta; Ciuffreda, Libero; Camandona, Michele; Gasparri, Guido; Bellone, Graziella

    2012-01-01

    Chemoresistance and self-renewal of cancer stem cells (CSC), found in many tumors including pancreatic ductal adenocarcinoma (PDAC), are believed to underlie tumor mass regrowth. The distribution of cells carrying the putative stem-cell markers CD133, Nestin, Notch1-4, Jagged1 and 2, ABCG2 and aldehyde dehydrogenase (ALDH1) was assessed immunohistochemically using PDAC and normal pancreas tissue microarrays. The immunoreactivity was semi-quantitatively graded against the normal pancreas and was correlated with the differentiation grade and disease stage. No statistical significant differences were found between normal pancreas and PDAC in the expression of Nestin, Notch1, 3 and 4, ABCG2 or ALDH1. Notch2 and Jagged1 and 2 expression were increased in PDAC. CD133-positive cells were above-normal in PDAC, but the difference was not statistically significant. Nestin, Notch1-4, Jagged1, ABCG2 and ALDH1 immunostaining scores were not correlated with tumor grade or disease stage. CD133 and Notch2 expression was significantly inversely correlated with tumor grade, but not disease stage. Notch3 immunostaining positively correlated with tumor stage, but not with differentiation grade. Jagged2 protein expression correlated inversely with disease stage, but not with tumor grade. From the clinical standpoint, improved delineation of the tumor CSC signature, putatively responsible for tumor initiation and recurrence after initial response to chemotherapy, may offer novel therapeutic targets for this highly lethal cancer.

  4. MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism

    Science.gov (United States)

    Chugh, Seema; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Gupta, Suprit; Seshacharyulu, Parthasarathy; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK-mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis. PMID:27382435

  5. 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.

  6. A Cholecystokinin B Receptor-Specific DNA Aptamer for Targeting Pancreatic Ductal Adenocarcinoma

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    Abraham, Thomas; Pan, Weihua; Tang, Xiaomeng; Linton, Samuel S.; McGovern, Christopher O.; Loc, Welley S.; Smith, Jill P.; Butler, Peter J.; Kester, Mark; Adair, James H.; Matters, Gail L.

    2017-01-01

    Pancreatic ductal adenocarcinomas (PDACs) constitutively express the G-protein-coupled cholecystokinin B receptor (CCKBR). In this study, we identified DNA aptamers (APs) that bind to the CCKBR and describe their characterization and targeting efficacy. Using dual SELEX selection against “exposed” CCKBR peptides and CCKBR-expressing PDAC cells, a pool of DNA APs was identified. Further downselection was based on predicted structures and properties, and we selected eight APs for initial characterizations. The APs bound specifically to the CCKBR, and we showed not only that they did not stimulate proliferation of PDAC cell lines but rather inhibited their proliferation. We chose one AP, termed AP1153, for further binding and localization studies. We found that AP1153 did not activate CCKBR signaling pathways, and three-dimensional Confocal microscopy showed that AP1153 was internalized by PDAC cells in a receptor-mediated manner. AP1153 showed a binding affinity of 15 pM. Bioconjugation of AP1153 to the surface of fluorescent NPs greatly facilitated delivery of NPs to PDAC tumors in vivo. The selectivity of this AP-targeted NP delivery system holds promise for enhanced early detection of PDAC lesions as well as improved chemotherapeutic treatments for PDAC patients. PMID:27754762

  7. The use of Multidimensional Data to Identify the Molecular Biomarker for Pancreatic Ductal Adenocarcinoma

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    Liwei Zhuang

    2013-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a lethal disease, and the patient has an extremely poor overall survival with a less than 5% 5-year survival rate. Development of potential biomarkers provides a critical foundation for the diagnosis of PDAC. In this project, we have adopted an integrative approach to simultaneously identify biomarker and generate testable hypothesis from multidimensional omics data. We first examine genes for which expression levels are correlated with survival data. The gene list was screened with TF regulation, predicted miRNA targets information, and KEGG pathways. We identified that 273 candidate genes are correlated with patient survival data. 12 TF regulation gene sets, 11 miRNAs targets gene sets, and 15 KEGG pathways are enriched with these survival genes. Notably, CEBPA/miRNA32/PER2 signaling to the clock rhythm qualifies this pathway as a suitable target for therapeutic intervention in PDAC. PER2 expression was highly associated with survival data, thus representing a novel biomarker for earlier detection of PDAC.

  8. Nuclear Position and Shape Deformation of Chromosome 8 Territories in Pancreatic Ductal Adenocarcinoma

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    Sylvia Timme

    2011-01-01

    Full Text Available Cell type specific radial positioning of chromosome territories (CTs and their sub-domains in the interphase seem to have functional relevance in non-neoplastic human nuclei, while much less is known about nuclear architecture in carcinoma cells and its development during tumor progression. We analyzed the 3D-architecture of the chromosome 8 territory (CT8 in carcinoma and corresponding non-neoplastic ductal pancreatic epithelium. Fluorescence-in-situ-hybridization (FISH with whole chromosome painting (WCP probes on sections from formalin-fixed, paraffin wax-embedded tissues from six patients with ductal adenocarcinoma of the pancreas was used. Radial positions and shape parameters of CT8 were analyzed by 3D-microscopy. None of the parameters showed significant inter-individual changes. CT8 was localized in the nuclear periphery in carcinoma cells and normal ductal epithelial cells. Normalized volume and surface of CT8 did not differ significantly. In contrast, the normalized roundness was significantly lower in carcinoma cells, implying an elongation of neoplastic cell nuclei. Unexpectedly, radial positioning of CT8, a dominant parameter of nuclear architecture, did not change significantly when comparing neoplastic with non-neoplastic cells. A significant deformation of CT8, however, accompanies nuclear atypia of carcinoma cells. This decreased roundness of CTs may reflect the genomic and transcriptional alterations in carcinoma.

  9. Resection of non-cystic adenocarcinoma in pancreatic body and tail

    Institute of Scientific and Technical Information of China (English)

    Hai-Chao Yan; Yu-Lian Wu; Li-Rong Chen; Shun-Liang Gao

    2006-01-01

    AIM: To report the outcome of Chinese patents with non-cystic adenocarcinoma in pancreatic body and tail (NCAPBT) after resection and to discuss its surgical strategy.METHODS: Resection of NCAPBT was performed in eight Chinese patients with complete clinical-pathological data in our hospital from January 2000 to May 2004. The surgical strategy was explored by analyzing the results of these patients.RESULTS: The resection rate of NCAPBT in patients without back pain was higher than that in patients with back pain (66.67% vs 20%, 2/3 vs 1/5). The prognosis in the group receiving palliative resection was poorer than that in the group receiving curative resection. The median survival time was 12 mo in the curative resection group and 6 mo in the palliative resection group,respectively. CONCLUSION: The overall survival time of the Chinese patients with NCAPBT is dismal. The Chinese patients after curative resection of NCAPBT have a longer survival time. The Chinese NCAPBT patients with back pain trend to have a lower curative resection rate, but back pain should not be considered a contraindication for curative resection.

  10. CCR7 regulates Twist to induce the epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Li, Kexin; Xu, Baofeng; Xu, Guangying; Liu, Rui

    2016-01-01

    As reported, the CC chemokine receptor 7 (CCR7) trigger a series of signaling cascades in the epithelial-mesenchymal transition (EMT) of some malignancies. Meanwhile, Twist promotes EMT in pancreatic ductal adenocarcinoma (PDAC) progression. Here, effects of Twist on CCR7-induced EMT in the PDAC were investigated in detail. The immunohistochemistry was used to detect the expression of Twist, and then, in vitro assays were applied. The expression rate of Twist was 72.0 % in PDAC samples and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When PDAC cell line PANC1 was subjected to CCL19 stimulation, the expression of p-ERK, p-AKT, Twist, N-cadherin, MMP9, and α-smooth muscle actin (α-SMA) was induced, while the GSK1120212, BEZ235, and MK2206 prohibited the increase of Twist and EMT biomarkers. For another thing, the si-Twist treatment attenuated CCL19-stimulated EMT occurrence, migration, and invasion phenotypes of PANC1 cells. In conclusion, CCR7 pathway up-regulates Twist expression via ERK and PI3K/AKT signaling to manage the EMT of PDAC. Our work allows for clinical gene or protein-targeted regimen of PDAC patients in the near future.

  11. Disclosure of Erlotinib as a Multikinase Inhibitor in Pancreatic Ductal Adenocarcinoma

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    Laura Conradt

    2011-11-01

    Full Text Available A placebo-controlled phase 3 trial demonstrated that the epidermal growth factor receptor (EGFR inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response, and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work, we observed high erlotinib IC50 values in a panel of human and murine PDAC cell lines. Using EGFR small interfering RNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets, we used an unbiased chemical proteomics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture. In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (Kd = 0.09-0.358 μM than the EGFR (Kd 0.434 μM. We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multikinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.

  12. 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

  13. A patient with unresectable advanced pancreatic cancer achieving long-term survival with Gemcitabine chemotherapy

    Institute of Scientific and Technical Information of China (English)

    Yoshiki Okamoto; Takashi Maeba; Keitarou Kakinoki; Keiichi Okano; Kunihiko Izuishi; Hisao Wakabayashi; Hisashi Usuki; Yasuvuki Suzuki

    2008-01-01

    A 68-year-old female visited a local clinic with epigastralgia. A routine laboratory test revealed jaundice and liver dysfunction. She was referred to this hospital. Abdominal computed tomography (CT) and endoscopic retrograde cholangio-pancreatography (ERCP) revealed that the density of the entire pancreas had decreased, and showed dilatation of the common bile duct (CBD) and the main pancreatic duct (MPD). Pancreatic cancer was diagnosed by cytological examination analyzing the pancreatic juice obtained by ERCP. When jaundice had decreased the tumor was observed via laparotomy. No ascites, liver metastasis, or peritoneal dissemination was observed. The entire pancreas was a hard mass, and a needle biopsy was obtained from the head, body and tail of the pancreas. These biopsies diagnosed a poorly differentiated adenocarcinoma. Hepaticojejunostomy was thus performed, and postoperative progress was good. Chemotherapy with 1000 mg/body per week of gemcitabine was administered beginning 15 d postoperatively. However, the patient suffered relatively severe side effects, and it was necessary to change the dosing schedule of gemcitabine. Abdominal CT revealed a complete response (CR) after 3 treatments. Therefore, weekly chemotherapy was stopped and was changed to monthly administration. To date, for 4 years after chemotherapy, the tumor has not reappeared.Key werds: Gemcitabine; Long-term survival; Unresectable advanced pancreatic cancer

  14. Detection of circulating tumor cells in patients with esophagogastric or pancreatic adenocarcinoma using the CellSearch(®) system: An observational feasibility study.

    Science.gov (United States)

    Piegeler, Tobias; Winder, Thomas; Kern, Sabine; Pestalozzi, Bernhard; Schneider, Paul Magnus; Beck-Schimmer, Beatrice

    2016-08-01

    Circulating tumor cells (CTCs) in the blood of cancer patients have been demonstrated to be of prognostic value regarding metastasis and survival. The CellSearch(®) system has been certified for the detection of CTCs and as a prognostic tool in patients with metastatic breast, colon and prostate cancer. Few studies have evaluated the detection of CTCs originating from esophagogastric or pancreatic cancer with the CellSearch(®) system. In the present small pilot study, a total of 16 patients with either esophagogastric (n=8) or pancreatic (n=8) adenocarcinomas at various disease stages were randomly screened and included. A total of 7.5 ml of blood was drawn from each patient and analyzed for CTCs using the CellSearch(®) device. CTCs could be detected in 1 out of 8 patients (12.5%) with esophagogastric and in 7 out of 8 patients (87.5%) with pancreatic cancer. The preliminary data obtained from this observational feasibility study suggested that the CellSearch(®) system may become a valuable tool for the detection of CTCs in patients with pancreatic adenocarcinoma, whereas the usefulness in patients with early-stage esophagogastric adenocarcinoma may be limited. This study clearly points towards a requirement for larger studies focusing on patients with pancreatic adenocarcinoma at various disease stages and assessing CTCs, whereas patients with esophagogastric adenocarcinomas should be part of further pilot studies.

  15. Detection of circulating tumor cells in patients with esophagogastric or pancreatic adenocarcinoma using the CellSearch® system: An observational feasibility study

    Science.gov (United States)

    Piegeler, Tobias; Winder, Thomas; Kern, Sabine; Pestalozzi, Bernhard; Schneider, Paul Magnus; Beck-Schimmer, Beatrice

    2016-01-01

    Circulating tumor cells (CTCs) in the blood of cancer patients have been demonstrated to be of prognostic value regarding metastasis and survival. The CellSearch® system has been certified for the detection of CTCs and as a prognostic tool in patients with metastatic breast, colon and prostate cancer. Few studies have evaluated the detection of CTCs originating from esophagogastric or pancreatic cancer with the CellSearch® system. In the present small pilot study, a total of 16 patients with either esophagogastric (n=8) or pancreatic (n=8) adenocarcinomas at various disease stages were randomly screened and included. A total of 7.5 ml of blood was drawn from each patient and analyzed for CTCs using the CellSearch® device. CTCs could be detected in 1 out of 8 patients (12.5%) with esophagogastric and in 7 out of 8 patients (87.5%) with pancreatic cancer. The preliminary data obtained from this observational feasibility study suggested that the CellSearch® system may become a valuable tool for the detection of CTCs in patients with pancreatic adenocarcinoma, whereas the usefulness in patients with early-stage esophagogastric adenocarcinoma may be limited. This study clearly points towards a requirement for larger studies focusing on patients with pancreatic adenocarcinoma at various disease stages and assessing CTCs, whereas patients with esophagogastric adenocarcinomas should be part of further pilot studies. PMID:27446462

  16. Enhancement patterns of pancreatic adenocarcinoma on conventional dynamic multi-detector row CT: Correlation with angiogenesis and fibrosis

    Institute of Scientific and Technical Information of China (English)

    Yuki Hattori; Toshifumi Gabata; Osamu Matsui; Kentaro Mochizuki; Hirohisa Kitagawa; Masato Kayahara; Tetsuo Ohta; Yasuni Nakanuma

    2009-01-01

    AIM: To evaluate retrospectively the correlation between enhancement patterns on dynamic computed tomography (CT) and angiogenesis and fibrosis in pancreatic adenocarcinoma.METHODS: Twenty-three patients with pancreatic adenocarcinoma underwent dynamic CT and tumor resection. In addition to the absolute and relative enhanced value that was calculated by subtracting the attenuation value on pre-contrast from those on contrast-enhanced CT in each phase, we defined one parameter, "tumor-aorta enhancement ratio", which was calculated by dividing enhancement of pancreatic cancer by enhancement of abdominal aorta in each phase. These enhancement patterns were correlated with the level of vascular endothelial growth factor (VEGF), microvessel density (MVD), and extent of fibrosis.RESULTS: The absolute enhanced value in the arterial phase correlated with the level of VEGF and MVD (P = 0.047, P = 0.001). The relative enhanced value in arterial phase and tumor-aorta enhancement ratio (arterial) correlated with MVD (P = 0.003, P = 0.022). Tumor-aorta enhancement ratio (arterial) correlated negatively with the extent of fibrosis (P = 0.004). The tumors with greater MVD and higher expression of VEGF tended to show high enhancement in the arterial dominant phase. On the other hand, the tumors with a larger amount of fibrosis showed a negative correlation with the grade of enhancement during the arterial phase.CONCLUSION: Enhancement patterns on dynamic CT correlated with angiogenesis and may be modified by the extent of fibrosis.

  17. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3(+)Treg cells in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Wang, X; Lang, M; Zhao, T; Feng, X; Zheng, C; Huang, C; Hao, J; Dong, J; Luo, L; Li, X; Lan, C; Yu, W; Yu, M; Yang, S; Ren, H

    2016-12-19

    Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy.Oncogene advance online publication, 19 December 2016; doi:10.1038/onc.2016.458.

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

    Directory of Open Access Journals (Sweden)

    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

  19. Tumor Size on Abdominal MRI Versus Pathologic Specimen in Resected Pancreatic Adenocarcinoma: Implications for Radiation Treatment Planning

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    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

  20. 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.

  1. Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging.

    Science.gov (United States)

    England, Christopher G; Huang, Justin S; James, Kurtis T; Zhang, Guandong; Gobin, André M; Frieboes, Hermann B

    2015-01-01

    Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5 ± 8.2 and 23.3 ± 4.1 particles/100 μm2 within 10 μm from the nearest source and few nanoparticles beyond 50 μm, respectively. The spleen had 35.5 ± 9.3 particles/100 μm2 within 10 μm with penetration also limited to 50 μm. For SGN, the liver showed 31.1 ± 4.1 particles/100 μm2 within 10 μm of the nearest source with penetration hindered beyond 30 μm. The spleen and tumor showed uptake of 22.1 ± 6.2 and 15.8 ± 6.1 particles/100 μm2 within 10 μm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/μm2) was 1.09 ± 0.14 in the liver, 0.74 ± 0.12 in the spleen, and 0.43 ± 0.07 in the tumor. SGN average concentration (nanoparticles/μm2) was 0.43 ± 0.07 in the liver, 0.30 ± 0.06 in the spleen, and 0.20 ± 0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in

  2. Advanced endoscopic ultrasound management techniques for preneoplastic pancreatic cystic lesions

    Science.gov (United States)

    Arshad, Hafiz Muhammad Sharjeel; Bharmal, Sheila; Duman, Deniz Guney; Liangpunsakul, Suthat; Turner, Brian G

    2017-01-01

    Pancreatic cystic lesions can be benign, premalignant or malignant. The recent increase in detection and tremendous clinical variability of pancreatic cysts has presented a significant therapeutic challenge to physicians. Mucinous cystic neoplasms are of particular interest given their known malignant potential. This review article provides a brief but comprehensive review of premalignant pancreatic cystic lesions with advanced endoscopic ultrasound (EUS) management approaches. A comprehensive literature search was performed using PubMed, Cochrane, OVID and EMBASE databases. Preneoplastic pancreatic cystic lesions include mucinous cystadenoma and intraductal papillary mucinous neoplasm. The 2012 International Sendai Guidelines guide physicians in their management of pancreatic cystic lesions. Some of the advanced EUS management techniques include ethanol ablation, chemotherapeutic (paclitaxel) ablation, radiofrequency ablation and cryotherapy. In future, EUS-guided injections of drug-eluting beads and neodymium:yttrium aluminum agent laser ablation is predicted to be an integral part of EUS-guided management techniques. In summary, International Sendai Consensus Guidelines should be used to make a decision regarding management of pancreatic cystic lesions. Advanced EUS techniques are proving extremely beneficial in management, especially in those patients who are at high surgical risk. PMID:27574295

  3. Differentiating Pancreatic Ductal Adenocarcinoma from Pancreatic Serous Cystadenoma, Mucinous Cystadenoma, and a Pseudocyst with Detailed Analysis of Cystic Features on CT Scans: a Preliminary Study

    Energy Technology Data Exchange (ETDEWEB)

    Lv, Peijie; Mahyoub, Radfan; Lin, Xiaozhu; Chen, Kemin; Chai, Weimin; Xie, Jing [Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai (China)

    2011-04-15

    To determine whether or not detailed cystic feature analysis on CT scans can assist in the differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) from serous cystadenoma (SCN), mucinous cystadenoma (MCN), and a pseudocyst. This study received Institutional Review Board approval and informed patient consent was waived. Electronic radiology and pathology databases were searched to identify patients with PDAC (n = 19), SCN (n = 26), MCN (n = 20) and a pseudocyst (n = 23) who underwent pancreatic CT imaging. The number, size, location, and contents of cysts, and the contour of the lesions were reviewed, in addition to the wall thickness, enhancement patterns, and other signs of pancreatic and peripancreatic involvement. Diagnosis was based on lesion resection (n = 82) or on a combination of cytological findings, biochemical markers, and tumor markers (n = 6). Fisher's exact test was used to analyze the results. A combination of the CT findings including irregular contour, multiple cysts, mural nodes, and localized thickening, had a relatively high sensitivity (74%) and specificity (75%) for differentiating PDAC from SCN, MCN, and pseudocysts (p < 0.05). Other CT findings such as location, greatest dimension, or the presence of calcification were not significantly different. The CT findings for PDAC are non-specific, but perhaps helpful for differentiation. PDAC should be included in the general differential diagnosis of pancreatic cystic neoplasms

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

    Science.gov (United States)

    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.

  5. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Chen, Ru; Pan, Sheng; Ottenhof, NIki A.; de Wilde, Roeland F.; Wolfgang, Christopher L.; Lane, Zhaoli; Post, Jane; Bronner, Mary P.; Willmann, Jürgen K.; Maitra, Anirban; Brentnall, Teresa A.

    2012-01-01

    The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival. PMID:22785208

  6. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing.

    Directory of Open Access Journals (Sweden)

    Winnie S Liang

    Full Text Available Pancreatic adenocarcinoma (PAC is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05, along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the

  7. 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.

  8. 1-MT Enhances Potency of Tumor Cell Lysate-pulsed Dendritic Cells against Pancreatic Adenocarcinoma by Downregulating the Percentage of Tregs

    Institute of Scientific and Technical Information of China (English)

    李元栋; 徐钧; 邹浩军; 王春友

    2010-01-01

    This study examined whether 1-methyl-tryptophan [1-MT,an indoleamine 2,3-dioxygenase(IDO) inhibitor] could reduce CD4+CD25+ regulatory T cells(Tregs) proliferation and improve the anti-tumor efficacy of dendritic cells(DCs) pulsed with tumor cell lysate in the mice bearing pancreatic adenocarcinoma.The models of pancreatic adenocarcinoma were established in C57BL/6 mice by subcutaneous injection of Pan02 cells.Eight mice which were subcutaneously injected with PBS served as control.The expression of IDO was...

  9. Assessment and optimization of electroporation-assisted tumoral nanoparticle uptake in a nude mouse model of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    West, Derek Lamont; White, Sarah B; Zhang, Zhouli; Larson, Andrew C; Omary, Reed A

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer. In 2012, the incidence of PDAC was 43,920. Five-year survival for patients with PDAC is around 6%, regardless of staging, making PDAC one of the deadliest forms of cancer. One reason for this dismal prognosis is chemoresistance to the current first-line therapy, gemcitabine. There are multiple factors that contribute to the chemoresistance observed in pancreatic cancer. Among them, desmoplasia has been increasingly seen as a significant contributor to chemoresistance. To overcome desmoplastic chemoresistance, several novel methods of treatment have been developed. Electroporation is one such novel treatment. High electrical fields are applied to cells to create pores that increase cell permeability. It has been previously demonstrated that electroporation enhances the therapeutic efficacy of anticancer drugs in pancreatic tumor models. Nanoparticle-based drug delivery systems constitute a second novel method to overcome desmoplastic chemoresistance. Due to their intrinsic design advantages, nanoparticles have been shown to increase the effectiveness of chemotherapeutic agents, while further reducing or even eliminating side effects. To date, there have been no studies evaluating the cumulative effect of combining both nanoparticle and electroporation strategies to overcome chemoresistance in PDAC. Our preliminary studies assessed the in vitro and in vivo uptake of doxorubicin-loaded iron oxide nanoparticles as a function of electroporation voltage and timing of administration in pancreatic adenocarcinoma cells. Our studies demonstrated that addition of electroporation to administration of nanoparticles significantly increased the amount of intracellular iron oxide nanoparticle uptake by a PANC-1 cell line in an athymic nude mouse model of PDAC. Further, electroporation-assisted nanoparticle uptake could be significantly altered by changing the timing of application of electroporation.

  10. A 56-year-old woman with ampullary adenocarcinoma and acute pancreatitis Mujer de 56 años con adenocarcinoma de la ampolla de Vater y pancreatitis aguda

    Directory of Open Access Journals (Sweden)

    V. M. Santos

    2012-12-01

    Full Text Available A 56-year-old woman was admitted with jaundice, and laboratory data were indicative of pancreatitis, which recurred in spite of adequate clinical and nutritional management. The patient was an overweight diabetic using metformin, who had antecedents of cholelithiasis and recent cholecystectomy. Clinical and laboratory features were not conclusive about the cause of this acute pancreatitis. However, imaging data contributed to diagnosis suspicion, and the histopathology study of the transpapillary biopsy confirmed the ampullary adenocarcinoma. Whipple´s surgery was the procedure of choice, associated with radical lymphadenectomy, followed by an uneventful outcome. Recrudescence of signs and symptoms of acute pancreatitis, with elevated serum levels of bilirrubins and of hepatic canalicular enzymes, should enhance the suspicion index about periampullary tumors. High levels of CA 19-9 can constitute a useful marker of this condition. Transpapillary biopsy can characterize the diagnosis of ampullary malignancies.Se presenta el caso de una mujer de 56 años, que presentaba ictericia y cuyos exámenes de laboratorio fueran indicativos de pancreatitis. Presentó recurrencia a pesar de las medidas clínicas y nutricionales adecuadas. La paciente era diabética, con sobrepeso, tomaba metformina y con antecedentes de colelitiasis y reciente colecistectomía. Los datos clínicos y del laboratorio no fueron concluyentes acerca del origen de esta pancreatitis aguda. Sin embargo, los estudios de imagen contribuyeron a la sospecha del diagnóstico; los estudios de citologia exfoliativa y de biopsia transpapilar confirmaron un adenocarcinoma ampular. La cirugía de Whipple fue el procedimiento de opción, asociado con linfadenectomía radical, con resultado favorable. El recrudecimiento de señales y síntomas de pancreatitis aguda, con niveles séricos elevados de bilirrubina y de enzimas hepáticos debe reforzar el índice de sospecha acerca de tumores

  11. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    Science.gov (United States)

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  12. 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 BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

  13. Differential Expression of Metabolic Genes in Tumor and Stromal Components of Primary and Metastatic Loci in Pancreatic Adenocarcinoma

    Science.gov (United States)

    Chaika, Nina V.; Yu, Fang; Purohit, Vinee; Mehla, Kamiya; Lazenby, Audrey J.; DiMaio, Dominick; Anderson, Judy M.; Yeh, Jen Jen; Johnson, Keith R.; Hollingsworth, Michael A.; Singh, Pankaj K.

    2012-01-01

    Background 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. Methods and Findings 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. Conclusions 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. PMID:22412968

  14. 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

  15. Duodenal adenocarcinoma: Advances in diagnosis and surgical management

    Institute of Scientific and Technical Information of China (English)

    Jordan M Cloyd; Elizabeth George; Brendan C Visser

    2016-01-01

    Duodenal adenocarcinoma is a rare but aggressive malignancy. Given its rarity, previous studies have traditionally combined duodenal adenocarcinoma(DA) with either other periampullary cancers or small bowel adenocarcinomas, limiting the available data to guide treatment decisions. Nevertheless, management primarily involves complete surgical resection when technically feasible. Surgery may require pancreaticoduodenectomy or segmental duodenal resection; either are acceptable options as long as negative margins are achievable and an adequate lymphadenectomy can be performed. Adjuvant chemotherapy and radiation are important components of multi-modality treatment for patients at high risk of recurrence. Further research would benefit from multiinstitutional trials that do not combine DA with other periampullary or small bowel malignancies. The purpose of this article is to perform a comprehensive review of DA with special focus on the surgical management and principles.

  16. Overexpression of Caspase-1 in adenocarcinoma of pancreas and chronic pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Yin-Mo Yang; Marco Ramadani; Yan-Ting Huang

    2003-01-01

    AIM: To identify the expression of Caspase-l(interleukin1.β converting enzyme) and its role in adenoma of the pancreas and chronic pancreatitis.METHODS: The expression of Caspase-1 was assessed in 42 pancreatic cancer tissue samples, 38 chronic pancreatitis specimens, and 9 normal pancreatic tissues by immunohistochemistry and Western blot analysis.RESULTS: Overexpression of Caspase-1 was observed in both disorders, but there were differences in the expression patterns in distinct morphologic compartments. Pancreatic cancer tissues showed a clear cytoplasmatic overexpression of Caspase-1 in tumor cells of 71% of the tumors, whereas normal pancreatic tissues showed only occasional immunoreactivity. In chronic pancreatitis, overexpression of Caspase-1 was found in atrophic acinar cells (89 %),hyperplastic ducts (87 %), and dedifferentiating acinar cells (84 %). Although in atrophic cells a clear nuclear expression was found, hyperplastic ducts and dedifferentiating acinar cells showed dear cytoplasmic expression. Western blot analysis revealed a marked expression of the 45 kDa precursor of Caspase-1 in pancreatic cancer and chronic pancreatitis (80 %and 86 %, respectively). Clear bands at 30 kDa, which suggested the p10-p20 heterodimer of active Caspase-1, were found in 60 % of the cancer tissue and 14 % of the pancreatitis tissue specimens, but not in normal pancreatic tissues.CONCLUSION: Overexpression of Caspase-1 is a frequent event in pancreatic disorders and its differential expression patterns may reflect two functions of the protease. One is its participation in the apoptotic pathway in atrophic acinar cells and tumor-surrounding pancreatitis tissue, the other is its possible role in proliferative processes in pancreatic cancer cells and hyperplastic duct cells and dedifferentiating acinar cells in chronic pancreatitis.

  17. Effect of multiple-phase regional intra-arterial infusion chemotherapy on patients with resectable pancreatic head adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    JIN Chen; YAO Lie; LONG Jiang; FU De-liang; YU Xian-jun; XU Jin; YANG Feng; NI Quan-xing

    2009-01-01

    Background Regional intra-arterial infusion chemotherapy (RIAC) has been more valuable to improve prognosis and quality of life of patients with inoperable pancreatic adenocarcinomas, and adjuvant RIAC plays an important role in prolonging survival and reducing risk of liver metastasis after radical resection of pancreatic cancer, but the effect of preoperative or multiple-phase RIAC (preoperative combined with postoperative RIAC) for resectable pancreatic cancers has not been investigated. In this prospective study, the effect of multiple-phase RIAC for patients with resectable pancreatic head adenocarcinoma was evaluated, and its safety and validity comparing with postoperative RIAC were also assessed.Methods Patients with resectable pancreatic head cancer were randomly assigned to two groups. Patients in group A (n=50) were treated with new therapeutic mode of extended pancreaticoduodenectomy combined with multiple-phase RIAC, and those in group B (n=50) were treated with extended pancreaticoduodenectomy combined with postoperative RIAC in the same period. The feasibility, compliance and efficiency of the new therapeutic mode were evaluated by tumor size, serum tumor markers, clinical benefit response (CBR), surgical complications, mortality and toxicity of RIAC. The disease-free survival time, median survival time, incidence of liver metastasis, survival rate at 1, 2, 3 and 5 years were also observed. Life curves were generated by the Kaplan-Meier method.Results The pain relief rate and CBR in group A was 80% and 84% respectively. Serum tumor markers decreased obviously and tumors size decreased in 26% of patients after preoperative RIAC in group A. No more surgical complications, mortality or severe systemic side effects were observed in group A compared with group B. The incidence of liver metastasis in group A was 34% which was lower than 50% in group B. The disease-free survival time and median survival time in group A were 15.5 months and 18 months

  18. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Dando, Ilaria; Fiorini, Claudia; Pozza, Elisa Dalla; Padroni, Chiara; Costanzo, Chiara; Palmieri, Marta; Donadelli, Massimo

    2013-03-01

    Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

  19. Contrast enhanced ultrasound with quantitative perfusion analysis for objective characterization of pancreatic ductal adenocarcinoma: A feasibility study.

    Science.gov (United States)

    D'Onofrio, Mirko; Canestrini, Stefano; Crosara, Stefano; De Robertis, Riccardo; Pozzi Mucelli, Roberto

    2014-03-28

    The aim of this study was to determine whether contrast enhanced ultrasound (CEUS) quantitative perfusion analysis allows an objective characterization of ductal adenocarcinoma (ADK) of the pancreas. Patients with pancreatic ADK underwent CEUS. All examinations were performed on an Acuson S2000 system (Siemens, Erlangen, Germany) after the iv administration of 2.4 mL contrast agent (SonoVue(®), Bracco, Milan, Italy). All lesions were pathologically proved. An operator manually drew different regions of interest within the tumor and the adjacent parenchyma to allow the quantitative perfusion analysis. The mean values of peak of enhancement, time to peak and ascending curve were calculated and compared using the Student's t test. The quantitative perfusion analysis was possible in all lesions. The mean values of the peak of enhancement, time to peak and ascending curve were 17.19%, 7.97 s and 159.52% s within the tumor and 33.57%, 8.89 s and 355.29% s within the adjacent parenchyma. The peak of enhancement and the ascending curve values were significantly different within the tumor and the adjacent parenchyma. Thus, CEUS allows the quantitative perfusion analysis of pancreatic ductal adenocarcinoma.

  20. Advanced Gastric Neuroendocrine Carcinoma with an Adenocarcinoma Component

    Directory of Open Access Journals (Sweden)

    Masashi Miguchi

    2012-01-01

    Full Text Available In the present study, we observed that the adenocarcinoma component in the mucosa was continuous with neuroendocrine carcinoma (NEC in the deeper layers; this suggests the normal course of NEC carcinogenesis at the histological level. A 72-year-old man was admitted to our hospital with a chief complaint of tarry stools. Endoscopic examination of the upper gastrointestinal tract revealed a 2-cm tumor, with a deep central depression, surrounded by a smooth elevated area, in the middle of the stomach body. A biopsy showed that the tumor was a moderately differentiated gastric adenocarcinoma. The patient underwent total gastrectomy and standard lymph node dissection. The resected tumor was a 3.5 × 2.5 cm type 2 lesion. It comprised two elements at the histological level: (i a moderately differentiated adenocarcinoma in the superficial portion of the mucous membrane layer, and (ii NEC-like cells with dark, round nuclei and scant cytoplasm, presenting a solid and trabecular pattern, in the submucosal and muscularis propria layers. Immunohistochemical findings showed that the NEC-like cells were diffusely positive for chromogranin A, synaptophysin, neural cell adhesion molecule, and neuron-specific enolase, but were negative for carcinoembryonic antigen. The Ki-67 labeling index was 95%. The final pathological diagnosis was gastric NEC with an adenocarcinoma component and a high cellular proliferative potential.

  1. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients

    Directory of Open Access Journals (Sweden)

    Wang Q

    2016-09-01

    Full Text Available Qingbing Wang,1,2 Xiaolin Wang,1,2 Rongfang Guo,2,3 Guoping Li1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, 2Shanghai Institute of Medical Imaging, 3Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China Abstract: Pancreatic acinar cell carcinoma (ACC is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14 of ACC tumors were homogeneous and 35.7% (5/14 had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14 and 7.1% (1/14, respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation. Keywords: acinar cell carcinoma, computed tomography, pancreatic ductal carcinoma, pancreas

  2. 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

  3. Inhibiting the growth of pancreatic adenocarcinoma in vitro and in vivo through targeted treatment with designer gold nanotherapeutics.

    Directory of Open Access Journals (Sweden)

    Rachel A Kudgus

    Full Text Available BACKGROUND: Pancreatic cancer is one of the deadliest of all human malignancies with limited options for therapy. Here, we report the development of an optimized targeted drug delivery system to inhibit advanced stage pancreatic tumor growth in an orthotopic mouse model. METHODPRINCIPAL FINDINGS: Targeting specificity in vitro was confirmed by preincubation of the pancreatic cancer cells with C225 as well as Nitrobenzylthioinosine (NBMPR - nucleoside transporter (NT inhibitor. Upon nanoconjugation functional activity of gemcitabine was retained as tested using a thymidine incorporation assay. Significant stability of the nanoconjugates was maintained, with only 12% release of gemcitabine over a 24-hour period in mouse plasma. Finally, an in vivo study demonstrated the inhibition of tumor growth through targeted delivery of a low dose of gemcitabine in an orthotopic model of pancreatic cancer, mimicking an advanced stage of the disease. CONCLUSION: We demonstrated in this study that the gold nanoparticle-based therapeutic containing gemcitabine inhibited tumor growth in an advanced stage of the disease in an orthotopic model of pancreatic cancer. Future work would focus on understanding the pharmacokinetics and combining active targeting with passive targeting to further improve the therapeutic efficacy and increase survival.

  4. Tumores de cólon - primeiro achado do adenocarcinoma de pâncreas: relato de caso Colon tumors - first find of the pancreatic adenocarcinoma: case report

    Directory of Open Access Journals (Sweden)

    Sandra Pedroso de Moraes

    2007-09-01

    Full Text Available OBJETIVO: Relatar um caso raro de adenocarcinoma de pâncreas que se apresentou como tumores colorretais sincrônicos. Paciente masculino, 76 anos, apresentava dor abdominal difusa de forte intensidade, diarréia e vômitos há sete dias. Tratava de gastrite há dois anos e nos últimos quatro meses apresentava hiporexia e perda de peso. Estava emagrecido, desidratado e desnutrido, com distensão abdominal importante, ruídos hidroaéreos ausentes e dor difusa à palpação abdominal. Exames evidenciaram hiperglicemia, distensão importante do intestino delgado ao raio x, ultra-som de abdome com colecistolitíase e endoscopia digestiva alta com pangastrite, bulboduodenite e papila normal. Tomografia abdominal confirmou colecistolitíase. A colonoscopia mostrou três lesões, em reto médio, cólon transverso e na válvula íleocecal. As biópsias revelaram apenas reação inflamatória. Persistiram os sintomas e decidiu-se submetê-lo a colecistectomia onde foram vistas lesões planas em diafragma cujas biópsias evidenciaram adenocarcinoma. No quinto dia de pós-operatório o paciente apresentava quadro obstrutivo e foi submetido à nova laparotomia com colectomia direita, ileostomia terminal dupla e biópsia pancreática. Esta mostrou adenocarcinoma e o estudo imunoistoquímico positivo para tumor primário do pâncreas. O paciente evoluiu para óbito um mês após. CONCLUSÃO: o exame de imagem normal não descarta a hipótese diagnóstica e quando a origem do tumor primário não está definida é essencial o exame imunoistoquímico para firmar o diagnóstico.OBJECTIVE: Report a case of a rare pancreatic adenocarcinoma presented as synchronic colorectal tumor. CASE REPORT: Seventy six year old man with high intensity and diffuse abdominal pain, diarrhea and vomiting during seven days. At that moment he had been in treatment for gastritis for 2 years and in the last four months he presented hyporexia and weight loss. He was dehydrated and

  5. Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Nishi, Takeshi; Maruyama, Riruke; Urano, Takeshi; Nakayama, Naomi; Kawabata, Yasunari; Yano, Seiji; Yoshida, Manabu; Nakayama, Kentaro; Miyazaki, Kohji; Takenaga, Keizo; Tanaka, Tsuneo; Tajima, Yoshitsugu

    2012-12-01

    Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

  6. Ductal adenocarcinoma of the pancreatic head: A focus on current diagnostic and surgical concepts

    Institute of Scientific and Technical Information of China (English)

    Mehdi Oua(i)ssi; Urs Giger; Guillaume Louis; Igor Sielezneff; Olivier Farges; Bernard Sastre

    2012-01-01

    Complete surgical resection still remains the only possibility of curing pancreatic cancer,however,only 10% of patients undergo curative surgery.Pancreatic resection currently remains the only method of curing patients,and has a 5-year overall survival rate between 7%-34% compared to a median survival of 3-11 mo for unresected cancer.Pancreatic surgery is a technically demanding procedure requiring highly standardized surgical techniques.Nevertheless,even in experienced hands,perioperative morbidity rates (delayed gastric emptying,pancreatic fistula etc.) are as high as 50%.Different strategies to reduce postoperative morbidity,such as different techniques of gastroenteric reconstruction (pancreatico-jejunostomy vs pancreatico-gastrostomy),intraoperative placement of a pancreatic main duct stent or temporary sealing of the main pancreatic duct with fibrin glue have not led to a significant improvement in clinical outcome.The perioperative application of somatostatin or its analogues may decrease the incidence of pancreatic fistulas in cases with soft pancreatic tissue and a small main pancreatic duct (< 3 mm).The positive effects of external pancreatic main duct drainage and antecolic gastrointestinal reconstruction have been observed to decrease the rate of pancreatic fistulas and delayed gastric emptying,respectively.Currently,the concept of extended radical lymphad-enectomy has been found to be associated with higher perioperative morbidity,but without any positive impact on overall survival.However,there is growing evidence that portal vein resections can be performed with acceptable low perioperative morbidity and mortality but does not achieve a cure.

  7. 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

  8. 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

  9. p-[{sup 123}I]iodo-l-phenylalanine for detection of pancreatic cancer: basic investigations of the uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel; Hellwig, Dirk; Kirsch, Carl-Martin [Department of Nuclear Medicine, Saarland University Medical Center, 66421, Homburg/Saar (Germany); Romeike, Bernd F.M.; Feiden, Wolfgang [Department of Neuropathology, Saarland University Medical Center, Homburg/Saar (Germany); Kubuschok, Boris [Department of Internal Medicine I, Saarland University Medical Center, Homburg/Saar (Germany); Amon, Michaela; Menger, Michael D. [Department of Clinical Experimental Surgery, Saarland University Medical Center, Homburg/Saar (Germany)

    2004-04-01

    Pancreatic cancer is associated with the worst 5-year survival rate of any human cancer. This high mortality is due, in part, to difficulties in establishing early and accurate diagnosis. Because most tumours share the ability to accumulate amino acids more effectively than normal tissues and any other pathology, assessment of amino acid transport in tumour cells using radiolabelled amino acids has become one of the most promising tools for tumour imaging. This study investigated the potential of p-[{sup 123}I]iodo-l-phenylalanine (IPA) for detection of pancreatic cancer by single-photon emission tomography. IPA affinity for pancreatic tumour was investigated in human pancreatic adenocarcinoma PaCa44 and PanC1 cells, followed by analysis of the underlying mechanisms of tracer accumulation in neoplastic cells. Thereafter, IPA was evaluated for targeting of pancreatic tumours using SCID mice engrafted with primary human pancreatic adenocarcinoma cells, as well as in acute inflammation models in immunocompetent mice and rats. IPA accumulated intensively in human pancreatic tumour cells. Radioactivity accumulation in tumour cells following a 30-min incubation at 37 C/pH 7.4 varied from 41% to 58% of the total loaded activity per 10{sup 6} cells. The cellular uptake was temperature and pH dependent and predominantly mediated by specific carriers for neutral amino acids, namely the sodium-independent and l-leucine-preferring (L-system) transporter and the alanine-, serine- and cysteine-preferring (ASC-system) transporter. Protein incorporation was less than 8%. Biodistribution studies showed rapid localization of the tracer to tumours, reaching 10%{+-}2.5% to 15%{+-}3% of the injected dose per gram (I.D./g) in heterotopic tumours compared with 17%{+-}3.5% to 22%{+-}4.3% I.D./g in the orthotopic tumours, at 60 and 240 min post injection of IPA, respectively. In contrast, IPA uptake in the gastrointestinal tract and areas of inflammation remained moderate and decreased

  10. 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.)

  11. [An IgG4-related pancreatitis mimicking an adenocarcinoma: A case report].

    Science.gov (United States)

    Courcet, Emilie; Beltjens, Françoise; Charon-Barra, Céline; Guy, France; Orry, David; Ghiringhelli, François; Arnould, Laurent

    2015-12-01

    Type 1 auto-immune pancreatitis (type 1 AIP) is the pancreatic manifestation of IgG4-related systemic disease (IgG4-RD). This disease has recently been individualized and is characterized by elevated serum IgG4 levels and extrapancreatic lesions with common histologic characteristic: dense infiltration of lymphocytes, IgG4-positive plasma cells and storiforme fibrosis. Obliterative phlebitis is frequently detected. The pancreas is frequently involved in this disease. As approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological and histopathological features. In pseudotumoral cases, AIP can be misdiagnosed as pancreatic cancer. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. We report here a case of a patient who underwent surgery for presumed pancreatic cancer. The final diagnosis was type 1 AIP.

  12. Advances in early diagnosis and therapy of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Qiang Xu; Tai-Ping Zhang; Yu-Pei Zhao

    2011-01-01

    BACKGROUND: Pancreatic cancer remains a devastating disease with a 5-year survival rate of less than 5%. Recent advances in diagnostic methods and therapeutic approaches have increased the possibility of improving the existing poor prognosis. DATA  SOURCES: English-language articles reporting early diagnosis and therapy of pancreatic cancer were searched from the MEDLINE and PubMed databases, Chinese-language articleswerefromCHKD(ChinaHospitalKnowledgeDatabase). RESULT: The current literature about pancreatic cancer was reviewed from three aspects: statistics, screening and early detection, and therapy. CONCLUSIONS: Early detection and screening of pancreatic cancer currently should be limited to high risk patients. Surgical resection is the only curative approach available, with some recent improvement in outcomes. Gemcitabine has been a standard treatment during the last decade. Gemcitabine-based combination treatment, especially combined with newer molecular targeted agents, is promising. The rationale for radiotherapy is controversial, but with the recent development of modern radiation delivery techniques, radiotherapy should be intensified. Patients with borderline pancreatic cancer could benefit from neoadjuvant therapy but more evidence is needed and the best neoadjuvant regimen is still to be determined.

  13. FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts

    Institute of Scientific and Technical Information of China (English)

    Cindy Neuzillet; Olivia Hentic; Beno(i)t Rousseau; Vinciane Rebours; Lé(i)la Bengrine-Lefèvre; Franck Bonnetain; Philippe Lévy

    2012-01-01

    AIM:To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.METHODS:All consecutive patients with histologically confirmed,metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m2 on day 1 and leucovorin 400 mg/m2 followed by 5-fluorouracil (5-FU) 400 mg/m2 bolus,then 5-FU 2400 mg/m2 as a 46-h infusion,biweekly] or FOLFIRI-3 (irinotecan 100 mg/m2 on day 1 and leucovorin 400 mg/m2,then 5-FU 2400 mg/m2 as a 46-h infusion and irinotecan 100 mg/m2 repeated on day 3,biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010.Tumor response,time to progression (TTP),overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied.Subgroup analyses were performed to search for prognostic factors.RESULTS:Sixty-three patients (52.4% male,median age 59 years) were analyzed.Among them,42.9% were PS 0,38.1% were PS 1 and 19.0% were PS 2.Fifty one patients (81.0%) had liver metastases.Before the FOLFIRI regimen,patients had received 1 line (n =19),2 lines (n =39) or 3 lines (n =5) of chemotherapy.Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI:3.4-5.3 mo).A total of 480 cycles was completed (median:6 cycles,range:1-51 cycles).The main reason for discontinuing FOLFIRI was tumor progression (90.3%).Tumor control was achieved in 25 patients (39.7%) (partial response:n =5,stable disease:n =20) with FOLFIRI.Median TTP was 3.0 mo (95% CI:2.1-3.9 mo) and median OS was 6.6 mo (95% CI:5.3-8.1 mo).Dose adaptation was required in 36 patients (57.1%).Fifteen patients (23.8%) had grade 3-4 toxicities,mainly hematological (n =11) or digestive (n =4).Febrile neutropenia occurred in 3 patients.There was no toxic death.PS 2 was significantly associated with poor TTP [hazard

  14. S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma

    DEFF Research Database (Denmark)

    Pfeiffer, Per; Qvortrup, Camilla; Krogh, Merete

    2017-01-01

    BACKGROUND: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended...

  15. Inflammatory response related scoring systems in assessing the prognosis of patients with pancreatic ductal adenocarcinoma:a systematic review

    Institute of Scientific and Technical Information of China (English)

    Jawad Ahmad; Nathan Grimes; Shahid Farid; Gareth Morris-Stiff

    2014-01-01

    BACKGROUND: Various scoring systems based on assessment of the systemic inflammatory response help assessing the prognosis of patients with pancreatic ductal adenocarcinoma. In the present systematic review we evaluated the validity of four pre-intervention scoring systems: Glasgow prognostic score (GPS) and its modified version (mGPS), platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), and prognostic nutrition index (PNI). DATA SOURCES: MOOSE guidelines were followed and EMBASE and MEDLINE databases were searched for all published studies until September 2013 using comprehensive text word and MeSH terms. All identified studies were analyzed, and relevant studies were included in the systematic review. RESULTS: Six studies were identified for GPS/mGPS with 3 reporting statistical significance for GPS/mGPS on both univariate analysis (UVA) and multivariate analysis (MVA). Two studies suggested prognostic significance on UVA but not MVA, and in the final study UVA failed to show significance. Eleven studies evaluated the prognostic value of NLR. Six of them reported prognostic significance for NLR on UVA that persisted at MVA in 4 studies, and in the remaining 2 studies NLR was the only significant factor on UVA. In the remaining 5 studies, all in patients undergoing resection, there was no significance on UVA. Seven studies evaluated PLR, with only one study demonstrated its prognostic significance on both UVA and MVA, the rest did not show the significance on UVA. Of the two studies identified for PNI, one demonstrated a statistically significant difference in survival on both UVA and MVA, and the other reported no significance for PNI on UVA. CONCLUSIONS: Both GPS/mGPS and NLR may be useful but further better-designed studies are required to confirm their value. PLR might be little useful, and there are at present inadequate data to assess the prognostic value of PNI. At present, no scoring system is reliable enough to be accepted into routine use

  16. 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

  17. The role of endoscopic ultrasound (EUS in relation to other imaging modalities in the differential diagnosis between mass forming chronic pancreatitis, autoimmune pancreatitis and ductal pancreatic adenocarcinoma Papel de la endoscopia en relación con otras modalidades de imagen en el diagnóstico diferencial entre pancreatitis crónica en forma de masa, pancreatitis autoinmune y adenocarcinoma pancreático

    Directory of Open Access Journals (Sweden)

    Julio Iglesias-García

    2012-06-01

    Full Text Available Differential diagnosis of solid pancreatic lesions remains as an important clinical challenge, mainly for the differentiation between mass forming chronic pancreatitis, autoimmune pancreatitis and pancreatic adenocarcinoma. Endoscopic ultrasound (EUS, computed tomography (CT and magnetic resonance imaging (MRI can all provide valuable and complementary information in this setting. Among them, EUS has the unique ability to obtain specimens for histopathological diagnosis and can therefore play a crucial role in the evaluation patients with inconclusive findings on initial examinations. Nowadays, new developed techniques associated to EUS, like elastography and contrast enhancement, have shown promising results for the differential diagnosis of these pancreatic lesions.El diagnóstico diferencial de las lesiones sólidas pancreáticas permanece como un reto clínico importante, sobre todo para la diferenciación entre la masa de conformación pancreatitis crónica, pancreatitis autoinmune y el adenocarcinoma de páncreas. Ecografía endoscópica (USE, la tomografía computarizada (TC y la resonancia magnética (MRI pueden proporcionar información valiosa y complementaria en este entorno. Entre ellos, la USE tiene la capacidad única de obtener muestras para diagnóstico histopatológico y por lo tanto, puede desempeñar un papel crucial en la evaluación de los pacientes con resultados poco concluyentes en los exámenes iniciales. Hoy en día, las nuevas técnicas desarrolladas asociadas a la USE, como la elastografía y realce de contraste, han mostrado resultados prometedores para el diagnóstico diferencial de las lesiones pancreáticas.

  18. 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.

  19. Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

    Science.gov (United States)

    Sahin, Ibrahim H; Lowery, Maeve A; Stadler, Zsofia K; Salo-Mullen, Erin; Iacobuzio-Donahue, Christine A; Kelsen, David P; O'Reilly, Eileen M

    2016-08-01

    Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach.

  20. Aggressive Multi-Visceral Pancreatic Resections for Locally Advanced Neuroendocrine Tumours. Is It Worth It?

    Directory of Open Access Journals (Sweden)

    Mohammed Abu Hilal

    2009-05-01

    Full Text Available Context Traditional surgical principles state that pancreatic resection should not be contemplated when malignancies arise in the pancreas and involve other organs. While this is logic for ductal adenocarcinoma and other tumours with aggressive biological behavior; for even large neuroendocrine tumours, aggressive multivisceral resection may achieve useful palliation and excellent survival. Design Case records were retrospectively analyzed. Patients and interventions Twelve consecutive patients (7 males, 5 females; median age 57 years, range: 37-79 years underwent multi-visceral en bloc resections for neuroendocrine tumour arising in the pancreas between 1994 and 2008. Results Three patients underwent pancreaticoduodenectomy; 9 patients had left sided pancreatic resections for neuroendocrine tumour of median diameter 9.5 cm ( 5-25 cm. They had a median of 3 (range: 1-4 additional organs resected. There were no post-operative deaths or late mortality with median follow up of 24 months. Five patients experienced a complication (major in 3 patients. Median disease free survival was not attained and 3 patients experienced recurrent disease mostly in the liver and may be candidates for further resection. Conclusion Aggressive multi-visceral resection for locally advanced neuroendocrine tumour involving the pancreas is technically feasible and in selected patients can be achieved with low mortality and acceptable morbidity, offering good disease free and overall survival. However this complex surgery should be only performed in specialist centers.

  1. 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.

  2. Identification of biomarkers of human pancreatic adenocarcinomas by expression profiling and validation with gene expression analysis in endoscopic ultrasound-guided fine needle aspiration samples

    Institute of Scientific and Technical Information of China (English)

    Henrik Laurell; Louis Buscail; Michèle Bouisson; Philippe Berthelémy; Philippe Rochaix; Sébastien Déjean; Philippe Besse; Christiane Susini; Lucien Pradayrol; Nicole Vaysse

    2006-01-01

    AIM: To compare gene expression profiles of pancreatic adenocarcinoma tissue specimens, human pancreatic and colon adenocarcinoma and leukemia cell lines and normal pancreas samples in order to distinguish differentially expressed genes and to validate the differential expression of a subset of genes by quantitative real-time RT-PCR (RT-QPCR) in endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) specimens.METHODS: Commercially dedicated cancer cDNA macroarrays (Atlas Human Cancer 1.2) containing 1176 genes were used. Different statistical approaches (hierarchical clustering, principal component analysis (PCA) and SAM) were used to analyze the expression data. RT-QPCR and immunohistochemical studies were used for validation of results.RESULTS: RT-QPCR validated the increased expression of LCN2 (lipocalin 2) and for the first time PLAT (tissue-type plasminogen activator or tPA) in malignant pancreas as compared with normal pancreas.Immunohistochemical analysis confirmed the increased expression of LCN2 protein localized in epithelial cells of ducts invaded by carcinoma. The analysis of PLAT and LCN2 transcripts in 12 samples obtained through EUS-guided FNA from patients with pancreatic adenocarcinoma showed significantly increased expression levels in comparison with those found in normal tissues, indicating that a sufficient amount of high quality RNA can be obtained with this technique.CONCLUSION: Expression profiling is a useful method to identify biomarkers and potential target genes.Molecular analysis of EUS-guided FNA samples in pancreatic cancer appears as a valuable strategy for the diagnosis of pancreatic adenocarcinomas.

  3. Definitive concurrent chemoradiotherapy in locally advanced pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kwak, Yoo Kang; Lee, Jong Hoon; Lee, Myung Ah; Chun, Hoo Geun; Kim, Dong Goo; You, Young Kyoung; Hong, Tae Ho; Jang, Hong Seok [Seoul St. Mary' s Hospital, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of)

    2014-06-15

    Survival outcome of locally advanced pancreatic cancer has been poor and little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiation. This study was to analyze overall survival and prognostic factors of patients treated with concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic cancer. Medical records of 34 patients diagnosed with unresectable pancreatic cancer and treated with definitive CCRT, from December 2003 to December 2012, were reviewed. Median prescribed radiation dose was 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, five times per week, 1.8 to 3 Gy per fraction. With a mean follow-up of 10 months (range, 0 to 49 months), median overall survival was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Prognostic parameters related to overall survival were post-CCRT CA19-9 (p = 0.02), the Eastern Cooperative Oncology Group (ECOG) status (p < 0.01), and radiation dose (p = 0.04) according to univariate analysis. In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved overall survival (p < 0.01 and p = 0.02, respectively). Overall treatment results in locally advanced pancreatic cancer are relatively poor and few improvements have been accomplished in the past decades. Post-treatment CA19-9 below 180 U/mL and ECOG performance status 0 and 1 were significantly associated with an improved overall survival.

  4. Adenocarcinoma of the Minor Duodenal Papilla: Report of a Case

    Directory of Open Access Journals (Sweden)

    Kazuhiro Takami

    2011-04-01

    Full Text Available An 81-year-old male was found to have a duodenal tumor by screening upper gastrointestinal endoscopy. The tumor was located in the minor duodenal papilla. Pathological examination of the biopsy specimen revealed adenocarcinoma, and endoscopic ultrasound showed an elevated hypoechoic mass in the minor duodenal papilla. The preoperative diagnosis was therefore considered to be either adenocarcinoma of the minor duodenal papilla or duodenal cancer. We performed a subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination of the resected specimen showed the tumor cells to be primarily located in the submucosa of the minor duodenal papilla, with slight invasion into the pancreatic parenchyma through the accessory pancreatic duct. We therefore diagnosed a primary adenocarcima of the minor duodenal papilla. Adenocarcinoma of the minor duodenal papilla is considered to be a rare disease, but it may be underestimated because of the difficulty in distinguishing advanced adenocarcinoma of the minor duodenal papilla from primary duodenal cancer and cancer of the pancreatic head.

  5. SIRT 1 Overexpression is Associated with Metastasis of Pancreatic Ductal Adenocarcinoma (PDAC) and Promotes Migration and Growth of PDAC Cells.

    Science.gov (United States)

    Li, Siqin; Hong, Hua; Lv, Huicheng; Wu, Guozhu; Wang, Zhigang

    2016-05-12

    BACKGROUND SIRT 1, as a class III histone deacetylase (HDAC), is implicated in the initiation and progression of malignancies. However, the association of SIRT 1 with tumorigenesis or progression of pancreatic ductal adenocarcinoma (PDAC) is not clear. MATERIAL AND METHODS In our study we investigated SIRT 1 expression in PDAC samples and evaluated the association of SIRT 1 level with the clinical and pathological characteristics of PDAC patients. We investigated the role of SIRT 1 in the migration and growth of PDAC PANC-1 or BxPC-3 cells using gain-of-function and loss-of-function approach. RESULTS We demonstrated that SIRT 1 mRNA level was significantly promoted in intra-tumor tissues compared to peri-tumor tissues of PDAC; and SIRT 1 overexpression was markedly associated with distant or lymph node (LN) metastasis of these PDAC tissues. Moreover, the in vitro wound healing assay demonstrated that SIRT 1 overexpression with lentivirus vector markedly promoted the migration of PANC-1 or BxPC-3 cells, whereas SIRT 1 knockdown using SIRT 1 specific siRNA transfection significantly inhibited the migration of PDAC cells. The colony forming assay confirmed SIRT 1 promotion of the growth of PANC-1 or BxPC-3 cells. CONCLUSIONS In summary, SIRT 1 overexpression is significantly associated with metastasis of PDAC, and overexpressed SIRT 1 plays an important role in pancreatic cancer cell migration and growth. Our data warrants further studies on SIRT 1 as a novel chemotherapeutic target in PDAC.

  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

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development...... 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...... pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium...

  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. MR imaging of pancreatic diseases

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Katsuyoshi E-mail: itokatsu@po.cc.yamaguchi-u.ac.jp; Koike, Shinji; Matsunaga, Naofumi

    2001-05-01

    This article presents current MR imaging techniques for the pancreas, and review a spectrum of MR imaging features of various pancreatic diseases. These include: 1) congenital anomalies such as anomalous union of pancreatobiliary ducts, divisum, and annular pancreas, 2) inflammatory diseases, including acute or chronic pancreatitis with complications, groove pancreatitis, and autoimmune pancreatitis, tumor-forming pancreatitis, 3) pancreatic neoplasms, including adenocarcinoma, islet cell tumors, and cystic neoplasms (microcystic adenoma, mucinous cystic neoplasms, and intraductal mucin-producing pancreatic tumor). Particular attention is paid to technical advances in MR imaging of the pancreas such as fat-suppression, MR pancreatography (single- or multi-slice HASTE), and thin-section 3D multiphasic contrast-enhanced dynamic sequences. Imaging characteristics that may lead to a specific diagnosis or narrow the differential diagnosis are also discussed.

  9. Life expectancy with perioperative chemotherapy and chemoradiotherapy for locally advanced gastric adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Sadighi S

    2008-12-01

    Full Text Available "nBackground: Although postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach, curative surgery occurs in less than 50% of nonmetastatic gastric cancers. A regimen of docetaxel, cisplatin and infusional fluorouracil improves survival of patients with incurable locally-advanced gastric adenocarcinoma. So we assessed the perioperative regimen of docetaxel, cisplatin and infusions 5FU (TCF and postoperative chemoradiotherapy to improve outcomes in patients with potentially resectable gastric adenocarcinoma. "nMethods: Between March 2005 and March 2008, we 100 enrolled patients with stage II to IV (M0 adenocarcinoma of the stomach who had not been treated previously. Treatment consisted of three preoperative and one postoperative cycles of TCF followed by chemoradiotherapy. The primary end point was overall survival. The secondary end points were progression-free survival and toxicity of treatment. "nResults: A total of 100 patients participated, 83 of whom received neoadjuvant and 17 received adjuvant chemotherapy. Seventy-five patients underwent at least D0 gastrectomy. After chemotherapy, tumor stages were significantly lower than before beginning the protocol. Out of 100 patients, 44 had stage IV before chemotherapy versus 15 after the treatment. Three patients showed complete pathologic response. The median survival time was 25 months. "nConclusion: Docetaxel, cisplatin and 5FU combination chemotherapy is an active preoperative treatment in locally advanced gastric cancer. Perioperative chemoradio-therapy should be considered as an option to lengthen patient survival.

  10. Radiation Therapy Improves Survival Outcome in Pancreatic Adenocarcinoma: Comparison of a 15-Year Institutional Experience at the University of Nebraska Medical Center with SEER Data

    OpenAIRE

    Baine, Michael J.; Chi Lin

    2014-01-01

    Objectives. We examined the role of radiation therapy (RT) in pancreatic adenocarcinoma (PA) treatment through a 15-year retrospective analysis of patients treated at University of Nebraska Medical Center (UNMC) as well as those from the SEER database. Methods. A total of 561 patients diagnosed with PA at UNMC between 1995 and 2011 and 60,587 patients diagnosed between 1995 and 2009 from the SEER were included. Examined prognostic factors for overall survival (OS) were age, gender, race, stag...

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

    OpenAIRE

    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 depleti...

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

    OpenAIRE

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

    2016-01-01

    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 tum...

  13. Recombinant immunomodulating lentogenic or mesogenic oncolytic newcastle disease virus for treatment of pancreatic adenocarcinoma

    NARCIS (Netherlands)

    P.R.A. Buijs (Pascal); S. van Nieuwkoop (Stefan); Vaes, V. (Vincent); R.A.M. Fouchier (Ron); C.H.J. van Eijck (Casper); B.G. van den Hoogen (Bernadette)

    2015-01-01

    textabstractOncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F0) or an IFN antagonistic protein (rNDV-NS1-F0), as well as rNDV with

  14. 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

  15. Cyclin D1, p16(INK) (4A) and p27(Kip1) in pancreatic adenocarcinoma: assessing prognostic implications through quantitative image analysis.

    Science.gov (United States)

    Georgiadou, Despoina; Sergentanis, Theodoros N; Sakellariou, Stratigoula; Filippakis, George M; Zagouri, Flora; Vlachodimitropoulos, Dimitris; Psaltopoulou, Theodora; Lazaris, Andreas C; Patsouris, Efstratios; Zografos, George C

    2014-12-01

    The prognostic significance of cyclin D1, p16(INK) (4A) and p27(Kip1) expression has been documented in several human malignancies; however, their prognostic potential in pancreatic adenocarcinoma is still unclear. This study aimed to assess the correlation of the aforementioned molecules with clinicopathological parameters and prognosis. Sixty patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution; immunohistochemical staining of the studied markers was quantified by Ιmage analysis system. Cyclin D1 overexpression was positively associated with grade, neural infiltration and vascular invasion, whereas p27 positively correlated with age. Higher cyclin D1 expression indicated poorer survival (adjusted HR = 9.75, 95%CI: 1.48-64.31, p = 0.018, increment: one unit in H-score), whereas a marginal trend toward an association between p16 positivity and improved survival was observed (adjusted HR = 0.58, 95%CI: 0.32-1.05, p = 0.072 regarding positive vs negative cases). No significant association with overall survival was noted regarding p27. In conclusion, cyclin D1 overexpression and possibly p16 loss of expression in pancreatic adenocarcinoma seem to be adverse prognostic factors, whereas p27 expression did not seem to possess such prognostic properties. Further validation of the present findings in studies encompassing larger samples seems to be needed.

  16. Role of endoscopic ultrasound in diagnosis and therapy of pancreatic adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Joseph Boujaoude

    2007-01-01

    Since its advent more than 20 years ago, endoscopic ultrasound (EUS) has undergone evolution from an experimental to a diagnostic instrument and is now established as a therapeutic tool for endoscopists.Endoscopic ultrasound cannot accurately distinguish benign from malignant changes in the primary lesion or lymph node on imaging alone. With the introduction of the curved linear array echoendoscope in the 1990s,the indications for EUS have expanded. The curved linear array echoendoscope enables the visualization of a needle as it exits from the biopsy channel in the same plane of ultrasound imaging in real time. This allows the endoscopist to perform a whole range of interventional applications ranging from fine needle aspiration (FNA) of lesions surrounding the gastrointestinal tract to celiac plexus block and drainage of pancreatic pseudocyst. This article reviews the current role of EUS and EUS-FNA in diagnosis, staging and interventional application of solid pancreatic cancer.

  17. Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis.

    Science.gov (United States)

    Arundhathi, Arivajiagane; Chuang, Wen-Han; Chen, Jen-Kun; Wang, Shin-E; Shyr, Yi-Ming; Chen, Jiun-Yu; Liao, Wei-Neng; Chen, Hsin-Wei; Teng, Yi-Min; Pai, Chiao-Chih; Wang, Chih-Hong

    2016-07-13

    Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single-photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer.

  18. 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 PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

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

    Science.gov (United States)

    Liu, Qingqing; Stewart, John; Wang, Hua; Rashid, Asif; Zhao, Jun; Katz, Matthew H.; Lee, Jeffrey E.; Fleming, Jason B.; Maitra, Anirban; Wolff, Robert A.; Varadhachary, Gauri R.; Krishnan, Sunil; Wang, Huamin

    2017-01-01

    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. PMID:28187218

  20. Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Dawkins, Joshua B N; Wang, Jun; Maniati, Eleni; Heward, James A; Koniali, Lola; Kocher, Hemant M; Martin, Sarah A; Chelala, Claude; Balkwill, Frances R; Fitzgibbon, Jude; Grose, Richard P

    2016-08-15

    Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0-G1 RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. Cancer Res; 76(16); 4861-71. ©2016 AACR.

  1. Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Dawkins, Joshua B.N.; Wang, Jun; Maniati, Eleni; Heward, James A.; Koniali, Lola; Kocher, Hemant M.; Martin, Sarah A.; Chelala, Claude; Balkwill, Frances R.; Fitzgibbon, Jude; Grose, Richard P.

    2017-01-01

    Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0–G1. RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. PMID:27280393

  2. Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Aboukameel, Amro; Muqbil, Irfana; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Shacham, Sharon; Kauffman, Michael; Philip, Philip A; Mohammad, Ramzi M; Azmi, Asfar S

    2017-01-01

    The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC). The toxicity and efficacy of PAMs were evaluated in multiple subcutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307, and KPT-9274) show antiproliferative activity in vitro against different PDAC cell lines while sparing normal HPDE. Cell growth inhibition was concurrent with apoptosis induction and suppression of colony formation in PDAC. PAMs inhibited proliferation and antiapoptotic signals downstream of PAK4. Co-immunoprecipitation experiments showed disruption of PAK4 complexes containing vimentin. PAMs disrupted CSC spheroid formation through suppression of PAK4. Moreover, PAMs synergize with gemcitabine and oxaliplatin in vitro KPT-9274, currently in a phase I clinical trial (clinicaltrials.gov; NCT02702492), possesses desirable pharmacokinetic properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally. KPT-9274 as a single agent showed remarkable antitumor activity in subcutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the antiproliferative effects of novel PAMs in PDAC and warrant further clinical investigations. Mol Cancer Ther; 16(1); 76-87. ©2016 AACR.

  3. RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients.

    Science.gov (United States)

    Muniz, Viviane P; Askeland, Ryan W; Zhang, Xuefeng; Reed, Sara M; Tompkins, Van S; Hagen, Jussara; McDowell, Bradley D; Button, Anna; Smith, Brian J; Weydert, Jamie A; Mezhir, James J; Quelle, Dawn E

    2013-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy.

  4. CT perfusion aid in the diagnosis of pancreatic adenocarcinoma%CT灌注成像辅助诊断胰腺癌

    Institute of Scientific and Technical Information of China (English)

    徐青; 唐金华; 徐化凤

    2011-01-01

    目的:CT灌注是一种新的功能成像方法,它能反映组织内的血液灌注的变化.本文旨在研究胰腺癌的CT灌注特征及探讨64层螺旋CT胰腺灌注成像在胰腺癌辅助诊断中的价值.方法:临床拟诊胰腺癌的患者49例,采用64层螺旋CT行胰腺灌注扫描,灌注扫描结束后进行常规胰腺双期扫描.对灌注参数:局部组织血流量(blood flow,BF)、血容量( blood volume,BV)、峰值(PE)、渗透性(permeability,P)和达峰时间(time to peak,TTP)进行统计分析.结果:12例因为技术原因或非胰腺癌病例而排除在外.剩下的37例包括13例正常胰腺和病理证实的胰腺癌24例.正常胰腺实质与胰腺癌周围的正常胰腺组织在BF( 146.23 vs.119 37),BV(194.51 vs.173.67).PE(85.08 Vs.72.47).TTP(126.48 Vs.135.07).Permeability(84.86 Vs.69.11)上无统计学差异(P>0 05)胰腺癌组织的BF (55.10 Vs.146.23).BV(89.19 Vs.194.51),and PE (42.97 vs.85.08)明显低于瘤周的正常胰腺组织,差异有显著性(P<0.05).但是两者的TTP (131.73 Vs.126.48) and Permeability (59.94 Vs.84.86)无明显差异(P>0.05).结论:64层螺旋CT胰腺癌的灌注研究显示肿瘤的BF.BV,and PE明显减低.CT灌注扫描对胰腺癌的诊断有一定价值.%Objective:CT perfusion is a new technique of function imaging, which can outline blood perfusion change in a tissue. We aimed to explore the perfusion characteristics of pancreatic adenocarcinoma and to determine whether 64-slice spiral CT with pancreas perfusion imaging could aid in diagnosing pancreatic adenocarcinoma. Methods: 49 patients with suspected pancreatic adenocarcinoma underwent pancreas perfusion examination with 64-slice CT. After dynamic enhancement scanning, routine dual-phase scanning was performed. Perfusion parameters including blood flow (BF). Blood Volume CBV) . Peak enhancement (PE) . Lime to peak (TTP) and permeability (P) were analyzed. Results: Total 12 patients were excluded due to technical reasons or other

  5. Predictive dosimetric parameters for gastrointestinal toxicity with hypofractioned radiotherapy in pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Liu X

    2016-04-01

    Full Text Available Xian Liu,* Gang Ren,* Liqin Li, Tingyi Xia Department of Radiation Oncology, Air Force General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: To better guide the development and optimization of radiotherapy planning, to reduce the incidence of radiation reactions, and to improve the quality of life of the patients with pancreatic cancer using radiotherapy, we conducted this study to explore the dosimetric parameters that predict the risk of gastrointestinal (GI toxicity with hypofractioned radiotherapy for pancreatic cancer. Between January 2014 and January 2015, the medical records of 68 patients with pancreatic cancer who underwent helical tomotherapy at the Air Force General Hospital were analyzed. The doses delivered to the planning target volume, clinical target volume, and gross tumor volume–internal gross tumor volume of the primary pancreatic lesions were 50, 60, and 70–80 Gy in 15–20 fractions, respectively. GI toxicity was scored according to version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. The stomach and duodenum were contoured separately to determine the dose–volume histogram parameters. Univariate and multivariate analyses were adopted to identify clinical and physical risk factors associated with GI toxicity. The median follow-up was 9 months (range: 4–16 months. Eighteen patients had grade II acute GI toxicity, one patient had grade III acute GI toxicity, 17 patients had grade II late GI toxicity, and one patient had grade III late GI toxicity. On univariate analysis, the volume, the average dose Dmean, the maximum dose to 1, 3, 5, and 10 cm3 of the stomach and duodenum (D1, D3, D5, and D10, and the relative volumes receiving 5–40 Gy (V5–V40, and the absolute volumes receiving 5–45 Gy (aV5–aV45 of the duodenum were significantly associated with grade II or higher GI toxicity (P<0.05. On multivariate

  6. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

    Science.gov (United States)

    Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas; Hollingsworth, Michael A.; Rizzino, Angie

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC. PMID:27145457

  7. 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

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development...... and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one...... 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...

  8. A Distinct Slow-Cycling Cancer Stem-like Subpopulation of Pancreatic Adenocarcinoma Cells is maintained in Vivo

    Energy Technology Data Exchange (ETDEWEB)

    Dembinski, Jennifer L., E-mail: jennifer.dembinski@rr-research.no; Krauss, Stefan [Cellular and Genetic Therapy, Department of Microbiology, Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital, Rikshospitalet, Oslo (Norway)

    2010-11-29

    Pancreatic adenocarcinoma has the worst prognosis of any major malignancy, with <5% of patients surviving five years. This can be contributed to the often late diagnosis, lack of sufficient treatment and metastatic spread. Heterogeneity within tumors is increasingly becoming a focus in cancer research, as novel therapies are required to target the most aggressive subpopulations of cells that are frequently termed cancer stem cells (CSCs). In the current study, we describe the identification of a slow-cycling cancer stem-like population of cells in vivo in BxPC-3 and Panc03.27 xenografts. A distinct slow-cycling label-retaining population of cells (DiI+/SCC) was found both at the edge of tumors, and in small circumscribed areas within the tumors. DiI+/SCC in these areas display an epithelial-to-mesenchymal transition (EMT) fingerprint, including an upregulation of the mesenchymal markers vimentin and N-cadherin and a loss of the epithelial marker E-cadherin. DiI+/SCC also displayed a critical re-localization of beta-catenin from the membrane to the nucleus. Additionally, the DiI+/SCC population was found to express the developmental signaling molecule sonic hedgehog. This study represents a novel step in defining the biological activities of a tumorigenic subpopulation within the heterogeneous tumor microenvironment in vivo. Understanding the interactions and functions of a CSC population within the context of the tumor microenvironment is critical to design targeted therapeutics.

  9. Orphan nuclear receptor Nurr1 as a potential novel marker for progression in human pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Ji, Li; Gong, Chen; Ge, Liangyu; Song, Linping; Chen, Fenfen; Jin, Chunjing; Zhu, Hongyan; Zhou, Guoxiong

    2017-01-01

    Nuclear receptor related-1 protein (Nurr1) is a novel orphan member of the nuclear receptor superfamily (the NR4A family) involved in tumorigenesis. The aim of the present study was to investigate the expression and possible function of Nurr1 in pancreatic ductal adenocarcinoma (PDAC). The expression pattern of Nurr1 protein was determined using immunohistochemical staining in 138 patients with PDAC. Elevated Nurr1 expression was more commonly observed in PDAC tissues and cell lines compared with healthy controls. Elevated expression was significantly associated with histological differentiation (P=0.041), lymph node metastasis (P=0.021), TNM classification of malignant tumors stage (P=0.031) and poor survival (P=0.001). Further experiments demonstrated that suppression of endogenous Nurr1 expression attenuated cell proliferation, migration and invasion, and induced apoptosis of PDAC cells. In conclusion, these results suggest that Nurr1 has an important role in the progression of PDAC and may be used as a novel marker for therapeutic targets.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  11. Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian; Ling, Jianhua; Fu, Jie; Lu, Yu; Wu, Min; Yang, Lifeng; Achreja, Abhinav; Chen, Gang; Zhuang, Zhuonan; Wang, Huamin; Nagrath, Deepak; Yao, Jun; Hung, Mien-Chie; DePinho, Ronald A.; Huang, Peng; Xu, Rui-Hua; Chiao, Paul J.

    2017-01-01

    Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC. PMID:28232723

  12. High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Colbert, Lauren E. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Fisher, Sarah B. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia (United States); Balci, Serdar; Saka, Burcu [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Pathology, Emory University, Atlanta, Georgia (United States); Chen, Zhengjia; Kim, Sungjin [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); El-Rayes, Bassel F. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia (United States); Adsay, N. Volkan [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Pathology, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); Maithel, Shishir K. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); Landry, Jerome C. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); and others

    2015-03-01

    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

  13. Pan FGFR Kinase Inhibitor BGJ398 and Combination Chemotherapy in Treating Patients With Untreated Metastatic Pancreatic Cancer

    Science.gov (United States)

    2016-05-19

    Colon Adenocarcinoma; Metastatic Pancreatic Adenocarcinoma; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Rectal Adenocarcinoma; Stage III Pancreatic Cancer; Stage IIIA Colon Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer; Stage IV Pancreatic Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  14. Screening for Early Pancreatic Ductal Adenocarcinoma: An Urgent Call! Highlights from the "2009 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 15-17, 2009

    Directory of Open Access Journals (Sweden)

    Michael Xiang Lee

    2009-03-01

    Full Text Available Cancer of the pancreas is the fourth leading cause of cancer mortality in the United States. The annual death rate from the disease almost equals the annual incidence due to the aggressive nature of the cancer as well as to the lack of effective means of screening for it during its early curable stage. Molecular markers and imaging have not proven to be accurate modalities for screening for pancreatic cancer. The diagnosis and management of pancreatic cancer continues to be an overwhelming challenge. The authors discuss the current status of screening for pancreatic cancer and summarize relevant studies presented in the 2009 GI Cancers Symposium: utility of endoscopic ultrasound in screening high risk patients (Abstract #112, diagnostic performance of a highly specific antibody for MUC1 (Abstract #113, use of metabonomics for the early detection of pancreatic adenocarcinoma (Abstract #126, and a report on the potential impact of delay in diagnosis and treatment on pancreatic cancer outcomes at a tertiary care center (Abstract #137.

  15. Fluorouracil Based Chemoradiation with Either Gemcitabine or Fluorouracil Chemotherapy Following Resection of Pancreatic Adenocarcinoma: 5-Year Analysis of the US Intergroup/RTOG 9704 Phase III Trial

    Science.gov (United States)

    Regine, William F.; Winter, K.A.; Abrams, R.; Safran, H.; Hoffman, J.P.; Konski, A.; Benson, A.B.; Macdonald, J.S.; Rich, T.A.; Willett, C.G.

    2011-01-01

    Background The impact of the addition of gemcitabine (G) to 5-FU chemoradiation (CRT) on 5-year overall survival (OS) in resected pancreatic adenocarcinoma are presented with updated results of a phase III trial. Methods Following resection of pancreatic adenocarcinoma patients were randomized to pre and post CRT 5-FU vs. pre and post CRT G. 5-FU = continuous (CI) at 250 mg/m2/day. G = 1000 mg/m2 weekly; both given over 3 weeks pre and 12 weeks post - CRT. CRT = 50.4 Gy with CI 5-FU. Primary endpoint was survival for all patients and for pancreatic head tumor patients. Results Four hundred and fifty-one patients were eligible. Univariate analysis showed no difference in OS. Pancreatic head tumor patients (n=388) had a median survival and 5-year OS of 20.5 months and 22% with G vs. 17.1 months and 18% with 5-FU. On multivariate analysis, patients on the G arm with pancreatic head tumors experienced a trend towards improved OS (p=0.08). First site of relapse local recurrence in 28% of patients vs. distant relapse in 73%. Conclusion(s) The sequencing of 5-FU CRT with G as done in this trial is not associated with a statistically significant improvement in OS. Despite local recurrence being approximately half of that reported in previous adjuvant trials, distant disease relapse still occurs in ≥ 70% of patients. These findings serve as the basis for the recently activated EORTC/US Intergroup RTOG 0848 phase III adjuvant trial evaluating the impact of CRT after completion of a full course of G. PMID:21499862

  16. 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...

  17. Pancreatic Mucinous Cyst Adenocarcinoma Producing CA 19-9. A Case Report

    Directory of Open Access Journals (Sweden)

    Sumiya Ishigami

    2007-03-01

    Full Text Available Context We herein present a rare case of a mucinous cystic neoplasm of the pancreas producing CA 19-9 and the clinical implications are discussed. Case report A 35-year-old woman with no history of abdominal surgery presented at Saisei Kai Sendai Hospital with an upper abdominal distention. Abdominal CT showed a large lobulated cystic tumor at the pancreatic tail. No distant metastases were identified. The preoperative serum CA 19-9 level was 6,200 U/mL (reference range: 0-37 U/mL. A mucinous cystic neoplasm of the pancreas was diagnosed and elective surgery was performed. On laparotomy, a round tumor 15 cm in diameter was encountered in the upper left abdomen. No invasion of neighboring organs or the portal vein was apparent. The entire tumor was curatively resected with a distal pancreatectomy. The final histopathological analysis revealed mucinous cystadenocarcinoma with no invasive component. Immunohistochemical staining disclosed CA 19-9 expression within the tumor cells. The CA 19-9 level normalized rapidly postoperatively and, although a minor pancreatic fistula occurred, this was resolved conservatively. She was discharged on the 45th postoperative day with no sign of tumor relapse; her CA 19-9 level was within the normal range 20 months postoperatively. Conclusion We present this rare case of a mucinous cystic neoplasm producing CA 19-9 and discuss the relevant literature. The CA 19-9 production in this tumor does not appear to be directly correlated to aggressive clinical behavior.

  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. The Canonical Wnt Pathway Regulates the Metastasis-Promoting Mucin MUC4 in Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Pai, Priya; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Macha, Muzafar A; Sheinin, Yuri; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2015-01-01

    Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane-mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/β-catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF-binding sites, leading us to hypothesize that MUC4 can be regulated by β-catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear β-catenin expression. Knock down (KD) of β-catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized β-catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., −2629/−2612) and furthest from the start site (i.e., −3425/−3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of β-catenin on −2629/−2612 and −3425/−3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 β-catenin KD cells showed decreased migration and decreased Vimentin, N-cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF β-catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that β-catenin directly governs MUC4 in PC. PMID:26526617

  20. 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.

  1. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Lastraioli, E; Perrone, G; Sette, A; Fiore, A; Crociani, O; Manoli, S; D'Amico, M; Masselli, M; Iorio, J; Callea, M; Borzomati, D; Nappo, G; Bartolozzi, F; Santini, D; Bencini, L; Farsi, M; Boni, L; Di Costanzo, F; Schwab, A; Onetti Muda, A; Coppola, R; Arcangeli, A

    2015-01-01

    Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID:25719829

  2. MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Sameer A Dhayat

    Full Text Available No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC. MicroRNAs (miR are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern.Gemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot.Both established PDAC clones showed a significant resistance to gemcitabine (p<0.02 with low apoptosis rate (p<0.001 vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR-99a, miR-100, miR-125b, miR-138, miR-210 and downregulated miRs (miR-31*, miR-330, miR-378 in chemoresistant PDAC (p<0.05. Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02 and Bcl-2 (p<0.003 were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023 in one clone.Consistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC.

  3. Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.

    Science.gov (United States)

    Slee, Roger B; Grimes, Brenda R; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray

    2014-02-01

    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.

  4. MiR-221 Promotes Capan-2 Pancreatic Ductal Adenocarcinoma Cells Proliferation by Targeting PTEN-Akt

    Directory of Open Access Journals (Sweden)

    Wenzhuo Yang

    2016-05-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs, miRs have emerged as critical regulators of cancer cell proliferation. The effect of miR-221 on cancer cell growth could be significantly changeable in different cell lines. Although miR-221 was reported to promote the cell growth of pancreatic ductal adenocarcinoma (PDAC cells, its role in Capan-2 cell line is largely unknown. Methods: Capan-2 cells were transfected with miR-221 mimics, inhibitors, or negative controls. Cell Counting Kit-8 was used to determine cell viability. EdU staining and cell cycle analysis were used to measure cell proliferation. Western blotting was used to detect the expression levels of PTEN and phospho-Akt. The PI3K-Akt pathway activator SC-79 and inhibitor LY294002 were used to perform the rescue experiment in determining cell proliferation. Results: Overexpressing miR-221 significantly increased cell vitality and promoted cell proliferation and G1-to-S phase transition of the cell cycle in Capan-2 cells, while inhibition of miR-221 decreased that. The protein level of PTEN in Capan-2 cells was downregulated by overexpressing miR-221, while upregulated by inhibiting miR-221. Consistently, enhanced phosphorylation of AktSer473 was observed in miR-221 overexpressed Capan-2 cells, and the opposite result was found in miR-221 inhibited cells. LY294002 restored the pro-proliferation effect of miR-221 on Capan-2 cells, while SC-79 had no additional effect on cell proliferation in Capan-2 cells transfected with miR-221 mimics. Conclusion: Our study indicates that miR-221 is an oncogenic miRNA which promotes Capan-2 cells proliferation by targeting PTEN-Akt pathway.

  5. A comprehensive examination of Smad4, Smad6 and Smad7 mRNA expression in pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    P Singh

    2011-01-01

    Full Text Available Background: Smad4, Smad6 and Smad7 are important molecules in TGF-beta pathway, which plays an important role in pancreatic ductal adenocarcinoma (PDAC biology. Aims : This study examined the expression profiles of Smad4, Smad6 and Smad7 mRNA in patient samples of PDAC and their relationship to Smad protein expression, SMAD4 gene mutations, clinicopathological parameters and patient survival. Settings and Design: Surgically resected, paired normal and tumor tissues of 25 patients of PDAC were studied. Materials and Methods: Protein and mRNA levels were assessed by immunohistochemistry and RT-PCR, respectively. Statistical Methods: Statistical analysis was done using Student′s t-test, Pearson′s chi-square test, Spearman′s Rank Correlation, Pearson′s Correlation test and Kaplan-Meier Logrank test. Results: While there was a highly significant difference in the protein levels of all three Smads in tumor as compared to normal samples, mRNA levels were significantly different only for Smad4. Protein levels did not correlate significantly with mRNA levels for any of the three Smads. The mRNA levels of Smad4 and Smad6, Smad4 and Smad7, and Smad6 and Smad7 in tumor samples showed a significant positive correlation. The relationship of Smad4 mRNA expression to SMAD4 gene status and Smad4 protein expression was discordant and there was no significant correlation between mRNA expression and clinicopathological parameters and patient survival. Conclusion : The absence of concordance between SMAD4 gene status, mRNA expression and Smad4 protein expression suggests the presence of other regulatory mechanisms in Smad4 transcription and translation in PDAC.

  6. HER2/neu Expression and Gene Alterations in Pancreatic Ductal Adenocarcinoma: A Comparative mmunohistochemistry and Chromogenic in Situ Hybridization Study Based on Tissue Microarrays and Computerized Image Analysis

    Directory of Open Access Journals (Sweden)

    Evangelos Tsiambas

    2006-05-01

    Full Text Available Context: HER2/neu overexpression is observed in many cancers including pancreatic ductal adenocarcinoma. Although immunohistochemistry remains the basic method for evaluating HER2/neu protein expression, significant information regarding gene status cannot be assessed. Design: Using tissue microarray technology, fifty histologically confirmed pancreatic ductal adenocarcinomas were cored twice and re-embedded in one paraffin block. Immunohistochemistry (clone TAB 250 and chromogenic (HER2/neu amplification Spot Light kit in situ hybridization protocols were performed. The immunostained slides were evaluated by conventional eye microscopy and digital image analysis. The chi square test and the kappa statistic were applied by running the SPSS package. Main outcome measures :The levels of staining intensity were estimated by the performance of a semi automated image analysis system. Results :HER2/neu gene amplification was detected in 8/50 cases (16%. Chromosome 17 aneuploidy was detected in 19 cases (38%. Significant improvement in interobserver agreement (kappa=0.76 vs. 0.94 was achieved correlating the immunohistochemical results obtained by conventional eye and digital microscopy, especially in the cases of overexpression (2+, 3+. Finally, 29 (58%, 11 (22%, 6 (12% and 4 (8% cases were characterized as 0, 1+, 2+ and 3+, respectively. HER2/neu protein expression was significantly associated with grade (P=0.019, but not with stage (P=0.466. in addition, chromosome 17 and gene status were not correlated with stage and grade.. Conclusion :Our results indicate that a subset of pancreatic ductal adenocarcinomas is characterized by HER2/neu gene amplification. In contrast to breast cancer, protein overexpression does not predict this specific gene deregulation mechanism. This event may reflect the different biological role of the molecule in those two solid tumours, affecting the response to novel targeted agents, such as monoclonal anti-HER2/neu

  7. A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels

    OpenAIRE

    Erkan, Murat Mert; Kong, Bo; Wu, Weiwei; Valkovska, Nataliya; Jager, Carsten; Hong, Xin; Nitsche, Ulrich; Friess, Helmut; Esposito, Irene; Kleeff, Joerg; Michalski, Christoph W.

    2015-01-01

    A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels Bo Kong1, Weiwei Wu1, Nataliya Valkovska1, Carsten Ja¨ger1, Xin Hong1, Ulrich Nitsche1, Helmut Friess1, Irene Esposito2, Mert Erkan3, Jo¨rg Kleeff1* & Christoph W. Michalski4* 1Department of Surgery, Technische Universita¨t Mu¨nchen, Munich, Germany, 2Institute of Pathology, Technische Universita¨t Mu¨nchen, Munich, Ge...

  8. Is it relevant that intra-arterial chemotherapy may be effective for advanced pancreatic cancer?

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Unresectable pancreatic cancers have an extremely dismal prognosis and chemoresistant nature. The treatment of pancreatic cancer is still problematic.Gemcitabine is a promising new agent that has been studied recently for palliation of advanced pancreatic cancer. However, the response rates have been highly variable, and are often irreproducible. To improve this low response rate, various treatments are needed because no standard treatment exists. Intra-arterial chemotherapy is considered to take advantage of the first pass effect of the drug, generating higher local drug concentrations in tumor cells with lower toxicity.Regional intra-arterial chemotherapy may provide high levels of cytostatic concentrations within the tumor and, simultaneously, a low rate of systemic side effects compared with systemic administration of anti-neoplastic drugs. Intra-arterial chemotherapy has been introduced as an alternative treatment for advanced pancreatic cancer. Further clinical trials of this method should be subjected to a prospective randomized controlled study for advanced pancreatic cancer.

  9. Evaluation of two preoparative chemotherapy regimens for complete operability of advanced gastric adenocarcinoma: a clinical trial

    Directory of Open Access Journals (Sweden)

    S. Sedighi

    2006-08-01

    Full Text Available Background: This prospective phase III study was designed to compare the activity of two combinations chemotherapy drugs in advanced gastric adenocarcinoma Methods: In a double blinded clinical trial, From Jan. 2002 to Jan. 2005, ninety patients with advanced gastric adenocarcinoma were randomly assigned to 1 Cisplatin and continuous infusion of 5FU and Epirubicin (ECF, and 2 Cisplatin and continuous infusion of 5FU with Docetaxel (TCF. Reduction in tumor mass, overall survival (OS, time to progression (TTP, and safety were measured outcome. Results: About 90% of patients had stage III or IV disease and the most common sites of tumor spread were peritoneal surfaces, liver and Paraaortic lymph nodes in either group. The objective clinical response rate (more than 50% decreases in tumor mass was 38% and 43% in ECF and TCF group respectively. Global quality of life increased (p=0 002 and symptoms of pain and insomnia decreased after chemotherapy. Patients in TCF had more grade one or two skin reactions, neuropathy and diarrhea. Fourteen patients underwent surgery. Complete microscopic (R0 resection had done in two of ECF and six of TCF tumors (p=0.015. Two cases in TCF group showed complete pathologic response. Median TTP was nine months and 10 months in ECF and TCF group respectively. Median OS was 12 months in both groups. Conclusion: Although there wasn’t statistically significant difference regarded to clinical response or survival between two groups, TCF showed more complete pathologic response.

  10. Vandetanib Treatment in Refractory Advanced Lung Adenocarcinoma Patients: 
Five Cases and Review of Literature

    Directory of Open Access Journals (Sweden)

    Lili GUO

    2012-02-01

    Full Text Available Background and objective Vandetanib is a once-daily oral multi-target inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET tyrosine kinases. The current study aimed to evaluate the effect and safety of vandetanib administered in refractory advanced lung adenocarcinoma patients. Methods Five patients who accepted chemotherapy and Tarceva therapy as first- and second-line treatments received vandetanib (300 mg, oral, once daily. Results The effects are stable disease on two patients (40% and progressive disease on three patients (60%. With a median follow-up of 36 months, one patient remained on follow-up. The median progression free survival (PFS is 2 months, and the mean overall survival is 22.6 months. The adverse events include rash (n=2, skin change (n=2, paronychia (n=2, asymptomatic QTc prolongation (n=2, ST-T change (n=1, diarrhea (n=1, and increased transaminase (n=1. Conclusion There were lower incidences of severe side effects with vandetanib therapy in refractory advanced lung adenocarcinoma patients. The results of effect and safety of vandetanib are similar with the related reviewed articles.

  11. 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 ...

  12. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970359 CT diagnosis of pancreatic carcinoma andchronic pancreatitis. LUAN Baoqing(栾宝庆), et al,Dept Radiol, Beijing Friendship Hosp, Capital Med U-niv, Beijing, 100050. Chin J Radiol 1997; 31(2): 114-118. Objective: To improve the diagnostic accuracy ofpancreatic carcinoma and chronic pancreatitis. Materi-

  13. Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis.

    Science.gov (United States)

    Okazaki, Kazuichi; Uchida, Kazushige; Fukui, Toshiro

    2008-01-01

    Recent advances support the concept of autoimmune pancreatitis (AIP) as a unique systemic disease, because it shows occasional extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialoadenitis, and retroperitoneal fibrosis, pathological features similar to those of fibrosis, and abundant infiltration of IgG4-positive plasma cells, and it is steroid responsive. Based on these findings, several diagnostic criteria have been proposed. Although AIP is accepted worldwide as a unique clinical entity, its pathogenetic mechanism remains unclear. To clarify its pathogenesis, its genetic background, humoral immunity, candidate target antigens including self-antigens and molecular mimicry by microbes, and cellular immunity including regulatory T cells, the complement system, and experimental models are reviewed. On the basis of this review, we hypothesize that the pathogenesis of AIP involves a biphasic mechanism consisting of "induction" and "progression." In the early stage, the initial response to self-antigens [lactoferrin, carbonic anhydrase (CA)-II, CA-IV, pancreatic secretory trypsin inhibitor, and alpha-fodrin] and molecular mimicry (Helicobacter pylori) are induced by decreased naïve regulatory T cells (Tregs), and T-helper (Th) 1 cells release proinflammatory cytokines [interferon-gamma, interleukin (IL)-1beta, IL-2, and tumor necrosis factor alpha]. In the chronic stage, progression is supported by increased memory Tregs and Th2 immune responses. The classical complement system pathway may be activated by the IgG1 immune complex. As Tregs seem to play an important role in progression as well as in induction of the disease, further studies are necessary to clarify the pathogenesis of AIP.

  14. Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer

    DEFF Research Database (Denmark)

    Bjerregaard, Jon K; Mortensen, Michael B; Jensen, Helle A;

    2009-01-01

    BACKGROUND: Definition and treatment options for locally advanced non-resectable pancreatic cancer (LAPC) vary. Treatment options range from palliative chemotherapy to chemoradiotherapy (CRT). Several studies have shown that a number of patients become resectable after complementary treatment prior...

  15. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    1995-01-01

    950347 Pancreatic endorcine response to parenteralnutrition in experimental acute pancreatitis.SUN Xi-aoguang(孙晓光),et al.Dept Nucl Med,ZhongshanHosp,Shanghai Med Univ,Shanghai.Shanghai Med J1995;18(2),74-70.In order to study the pancreatic endocrine responseto parenteral nutrition (PN) in acute pancreatitis,thedisease was induced in dogs by injecting 4% tauro-cholate sodium 0.5ml/kg plus trypsin 0.5mg/kg into the pancreatic duct.Intravenous infusion of PN wasinitiated one hour after the establishment of the dis-

  16. 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.

  17. Preoperative docetaxel/cisplatin/5-fluorouracil chemotherapy in patients with locally advanced gastro-esophageal adenocarcinoma.

    Science.gov (United States)

    Bayraktar, Ulas Darda; Bayraktar, Soley; Hosein, Peter; Chen, Emerson; Koniaris, Leonidas G; Rocha-Lima, Caio Max S; Montero, Alberto J

    2012-09-01

    Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.

  18. Advances in understanding the molecular mechanism of pancreatic cancer metastasis

    Institute of Scientific and Technical Information of China (English)

    Yong-Xing Du; Zi-Wen Liu; Lei You; Wen-Ming Wu; Yu-Pei Zhao

    2016-01-01

    BACKGROUND: Pancreatic cancer (PC) is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identiifed groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecu-lar mechanisms of PC metastasis. DATA SOURCES: Relevant articles on PC metastasis were searched in MEDLINE via PubMed prior to April 2015. The search was limited in English publications. RESULTS: PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inlfammation, stress response, and circulating tumor cells. CONCLUSIONS: Analyses of relevant gene functions and signaling pathways are needed to establish the gene regula-tory network and to deifne the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of per-sonalized therapy by identifying speciifc markers and targets.

  19. 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.

  20. Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    Hong-Li Xu; Jia-Rong Cheng; Wei Zhang; Jing Wang; Herbert Yu; Quan-Xing Ni; Harvey A. Risch; Yu-Tang Gao

    2014-01-01

    Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologicaly confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C alele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.

  1. A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Gustav J Ullenhag

    Full Text Available Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15, each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily. The maximum tolerated dose (MTD of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25% subjects experiences a dose-limiting toxicity (DLT. Patients should also be able to receive daily low molecular weight heparin (LMWH (e.g. dalteparin 5000 IU s.c. daily as a prophylactic anticoagulant for venous thromboembolic events (VTEs. Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively were enrolled in this study.Median duration of treatment was 11 weeks (range 1-66, and median number of treatment cycles were three (range 1-14. The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs (all grades included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia; thrombocytopenia (75%; dermatological toxicity (75%; diarrhea and nausea (42% each; and neuropathy (42%.This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.ClinicalTrials.gov NCT

  2. Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells.

    Science.gov (United States)

    Abdelalim, Essam M; Emara, Mohamed M

    2015-01-26

    Pluripotent stem cells (PSCs) are able to differentiate into several cell types, including pancreatic β cells. Differentiation of pancreatic β cells depends on certain transcription factors, which function in a coordinated way during pancreas development. The existing protocols for in vitro differentiation produce pancreatic β cells, which are not highly responsive to glucose stimulation except after their transplantation into immune-compromised mice and allowing several weeks for further differentiation to ensure the maturation of these cells in vivo. Thus, although the substantial improvement that has been made for the differentiation of induced PSCs and embryonic stem cells toward pancreatic β cells, several challenges still hindering their full generation. Here, we summarize recent advances in the differentiation of PSCs into pancreatic β cells and discuss the challenges facing their differentiation as well as the different applications of these potential PSC-derived β cells.

  3. First-Line Treatment of Metastatic Pancreatic Adenocarcinoma: Can We Do Better? Highlights from the "2010 ASCO Annual Meeting'. Chicago, IL, USA. June 4-8, 2010

    Directory of Open Access Journals (Sweden)

    Man Yee Merl

    2010-07-01

    Full Text Available Pancreatic cancer is one of the most devastating solid tumor malignancies. Majority of patients have metastatic disease upon diagnosis. Five-year survival is less than 5% for all stages of pancreatic cancer combined. Gemcitabine has been the standard palliative therapy for advanced pancreatic cancer over the past decade. Many studies attempted to develop combination regimens, but they failed to improve overall survival in the metastatic settings. The combination of gemcitabine and erlotinib was the first combination regimen to show improvements in survival benefit compared with gemcitabine alone and became the first-line combination therapy in advanced pancreatic cancer. The search for better treatment strategies to prolong survival in this deadly disease is very much needed and is a worldwide effort. There were many studies presented at the 2010 American Society of Clinical Oncology (ASCO Annual Meeting focused on first-line therapy in metastatic pancreatic cancer. This article highlights a few phase III and II studies that have demonstrated encouraging results.

  4. 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 ge

  5. The Efficacy of High-Intensity Focused Ultrasound (HIFU) in Advanced Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    Bo Xie; Jiajun Ling; Weiming Zhang; Xueqin Huang; Jihua Zhen; Yanzhe Huang

    2008-01-01

    OBJECTIVE To observe the efficacy of high-intensity focused ultrasound (HIFU)in the treatment of late-stage pancreatic cancer.METHODS Sixteen patients with advanced pancreatic cancer received HIFU therapy.Evaluation of efficacy was made on the basis of changes in clinical symptoms and variations in the tumor echo and size.RESULTS Clinical symptoms such as pain were significantly alleviated,echo of the tumor was enhanced with B-US and the quality of life such as eating,sleeping and mental status was markedly improved;no serious complications were observed.CONCLUSION The use of HIFU in the treatment of advanced pancreatic cancer is feasible and safe.It is effective in killing the carcinoma cells and alleviaring pain.This technique may offer non-invasive therapy for the treatment of patients with late-stage pancreatic cancer.

  6. Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed By the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed By Surgery

    Science.gov (United States)

    2016-10-19

    Pancreatic Acinar Cell Carcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraductal Papillary-Mucinous Neoplasm; Stage IA Pancreatic Cancer; Stage IB Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer

  7. Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients

    Science.gov (United States)

    A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer.

  8. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma

    DEFF Research Database (Denmark)

    Høyer, Morten; Roed, Henrik; Sengeløv, Lisa;

    2005-01-01

    BACKGROUND AND PURPOSE: The majority of patients with pancreatic cancer have advanced disease at the time of diagnosis and are not amenable for surgery. Stereotactic radiotherapy (SRT) may be an alternative treatment for patients with locally advanced disease. The effect of SRT was investigated...

  9. Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer

    Science.gov (United States)

    Rich, Tyvin A; Winter, Kathryn; Safran, Howard; Hoffman, John P; Erickson, Beth; Anne, Pramila R; Myerson, Robert J; Cline-Burkhardt, Vivian JM; Perez, Kimberly; Willett, Christopher

    2012-01-01

    Purpose The Radiation Therapy Oncology Group (RTOG) multi-institutional Phase II study 98-12, evaluating paclitaxel and concurrent radiation (RT) for locally advanced pancreatic cancer, demonstrated a median survival of 11.3 months and a 1-year survival of 43%. The purpose of the randomized Phase II study by RTOG 0020 was to evaluate the addition of weekly low- dose gemcitabine with concurrent paclitaxel/RT and to evaluate the efficacy and safety of the farnesyl transferase inhibitor R115777 following chemoradiation. Patients and methods Patients with unresectable, nonmetastatic adenocarcinoma of the pancreas were eligible. Patients in Arm 1 received gemcitabine, 75 mg/m2/week, and paclitaxel, 40 mg/m2/week, for 6 weeks, with 50.4 Gy radiation (CXRT). Patients in Arm 2 received an identical chemoradiation regimen but then received maintenance R115777, 300 mg twice a day for 21 days every 28 days (CXRT+R115777), until disease progression or unacceptable toxicity. Results One hundred ninety-five patients were entered into this study, and 184 were analyzable. Grade 4 nonhematologic toxicities occurred in less than 5% of CXRT patients. The most common grade 3/4 toxicity from R115777 was myelosuppression; however, grade 3/4 hepatic, metabolic, musculoskeletal, and neurologic toxicities were also reported. The median survival time was 11.5 months and 8.9 months for the CXRT and CXRT+R115777 arms, respectively. Conclusions The CXRT arm achieved a median survival of almost 1-year, supporting chemoradiation as an important therapeutic modality for locally advanced pancreatic cancer. Maintenance R115777 is not effective and is associated with a broad range of toxicities. These findings provide clinical evidence that inhibition of farnesylation affects many metabolic pathways, underscoring the challenge of developing an effective K-ras inhibitor. PMID:22977306

  10. Lineage analysis of early and advanced tubular adenocarcinomas of the stomach: continuous or discontinuous?

    Directory of Open Access Journals (Sweden)

    Mukaisho Ken-ichi

    2010-06-01

    Full Text Available Abstract Background Eradication of early gastric carcinoma (GC is thought to contribute to reduction in the mortality of GC, given that most of the early GCs progress to the advanced GCs. However, early GC is alternatively considered a dormant variant of GC, and it infrequently progresses to advanced GC. The aim of this study was to clarify the extent of overlap of genetic lineages between early and advanced tubular adenocarcinomas (TUBs of the stomach. Methods Immunohistochemical staining for p53 was performed using 28 surgically resected stomachs with 13 intramucosal and 15 invasive TUBs. By chromosome- and array-based comparative genomic hybridization (CGH, genomic copy number constitution was compared between the mucosal and invasive parts of the invasive TUBs and between the mucosal parts of the invasive and intramucosal TUBs, using 25 and 22 TUBs, respectively. TP53 mutation in exons 5-8 was examined in 20 TUBs. Results Chromosomal CGH revealed that 4q+ and 11q+ were more common in advanced and early TUBs, respectively, whereas copy number changes in 8q and 17p showed no significant differences between early and advanced TUBs. However, array CGH revealed that, of the 13 intramucosal TUBs examined, loss of MYC (MYC- and gain of TP53 (TP53+ was detected in 9 TUBs and MYC+ and/or TP53- was detected in 3 TUBs. Of the mucosal samples of 9 invasive TUBs, 7 showed MYC-/TP53+ and none showed MYC+ and/or TP53-. Of the 9 samples from the invasive parts, 1 (from submucosal cancers showed MYC-/TP53+ and 6 (1 from submucosal and 5 from advanced cancers showed MYC+ and/or TP53-. The latter 6 tumours commonly showed a mutant pattern (diffuse or null in p53 immunohistochemistry, and 4 of the 6 tumours assessable for TP53 sequence analysis revealed mutations. The overall array CGH pattern indicated that, between the mucosal and invasive parts, genetic lineage was found discontinuous in 5 advanced cancers and continuous in 3 submucosal cancers. Conclusions

  11. High Expression of HIF1a Is a Predictor of Clinical Outcome in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA, VEGF, and bFGF

    Directory of Open Access Journals (Sweden)

    Andreas-Claudius Hoffmann

    2008-07-01

    Full Text Available PURPOSE: Pancreatic cancer still has one of the worst prognoses in gastrointestinal cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. In this study, we investigated the prognostic values of HIF1a, bFGF, VEGF, and PDGFA gene expressions as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma (age, 65; range, 34–85 years. After laser capture microdissection, direct quantitative real-time reverse transcription-polymerase chain reaction assays were performed in triplicates to determine HIF1a, PDGFA, VEGF, and bFGF gene expression levels. Multivariate Cox proportional hazards regression analysis was used to assess the impact of HIF1a gene expression on prognosis. RESULTS:HIF1a was significantly correlated to every gene we tested: bFGF (P = .04, VEGF (P = .02, and PDGFA (P = .03. Tumor size, P = .04, and high HIF1a mRNA expression (cutoff, 75th percentile had a significant impact on survival, P = .009 (overall model fit, P = .02. High HIF1a expression had a sensitivity of 87.1% and a specificity of 55.6% for the diagnosis short (<6 months versus long (6–60 months survival. CONCLUSIONS: Measuring PDGFA, bFGF, and HIF1a expression may contribute to a better understanding of the prognosis of patients with pancreatic cancer and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Larger studies including patients treated with actual chemotherapeutics seem to be warranted.

  12. Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I131 KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Bosonnet Lorraine

    2009-02-01

    Full Text Available Abstract Background Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I131 in pancreatic cancer (ISRCTN 16857581. Methods Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death. Results Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33% patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3. The overall response rate was 6% (1/18. Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months, with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79. One patient was still alive at the time of this analysis. Conclusion Dose limiting toxicity for KAb201 with I131 by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.

  13. Increase in Annual Number of Pancreatic Head Resections Does not Affect Mortality of Pancreatic Cancer in the United Kingdom

    Directory of Open Access Journals (Sweden)

    Efthymios Ypsilantis

    2009-07-01

    Full Text Available Dear Sir, Lee and Saif urged for new effective methods for early diagnosis of pancreatic head adenocarcinoma, emphasizing that at the time of initial presentation, the majority of patients have non-resectable tumours [1]. Also, Li and Saif, in their thorough overview of current advancements in the management of the disease, summarized that pancreatic cancer requires a multidisciplinary therapeutic approach that should aim to increase the chances of surgical resection [2].

  14. Potential Therapeutic Benefit of Combining Gefitinib and Tamoxifen for Treating Advanced Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Chien-Ming Liu

    2015-01-01

    Full Text Available Introduction. Epidermal growth factor receptor (EGFR mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor α or β (ERα/β promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. Methods. We assessed the association between EGFR mutations as well as ERα/β expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells and A549 (EGFR wild type; Gefitinib-resistant cells cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. Results. We found that the cytosolic but not the nuclear expression of ERβ was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERβ. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. Conclusion. Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERβ in cytosol.

  15. Efficacy of Gefitinib for Young Patients with Unknown EGFR Gene Mutation 
in Advanced Lung Adenocarcinoma

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    Yutao LIU

    2014-05-01

    Full Text Available Background and objective Lung cancer in young patients (less or equal to 45 years is relatively rare. We explored the efficacy and survival of Gefitinib for young patients with unknown epidermal growth factor receptor (EGFR gene mutation of advanced lung adenocarcinoma. Methods The clinical data of 55 young patients with unknown EGFR gene mutation in advanced lung adenocarcinoma referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from Jan 2006 through Dec 2010 were analyzed retrospectively. Results Of 55 young patients enrolled, the median age was 41 years. The objective response rate and disease control rate were 43.6% and 90.9%, respectively.. The median progression-free survival (PFS was 9.0 months. Among the factors analyzed, brain metastasis had significant effect on PFS (P=0.017. The median overall survival (OS was 24.0 months. The independent prognostic factors to significantly improve OS included non-smoking history (P=0.028 and receiving other anti-cancer treatment after Gefitinib therapy (P<0.001. Conclusion The median PFS and OS of the young patients with Unknown EGFR gene mutation in advanced lung adenocarcinoma were similar with general population.

  16. Percutaneous Irreversible Electroporation of Locally Advanced Pancreatic Carcinoma Using the Dorsal Approach: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Scheffer, Hester J., E-mail: hj.scheffer@vumc.nl; Melenhorst, Marleen C. A. M., E-mail: m.melenhorst@vumc.nl [VU University Medical Center, Department of Radiology and Nuclear Medicine (Netherlands); Vogel, Jantien A., E-mail: j.a.vogel@amc.uva.nl [Academic Medical Center, Department of Surgery (Netherlands); Tilborg, Aukje A. J. M. van, E-mail: a.vantilborg@vumc.nl [VU University Medical Center, Department of Radiology and Nuclear Medicine (Netherlands); Nielsen, Karin, E-mail: k.nielsen@vumc.nl; Kazemier, Geert, E-mail: g.kazemier@vumc.nl [VU University Medical Center, Department of Surgery (Netherlands); Meijerink, Martijn R., E-mail: mr.meijerink@vumc.nl [VU University Medical Center, Department of Radiology and Nuclear Medicine (Netherlands)

    2015-06-15

    Irreversible electroporation (IRE) is a novel image-guided ablation technique that is increasingly used to treat locally advanced pancreatic carcinoma (LAPC). We describe a 67-year-old male patient with a 5 cm stage III pancreatic tumor who was referred for IRE. Because the ventral approach for electrode placement was considered dangerous due to vicinity of the tumor to collateral vessels and duodenum, the dorsal approach was chosen. Under CT-guidance, six electrodes were advanced in the tumor, approaching paravertebrally alongside the aorta and inferior vena cava. Ablation was performed without complications. This case describes that when ventral electrode placement for pancreatic IRE is impaired, the dorsal approach could be considered alternatively.

  17. Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lind, Pehr A.; Bystroem, Per (Dept. of Oncology and Pathology, Karolinska Inst., Stockholm (SE)); Isaksson, Bengt; Almstroem, Markus; Permert, Johan (Div. of Surgery, Dept. of Clinical Science, Intervention and Technology, Karolinska Inst. at Karolinska Univ. Hospital-Huddinge, Stockholm (SE)); Johnsson, Anders (Dept. of Oncology, Lund Univ. Hospital, Lund (SE)); Albiin, Nils (Div. of Radiology, Dept. of Clinical Science, Intervention and Technology, Karolinska Inst., Stockholm (SE))

    2008-03-15

    Background. The optimal care for patients with unresectable, non-metastatic pancreatic adenocarcinoma (PAC) is debated. We treated 17 consecutive cases with preoperative radiochemotherapy (RCT) as a means for downstaging their tumours and compared outcome with 35 patients undergoing direct surgery for primarily resectable PAC during the same time period. Methods. The patients had biopsy proven, unresectable, non-metastatic PAC which engaged >= 50% of the circumference of a patent mesenteric/portal vein for a distance >= 2 cm and/or < 50% of the circumference of a central artery for < 2 cm. The preop therapy included two courses of Xelox (oxaliplatin 130 mg/m2 d1; capecitabine 2 000 mg/m2 d1-14 q 3 w) followed by 3-D conformal radiotherapy (50.4 Gy; 1.8 Gy fractions) with reduced Xelox (d1-5 q 1 w X 6). Results. No incident of RCT-related CTC Grade 3-4 haematologic and six cases of non-haematologic side-effects were diagnosed. Sixteen patients completed the RCT and were rescanned with CT and reevaluated for surgery 4 weeks post-RCT. Five cases were diagnosed with new metastases to the liver. Eleven patients were accepted for surgery whereof eight underwent a curative R{sub 0}-resection. The median overall survival for the latter group was 29 months, which compared favourably with our control group of patients undergoing direct curative surgery for primarily resectable PAC (median OS: 16 months; RO-rate: 75%). Perioperative morbidity was similar in the two cohorts but the duration of surgery was longer (576 vs. 477 min) and the op blood loss was greater (3288 vs. 1460 ml) in the RCT-cohort (p < 0.05). The 30-day mortality was zero in both groups. Conclusion. Preoperative RCT in patients with locally advanced PAC resulted in a high rate of curative resections and promising median survival in our treatment series. This trimodality approach merits further exploration in new studies, which are currently underway at our Dept.

  18. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008318 Proteomics of hyperlipidemia-associated pancreatitis using differential gel electrophoresis and tandem mass spectrometry: experiment with rats. ZHANG Wei(张伟), et al. Dept Gastroenterol, Shanghai 1st Hosp, Shanghai Jiaotong Univ, Shanghai 200080. Natl Med J China 2008;88(16):1132-1131.Objective To analyze the injury mechanismof hyperlipidemia-associated acute pancreatitis utilizing pro-teomics.Methods Ten SD rats were fed with high fat feed to establish hyperlipidemic models,and 10 SD rats were fed with normal feed to be used as control group.

  19. 2011版《NCCN胰腺癌临床实践指南》中若干问题的探讨%The discussion on the issues related to NCCN clinical practice guidelines in oncology for pancreatic adenocarcinoma ( V2011 )

    Institute of Scientific and Technical Information of China (English)

    刘子文; 赵玉沛

    2011-01-01

    《NCCN胰腺癌临床实践指南》2011中国版已修订完成,新版指南在原有内容基础上结合近年来临床研究进展,在胰腺癌的诊断和治疗路线、原则、循证医学证据上进行了细微更新,并在理念上有了新的阐述,本文就更新中的相关问题进行探讨.《NCCN胰腺癌临床实践指南》2011版中针对胰腺癌的诊断提出了多学科评估的理念,治疗上重视肿瘤可切除性判定标准,化疗中对于体力状态好的患者可选用FOLFIRINOX方案,强调了吉西他滨和5-氟尿嘧啶(5-FU)均作为胰腺癌化疗的Ⅰ类证据.%The revision of the Chinese version of NCCN clinical practice guidelines in oncology for pancreatic adenocarcinoma ( V2011) has been completed. Based on the clinical research in recent years, the new version of the guidelines expressed new ideas and made minor updates on the diagnosis, treatment, and evidence based medicine of pancreatic adenocarcinoma. This article discusses issues related to these new updates. NCCN pancreatic adenocarcinoma guidelines (V2011) presented the concept of multidisciplinary review and emphasized the criteria defining resectability status in treatment. In addition, greater emphasis was placed on the principles of chemotherapy. FOLFIRINOX therapy was recommended for patients in good physical condition. Gemcitabine and 5 - FU were also highlighted as Category 1 evidence for chemotherapy of pancreatic adenocarcinoma.

  20. Recent advances in the surgical treatment of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    A Shankar; RCG Russell

    2001-01-01

    @@ INTRODUCTION Pancreatic cancer remains the fourth commonest cause of cancer related death in the western world[1]. The prognosis remains dismal due partly to late presentation, with associated low resectability rates, and the aggressive biological nature of these tumors. The median survival time from diagnosis in unresectable tumors remains only 4 6 months.For those patients amenable to surgical resection over the last 20 years have seen marked improvements in postoperative mortality and morbidity, especially in specialist pancreatic centres 23. Despite these changes long-term survival remains low. with a total 5-year survival rate remaining less than 5%.Patients with ampullary cancer have a better 5-year survival of 40°%-60°%.

  1. Recent advances in autoimmune pancreatitis: type 1 and type 2.

    Science.gov (United States)

    Kamisawa, Terumi; Chari, Suresh T; Lerch, Markus M; Kim, Myung-Hwan; Gress, Thomas M; Shimosegawa, Tooru

    2013-09-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

  2. Technical advances in endoscopic ultrasound-guided fiducial placement for the treatment of pancreatic cancer

    NARCIS (Netherlands)

    Chavalitdhamrong, D.; DiMaio, C.J.; Siersema, P.D.; Wagh, M.S.

    2015-01-01

    Radiation therapy has an important role in the treatment of locally advanced or metastatic pancreatic cancer and can be used alone or in conjunction with surgery and/or systemic chemotherapy. Because of the challenge of delivering an accurate and optimal radiation dose, image-guided radiation therap

  3. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009216 Relation of inositol 1,4,5-trisphosphate with calcium metabolism in rats with severe acute pancreatitis.SHI Chengxian(石承先),et al.Dept Live Bili Pancre Surg,Guizhou Prov Hosp,Guiyang 550002.World Chin J Digestol,2009;17(6):598-601.

  4. A Multicenter Phase II Trial of S-1 With Concurrent Radiation Therapy for Locally Advanced Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, Masafumi, E-mail: masikeda@east.ncc.go.jp [Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba (Japan); Ioka, Tatsuya [Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (Japan); Ito, Yoshinori [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Yonemoto, Naohiro [Department of Epidemiology and Biostatistics, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo (Japan); Nagase, Michitaka [Department of Clinical Oncology, Jichi Medical University, Tochigi (Japan); Yamao, Kenji [Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya (Japan); Miyakawa, Hiroyuki [Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo (Japan); Ishii, Hiroshi [Hepatobiliary and Pancreatic Division, Cancer Institute Hospital, Tokyo (Japan); Furuse, Junji [Department of Internal Medicine, Medical Oncology School of Medicine, Kyorin University, Tokyo (Japan); Sato, Keiko [Kyoto Unit Center, Japan Environment and Children' s Study, Kyoto University Graduate School of Medicine, Kyoto (Japan); Sato, Tosiya [Department of Biostatistics, Kyoto University School of Public Health, Kyoto (Japan); Okusaka, Takuji [Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo (Japan)

    2013-01-01

    Purpose: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Methods and Materials: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m{sup 2} twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m{sup 2}/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Results: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of {>=}100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. Conclusions: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.

  5. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial

    OpenAIRE

    Kraft Matthias; Kraft Kathleen; Gärtner Simone; Mayerle Julia; Simon Peter; Weber Eckhard; Schütte Kerstin; Stieler Jens; Koula-Jenik Heide; Holzhauer Peter; Gröber Uwe; Engel Georg; Müller Cornelia; Feng You-Shan; Aghdassi Ali

    2012-01-01

    Abstract Background Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia. Findings We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM)...

  6. Recent Advances in Managing Acute Pancreatitis [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Nigeen Janisch

    2015-12-01

    Full Text Available This article will review the recent advances in managing acute pancreatitis. Supportive care has long been the standard of treatment for this disease despite extensive, but ultimately unsuccessful, efforts to develop disease-specific pharmacologic therapies. The primary interventions center on aggressive fluid resuscitation, initiation of early enteral nutrition, targeted antibiotic therapy, and the management of complications. In this article, we will detail treatment of acute pancreatitis with a focus on intravenous fluid resuscitation, enteral feeding, and the current evidence behind the use of antibiotics and other pharmacologic therapies.

  7. MicroRNA-181b-5p, ETS1, and the c-Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy.

    Science.gov (United States)

    Tomihara, Hideo; Yamada, Daisaku; Eguchi, Hidetoshi; Iwagami, Yoshifumi; Noda, Takehiro; Asaoka, Tadafumi; Wada, Hiroshi; Kawamoto, Koichi; Gotoh, Kunihito; Takeda, Yutaka; Tanemura, Masahiro; Mori, Masaki; Doki, Yuichiro

    2017-03-01

    Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c-Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c-Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c-Met expression, and these cells may exacerbate patients' prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c-Met expression; moreover, high c-Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c-Met upregulation in PDAC cells. We established GEM-resistant and radioresistant PDAC cells to analyze the transcriptome involved in c-Met expression. The microarray data for the established radiation-resistant PDAC cells indicated miR-181b-5p downregulation, which targets ETS1, one of the transcription factors for c-Met, and it was shown that radiation exposure induced c-Met expression through ETS1 increase by the suppression of miR-181b-5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.

  8. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.

    Science.gov (United States)

    Nones, Katia; Waddell, Nic; Song, Sarah; Patch, Ann-Marie; Miller, David; Johns, Amber; Wu, Jianmin; Kassahn, Karin S; Wood, David; Bailey, Peter; Fink, Lynn; Manning, Suzanne; Christ, Angelika N; Nourse, Craig; Kazakoff, Stephen; Taylor, Darrin; Leonard, Conrad; Chang, David K; Jones, Marc D; Thomas, Michelle; Watson, Clare; Pinese, Mark; Cowley, Mark; Rooman, Ilse; Pajic, Marina; Butturini, Giovanni; Malpaga, Anna; Corbo, Vincenzo; Crippa, Stefano; Falconi, Massimo; Zamboni, Giuseppe; Castelli, Paola; Lawlor, Rita T; Gill, Anthony J; Scarpa, Aldo; Pearson, John V; Biankin, Andrew V; Grimmond, Sean M

    2014-09-01

    The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

  9. Progesterone inhibits proliferation and modulates expression of proliferation-Related genes in classical progesterone receptor-negative human BxPC3 pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Goncharov, Alexey I; Maslakova, Aitsana A; Polikarpova, Anna V; Bulanova, Elena A; Guseva, Alexandra A; Morozov, Ivan A; Rubtsov, Petr M; Smirnova, Olga V; Shchelkunova, Tatiana A

    2017-01-01

    Recent studies suggest that progesterone may possess anti-tumorigenic properties. However, a growth-modulatory role of progestins in human cancer cells remains obscure. With the discovery of a new class of membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor gene family, it becomes important to study the effect of this hormone on proliferation of tumor cells that do not express classical nuclear progesterone receptors (nPRs). To identify a cell line expressing high levels of mPRs and lacking nPRs, we examined mRNA levels of nPRs and three forms of mPRs in sixteen human tumor cell lines of different origin. High expression of mPR mRNA has been found in pancreatic adenocarcinoma BxPC3 cells, while nPR mRNA has not been detected in these cells. Western blot analysis confirmed these findings at the protein level. We revealed specific binding of labeled progesterone in these cells with affinity constant similar to that of human mPR expressed in yeast cells. Progesterone at high concentration of 20 μM significantly reduced the mRNA levels of proliferation markers Ki67 and PCNA, as well as of cyclin D1, and increased the mRNA levels of cyclin dependent kinase inhibitors p21 and p27. Progesterone (1 μM and 20 μM) significantly inhibited proliferative activity of BxPC3 cells. These results point to anti-proliferative effects of the progesterone high concentrations on BxPC3 cells and suggest that activation of mPRs may mediate this action. Our data are a starting point for further investigations regarding the application of progesterone in pancreatic cancer.

  10. NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone.

    Science.gov (United States)

    Moore, Z; Chakrabarti, G; Luo, X; Ali, A; Hu, Z; Fattah, F J; Vemireddy, R; DeBerardinis, R J; Brekken, R A; Boothman, D A

    2015-01-15

    Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD(+) synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD(+) pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD(+) consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD(+) synthesis while increasing NAD(+) consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)(+) depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD(+)-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD(+) synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD(+) pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors.

  11. 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.

  12. Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Houtmeyers François

    2011-01-01

    Full Text Available Abstract Background Epithelial cell adhesion molecule (EpCAM has been used as surrogate marker for the quantification of circulating tumour cells (CTC. Our aim was to prospectively study the value of a real-time RT-PCR assay for EpCAM detection in the peripheral blood and peritoneal cavity of patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC. Methods From 48 patients with PDAC (40 resectable, 8 unresectable and 10 patients with chronic pancreatitis undergoing pancreatectomy 10 ml of venous blood was drawn preoperatively (PB and postoperatively (POB, day 1 (D1B, day 7 (D7B and after 6 weeks (6WB. Of all patients undergoing pancreatectomy, 40 ml peritoneal lavage fluid was taken preoperatively and postoperatively. A real-time RT-PCR assay (TaqMan, ABI Prism 7700 was developed for the detection of EpCAM mRNA. To discriminate between EpCAM-positive and negative samples a cut-off was applied. Median postoperative follow-up was 24.0 months (range: 0.7 - 41.3. Results PB was EpCAM-positive (+ in 25% of patients versus 65% of patients in POB (p At none of the time-points, an association was found between EpCAM positivity in blood and/or peritoneal cavity and cancer-specific or disease-free survival. Also, no significant associations were found between clinicopathological variables and perioperative EpCAM positivity. Conclusions Despite a significant increase in EpCAM counts in postoperative blood and peritoneal lavage fluid this was not associated with worse prognosis after pancreatectomy for PDAC. Trial registration Clinicaltrials.gov NCT00495924

  13. Gemcitabine alone versus combination of gemcitabine and cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a retrospective analysis of multicenter study.

    Science.gov (United States)

    Inal, A; Kos, F T; Algin, E; Yildiz, R; Dikiltas, M; Unek, I T; Colak, D; Elkiran, E T; Helvaci, K; Geredeli, C; Dane, F; Balakan, O; Kaplan, M A; Durnali, A G; Harputoglu, H; Goksel, G; Ozdemir, N; Buyukberber, S; Gumus, M; Kucukoner, M; Ozkan, M; Uncu, D; Benekli, M; Isikdogan, A

    2012-01-01

    The majority of patients with pancreatic cancer is of advanced disease. Several randomized Phase II and III trials suggest that the combination of gemcitabine and cisplatin (GemCis) response rates were higher than Gemcitabine (Gem) alone, however the trials were not enough powered to indicate a statistically significant prolongation of survival in patients with advanced pancreatic adenocarcinoma. The aim of this retrospective multicenter study is to evaluated the efficiency of Gem alone versus GemCis in patients with locally advanced and/or metastatic pancreatic adenocarcinoma .A total of 406 patients, from fourteen centers were evaluated retrospectively. All patients received Gem or GemCis as first-line treatment between September 2005 to March 2011. Primary end of this study were to evaluate the toxicity, clinical response rate, progression-free survival (PFS) and overall survival (OS) between the arms. There were 156 patients (M: 98, F: 58) in Gem arm and 250 patients (M: 175, F: 75) in the combination arm. Gemcitabin arm patients older than the combination arm ( median 63 vs 57.5, p=0.001). In patients with the combination arm had a higher dose reduction (25.2% vs 11.3%, p=0.001) and dose delay (34% vs 16.8%, p=0.001). Among patients with the combination and Gemcitabin arm gender, diabetes mellitus, performance status, cholestasis, grade, stage did not have a statistically difference (p>0.05). Clinical response rate to the combination arm was higher than the Gem arm (69.0% vs 49.7%, p=0.001). PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance (8.9 vs 6.0, p=0.08). OS was not significantly superior in the GemCis arm (12.0 vs 10.2, p>0.05). Grade III-IV hematologic and nonhematologic toxicity were higher in the combination arm. PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance. OS was not significantly superior in the GemCis arm.

  14. 血清肿瘤标志物联合检测在胰腺癌诊断中的应用价值%Application of combined test for serum tumor markers in diagnosis of pancreatic adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    杨锐; 太京华; 金珍婧; 潘留兰; 牟文玲

    2012-01-01

    Objective To investigate the application of combined test for serum tumor markers, I. E. Carbohydrate antigens (CA) 242 and 724, in diagnosis of pancreatic adenocarcinoma. Methods The CA242 and CA724 levels in sera of 34 patients with pancreatic adenocarcinoma, 26 patients with chronic pancreatitis and 60 healthy persons were determined by radioimmunoassay (RIA). Results The CA242 and CA724 levels in sera of patients with pancreatic adenocarcinoma at progressive stage were significantly higher than those at early stage and those of patients with chronic pancreatitis and healthy persons (each P 0. 05). The sensitivities of determination of CA242, CA724 and CA242 + CA724 in patients with pancreatic adenocarcinoma were 61. 7%, 57. 3% and 84. 9%, while the specificities were 91. 0%, 87. 6% and 90. 3%, respectively. Conclusion Quantitative determination of CA242 and CA724 were sensitive and specific for diagnosis of pancreatic adenocarcinoma, of which the sensitivity for early diagnosis was relatively low. The determination result was significantly related to the stage and prognosis of pancreatic adenocarcinoma. The sensitivity of combined test for CA242 and CA724 increased significantly, while the specificity showed no significant change.%目的 探讨血清肿瘤标志物糖类抗原(Carbohydrate antigen,CA )242(CA242)、CA724联合检测在胰腺癌诊断中的应用价值.方法 采用放射免疫法分别检测34例胰腺癌、26例慢性胰腺炎患者及60名健康体检者的血清CA242和CA724水平.结果 进展期胰腺癌组血清中CA242和CA724的水平均明显高于早期胰腺癌组、慢性胰腺炎组和正常对照组(P均<0.01),早期胰腺癌组、慢性胰腺炎组和正常对照组之间CA242和CA724的水平差异无统计学意义(P>0.05);胰腺癌患者血清中CA242、CA724单独和联合检测的敏感性分别为61.7%、57.3%和84.9%,特异性分别为91.0%、87.6%和90.3%.结论 血清肿瘤标志物CA242、CA724的定

  15. Difference between intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinoma%胰腺导管内乳头状黏液性肿瘤与胰腺导管腺癌的差异分析

    Institute of Scientific and Technical Information of China (English)

    徐彬; 楼文晖; 王单松; 靳大勇

    2011-01-01

    Objective To identify difference between intraductal papillary mucinous neoplasms (IPMN) and pancreatic common ductal adenocarcinoma. Methods Between March 2003 and June 2006, 29 patients with pathological diagnosis of IPMN and 46 patients with pancreatic adenocarcinoma in Zhongshan Hospital were retrospectively reviewed. Clinical, biochemical, and histopathologic factors were retrospectively analyzed. Prognosis between two groups were compared by log-rank test.Results The proportion with no symptom visit in IPMN was obviously higher than in pancreatic cancer. Twenty-one of 29 specimens were malignant in IPMN. Stage of the malignant IPMN was significantly earlier than that of the pancreatic adenocarcinoma (P=0.017). Intrapancreatic neural invasion was more common in pancreatic adenocarcinoma than in malignant IPMN (P=0.005). The survival curve of the malignant IPMN was significantly better than that of the pancreatic adenocarcinoma (P=0.014). Conclusion IPMN with less aggressive bionomics can be diagnosed and treated in an earlier stage. So its prognosis is better than that of pancreatic ductal adenocarcinoma. Prognosis of malignant IPMN which is more invasive than stage Ⅱ B is simular to that of common pancreatic cancer. However, this conclusion should be further investigated.%目的 探讨胰腺导管内乳头状黏液性肿瘤(IPMN)与胰腺导管腺癌的差异.方法 回顾性收集2003年3月至2006年6月收治的资料完整的29例IPMN病例和46例胰腺导管腺癌的临床、生化、病理和随访资料,利用单因素及生存分析方法探讨两者的差异.结果 IPMN中无症状就诊比例明显高于胰腺导管腺癌(P<0.05).29例IPMN中21例为恶性,其病理分期明显早于胰腺导管腺癌(P=0.017);肿瘤对胰腺内神经的侵犯较胰腺癌少见(P=0.005).IPMN 患者术后的生存时间长于胰腺导管腺癌,而ⅡB期及以上的恶性IPMN患者术后生存时间与胰腺导管腺癌比较无明显差异.结论 IPMN与胰腺

  16. Radiation Therapy Improves Survival Outcome in Pancreatic Adenocarcinoma: Comparison of a 15-Year Institutional Experience at the University of Nebraska Medical Center with SEER Data

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    Michael J. Baine

    2014-01-01

    Full Text Available Objectives. We examined the role of radiation therapy (RT in pancreatic adenocarcinoma (PA treatment through a 15-year retrospective analysis of patients treated at University of Nebraska Medical Center (UNMC as well as those from the SEER database. Methods. A total of 561 patients diagnosed with PA at UNMC between 1995 and 2011 and 60,587 patients diagnosed between 1995 and 2009 from the SEER were included. Examined prognostic factors for overall survival (OS were age, gender, race, stage, year of diagnosis, and treatment with surgery, chemotherapy (CT, or RT. Time to death was plotted by Kaplan-Meier method. A Cox proportional hazards model was used to evaluate prognostic factors for OS. Results. The median OS was 7.3 and 5 months for patients from UNMC and the SEER database, respectively. A Cox model of patients from UNMC showed that RT was associated with improved OS (HR 0.77, P=0.018 after adjusting for factors including age, race, gender, stage, year of diagnosis, having surgery, or having CT. Cox analysis of patients from the SEER showed similar results (HR 0.65, P<0.0001. Conclusions. RT confers an independent survival advantage in patients being treated for PA which is apparent both at UNMC and through SEER data.

  17. A study of Smad4, Smad6 and Smad7 in Surgically Resected Samples of Pancreatic Ductal Adenocarcinoma and Their Correlation with Clinicopathological Parameters and Patient Survival

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    Singh Puneet

    2011-12-01

    Full Text Available Abstract Background Smad4 is the common mediator of the tumor suppressive functions of TGF-beta. Smad6 and Smad7 are the antagonists of the TGF-beta pathway. This study investigates the differential protein expressions of Smad4, Smad6 and Smad7 in tumor as compared to normal tissue of pancreatic ductal adenocarcinoma (PDAC and compares them with clinicopathological parameters and patient survival. Results There was a significant difference in protein expressions of Smad4 (p = 0.0001, Smad6 (p = 0.0015 and Smad7 (p = 0.0005 protein in tumor as compared to paired normal samples. Loss of Smad7 expression correlated significantly with tumor size (r = 0.421, p Conclusion Loss of Smad4 significantly correlated with poor survival of PDAC patients. In the cases where Smad4 is expressed, Smad6 inhibition is possibly a novel mechanism for Smad4 inactivation. Smad7 has a role in pathobiology of PDAC. Further investigation in the roles of Smad6 and Smad7 would help in the identification of novel therapeutic targets for PDAC.

  18. 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

    2016-12-01

    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.

  19. Genomic alterations in pancreatic cancer and their relevance to therapy

    Institute of Scientific and Technical Information of China (English)

    Erina; Takai; Shinichi; Yachida

    2015-01-01

    Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.

  20. Mouse models of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

  1. Achievement of Cure with Gefitinib in Advanced Lung Adenocarcinoma Harboring an Activating EGFR Mutation: A Case Report

    Directory of Open Access Journals (Sweden)

    Taiji Kuwata

    2016-10-01

    Full Text Available Tyrosine kinase inhibitors (TKIs of the epidermal growth factor receptor (EGFR may achieve long-term survival in selected cases with advanced non-small cell lung cancer harboring activating mutations in the EGFR gene, but a cured case has not been reported yet. Here, we present the first case of EGFR-mutated lung adenocarcinoma cured with an EGFR-TKI, as the 75-year-old Japanese man has achieved complete response with gefitinib treatment and has survived without tumor 10 years after termination of gefitinib treatment.

  2. Analgesic effect of high intensity focused ultrasound in patients with advanced pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Xinjin Tan; Jian Chen; Li Ren; Ruilu Lin; Zailian Chen

    2013-01-01

    Objective:The aim of this study was to evaluate the analgesic ef ect of high intensity focused ultrasound (HIFU) in patients with advanced pancreatic cancer. Methods:A total of 106 patients with advanced pancreatic cancer accompanied by abdominal pain were treated by HIFU. Pain intensities and quantities of morphine consumption before and after treatment were observed and compared. Results:The average pain intensities before treatment, and at d3, d7 after treatment were 5.80 ± 2.14, 2.73 ± 2.68, 2.45 ± 2.43 respectively (P<0.01). Fifty-nine cases (55.7%) got to extremely ef ective, and 29 cases (27.4%) ef ective. Total ef icient rate was 83.0%. The average quantities of morphine consumption before and after treatment in the patients with grade III pain were 114.9 ± 132.5 mg, 16.8 ± 39.7 mg each person everyday respectively (P<0.01). Conclusion:HIFU can relieve pain suf ered by patients with pancreatic cancer ef ectively. It is a new adjuvant treatment for pancreatic cancer pain.

  3. Comparison of EGFR Mutation Status in Paired Pre- and Post-chemotherapy Serum for Advanced Pulmonary Adenocarcinoma

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    Rubing HAN

    2011-02-01

    Full Text Available Background and objective Non-small cell lung cancer (NSCLC with mutations in the epidermal growth factor receptor (EGFR is a distinct subgroup of NSCLC, which is particularly responsive to EGFR tyrosine kinase inhibitors (TKIs. The aim of this study is to detect EGFR mutations in paired serum of pre- and post-chemotherapy from advanced pulmonary adenocarcinoma patients to evaluate impact of chemotherapy on EGFR mutation status. Methods Magnetic beads were used for DNA extraction from paired serum of pre- and post-chemotherapy of 33 advanced pulmonary adenocarcinoma patients. The EGFR exon 19 and 21 were amplified by mutant-enriched nested PCR and analyzed by direct sequencing. Results EGFR mutations were detected in 39.4% (13/33 and 54.5% (18/33 serum samples of pre- and postchemotherapy, respectively. The EGFR mutation status was consistent in 54.5% (18/33 patients. Among 15 discordant cases, 10 changed from pre-chemo wild-type to post-chemo mutant-type status, while 5 from pre-chemo mutant-type to post-chemo wild-type status. Conclusion Chemotherapy may have influence on serum EGFR mutation status in advanced adenocacinoma patients.

  4. Anorexia-cachexia syndrome in pancreatic cancer: recent advances and new pharmacological approach.

    Science.gov (United States)

    Ronga, Ilaria; Gallucci, Fernando; Riccardi, Ferdinando; Uomo, Generoso

    2014-03-01

    About 80% of all pancreatic ductal adenocarcinoma patients suffer from a wasting syndrome referred to as the "cancer anorexia-cachexia syndrome" (CACS) characterized by abnormally low weight, weakness and loss of skeletal muscle mass with or without loss of body fat, which directly impacts overall survival, quality of life, and physical activity. The aim of this review was to examine recent findings about CACS' pathophysiology and to describe the current pharmacological approaches. In recent years many efforts were made to improve our knowledge of CACS; currently we know that cachexia arises from a complex and multifactorial interaction between various mechanisms including inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism; consequently its management requires multidisciplinary and multipharmacological approach that should address the different causes underlying this clinical event. On these premises, several drugs have been proposed starting from the first pharmacological treatment based on progestational agents or corticosteroids; most of them are in the preclinical phase, but some have already reached the clinical experimentation stage. In conclusion, to date, there is no standard effective treatment and further studies are needed to unravel the basic mechanisms underlying CACS and to develop newer therapeutic strategies with the hope to improve the quality of life of pancreatic cancer patients.

  5. Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Rich TA

    2012-08-01

    Full Text Available Tyvin A Rich,1 Kathryn Winter,2 Howard Safran,3 John P Hoffman,4 Beth Erickson,5 Pramila R Anne,6 Robert J Myerson,7 Vivian JM Cline-Burkhardt,8 Kimberly Perez,3 Christopher Willett91The Cancer Center, University of Virginia Health System West, University of Virginia, Charlottesville, VA, USA; 2RTOG Statistical Center, Philadelphia, PA, USA; 3Brown University, Providence, RI, USA; 4Foxchase Cancer Center, Philadelphia, PA, USA; 5Medical College of Wisconsin, Milwaukee, WI, USA; 6Thomas Jefferson University, Philadelphia, PA, USA; 7Washington University, St Louis, MO, USA; 8Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 9Duke University, Durham, NC, USAPurpose: The Radiation Therapy Oncology Group (RTOG multi-institutional Phase II study 98-12, evaluating paclitaxel and concurrent radiation (RT for locally advanced pancreatic cancer, demonstrated a median survival of 11.3 months and a 1-year survival of 43%. The purpose of the randomized Phase II study by RTOG 0020 was to evaluate the addition of weekly low-dose gemcitabine with concurrent paclitaxel/RT and to evaluate the efficacy and safety of the farnesyl transferase inhibitor R115777 following chemoradiation.Patients and methods: Patients with unresectable, nonmetastatic adenocarcinoma of the pancreas were eligible. Patients in Arm 1 received gemcitabine, 75 mg/m2/week, and paclitaxel, 40 mg/m2/week, for 6 weeks, with 50.4 Gy radiation (CXRT. Patients in Arm 2 received an identical chemoradiation regimen but then received maintenance R115777, 300 mg twice a day for 21 days every 28 days (CXRT+R115777, until disease progression or unacceptable toxicity.Results: One hundred ninety-five patients were entered into this study, and 184 were analyzable. Grade 4 nonhematologic toxicities occurred in less than 5% of CXRT patients. The most common grade 3/4 toxicity from R115777 was myelosuppression; however, grade 3/4 hepatic, metabolic, musculoskeletal, and neurologic toxicities were

  6. Ifosfamide in advanced adenocarcinoma of the oesophagus or oesophageal-gastric junction area

    NARCIS (Netherlands)

    T.C. Kok (Tjebbe); A. van der Gaast (Ate); T.A.W. Splinter (Ted); H.W. Tilanus (Hugo)

    1991-01-01

    markdownabstractAbstract 25 previously untreated patients with inoperable or metastatic adenocarcinoma of the oesophagus or oesophageal-gastric junction area were treated with ifosfamide 6 g/m2 over 48 hours, combined with mesna 6 g/m2. 1 complete response and 1 partial response were seen among 23

  7. Multimodality treatment of recurrent pancreatic cancer: Mith or reality?

    Institute of Scientific and Technical Information of China (English)

    Cosimo; Sperti; Lucia; Moletta; Stefano; Merigliano

    2015-01-01

    Pancreatic adenocarcinoma is the fourth cause of cancerrelated death in the United States. Surgery is the only potentially curative treatment, but most patients present at diagnosis with unresectable or metastatic disease. Moreover, even with an R0 resection, the majority of patients will die of disease recurrence. Most recurrencesoccur in the first 2-year after pancreatic resection, and are commonly located in the abdomen, even if distant metastases can occur. Recurrent pancreatic adenocarcinoma remains a significant therapeutic challenge, due to the limited role of surgery and radiochemotherapy. Surgical management of recurrence is usually unreliable because tumor relapse typically presents as a technically unresectable, or as multifocal disease with an aggressive growth. Therefore, treatment of patients with recurrent pancreatic adenocarcinoma has historically been limited to palliative chemotherapy or supportive care. Only few data are available in the Literature about this issue, even if in recent years more studies have been published to determine whether treatment after recurrence have any effect on patients outcome. Recent therapeutic advances have demonstrated the potential to improve survival in selected patients who had undergone resection for pancreatic cancer. Multimodality management of recurrent pancreatic carcinoma may lead to better survival and quality of life in a small but significant percentage of patients; however, more and larger studies are needed to clarify the role of the different therapeutic options and the optimal way to combine them.

  8. Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma.

    Science.gov (United States)

    Kokkinakis, Demetrius M; Liu, Xiaoyan; Neuner, Russell D

    2005-09-01

    The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.

  9. Hypofractionated Image-Guided IMRT in Advanced Pancreatic Cancer With Simultaneous Integrated Boost to Infiltrated Vessels Concomitant With Capecitabine: A Phase I Study

    Energy Technology Data Exchange (ETDEWEB)

    Passoni, Paolo, E-mail: passoni.paolo@hsr.it [Department of Radiation Oncology, San Raffaele Scientific Institute, Milan (Italy); Reni, Michele [Department of Medical Oncology, San Raffaele Scientific Institute, Milan (Italy); Cattaneo, Giovanni M. [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Slim, Najla [Department of Radiation Oncology, San Raffaele Scientific Institute, Milan (Italy); Cereda, Stefano [Department of Medical Oncology, San Raffaele Scientific Institute, Milan (Italy); Balzano, Gianpaolo; Castoldi, Renato [Department of Surgery, San Raffaele Scientific Institute, Milan (Italy); Longobardi, Barbara [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Bettinardi, Valentino; Gianolli, Luigi [Department of Nuclear Medicine, San Raffaele Scientific Institute, Milan (Italy); Gusmini, Simone [Department of Radiology, San Raffaele Scientific Institute, Milan (Italy); Staudacher, Carlo [Department of Surgery, San Raffaele Scientific Institute, Milan (Italy); Calandrino, Riccardo [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Di Muzio, Nadia [Department of Radiation Oncology, San Raffaele Scientific Institute, Milan (Italy)

    2013-12-01

    Purpose: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. Methods and Materials: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m{sup 2} daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. Results: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2{sup nd} dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. Conclusions: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small

  10. Radiotherapy Technical Considerations in the Management of Locally Advanced Pancreatic Cancer: American-French Consensus Recommendations

    Energy Technology Data Exchange (ETDEWEB)

    Huguet, Florence, E-mail: florence.huguet@tnn.aphp.fr [Department of Radiation Oncology, Tenon Hospital, APHP, University Paris VI, Paris (France); Goodman, Karyn A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Azria, David [Department of Radiation Oncology, CRLC Val d' Aurelle-Paul Lamarque, Montpellier (France); Racadot, Severine [Department of Radiation Oncology, CRLC Leon Berard, Lyon (France); Abrams, Ross A. [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States)

    2012-08-01

    Summary: Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose

  11. Radiotherapy technical considerations in the management of locally advanced pancreatic cancer: American-French consensus recommendations.

    Science.gov (United States)

    Huguet, Florence; Goodman, Karyn A; Azria, David; Racadot, Severine; Abrams, Ross A

    2012-08-01

    Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose intensity

  12. Advances in the Treatment of Pancreatic Neuroendocrine Tumors (pNETs)

    OpenAIRE

    Strosberg, Jonathan

    2013-01-01

    Recent clinical trials have led to significant advancements in treatment options for metastatic neuroendocrine tumors of the pancreas. Sunitinib and everolimus have been approved by the Food and Drug Administration for treatment of progressive pancreatic NETs based on phase III trial data demonstrating improvements in progression-free survival. Cytotoxic drugs such as temozolomide and capecitabine have been associated with high radiographic response rates; however data derives primarily from ...

  13. Rapid detection of K-ras gene point mutation in pancreatic adenocarcinoma by Pyrosequencing%焦磷酸测序法快速检测胰腺癌K-ras基因点突变

    Institute of Scientific and Technical Information of China (English)

    林勇; 关明; 王蓓; 吕元

    2008-01-01

    Objective To establish a method for detecting K-rag gene point mutation in pancreatic adenocarcinoma based on the pyrosequencing and to compare its performance with that of Sanger sequencing.Methods Genomic DNA was extracted from formalin-fixed,paraffin-embedded pancreatic tissues including 49 pancreatic adenocarcinoma,10 normal pancreas,11 chronic pancreatitis,18 benign pancreatic tumor,7 insulin carcinoma,9 ampullary carcinoma,7 bile duct carcinoma and 7 duodenum papillary adenocarcinoma tissues.K-rag gene point mutations at codon 12 were analyzed by pyrosequencing and Sanger sequencing,respectively.Results No mutant K-ras gene Wag detected in normal pancreas,chronic pancreatitis,benign pancreatic tumor,insulin carcinoma,ampullary carcinoma,bile duct carcinoma and duodenum papillary adenocarcinoma tissues by either pyrosequencing or Sanger sequencing.K-rag gene point mutation was detection rate in pancreatic adenocarcinoma tissues was 71.4%(35/49)by pyrosequencing and 61.2%(30/49)by Sanger sequencing,respectively.Conclusions Pyrosequencing is more sensitive than Sanger sequencing and is also accurate,rapid and of high throushput in detecting mutant K-ras gene.It may serve as a practical method for fast batch analysis of clinical samples.%目的 建立基于焦磷酸测序技术的胰腺癌K-ras基因点突变的检测方法,并与Sanger测序法作一比较.方法 用焦磷酸测序法(Pyrosequencing)和Sanger测序法(Sanger sequencing)分别在10名正常胰腺组织、49例胰腺癌、11例慢性胰腺炎、18例胰腺良性囊肿、7例胰岛素癌、9例壶腹癌、7例胆管癌及7例十二指肠乳头癌石蜡包埋组织的DNA中检测K-rag基因12密码子点突变.结果 采用上述两种方法在所有正常胰腺组织、慢性胰腺炎、胰腺良性囊肿、胰岛素癌、壶腹癌、胆管癌及十二指肠乳头癌均未见K-ras基因点突变,而采用焦磷酸测序法发现胰腺癌石蜡包埋组织K-ras基因点突变率为71.4%(35/49),显

  14. Pancreatic cancer-Pathology%胰腺癌:病理学

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    Frank Bergmann; Irene Esposito; Esther Herpel; Peter Schirmacher

    2007-01-01

    @@ Introductions Pancreatic ductal adenocarcinoma (frequently simply being referred to as "pancreatic cancer") represents the most frequent neoplasm of the pancreas, accounting for 85% to 90% of all pancreatic tumors [1, 2].

  15. Genetic abnormalities in pancreatic cancer

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    Zamboni Giuseppe

    2003-01-01

    Full Text Available Abstract The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16INK4, DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers.

  16. Radiologic presentation of chronic granulomatous prostatitis mimicking locally advanced prostate adenocarcinoma.

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    Lee, Su-Min; Joshi, Jay; Wolfe, Konrad; Acher, Peter; Liyanage, Sidath H

    2016-06-01

    We present a case of nonspecific granulomatous prostatitis (GP), a clinical mimic of prostate adenocarcinoma. A 54-year-old man presented with lower urinary tract symptoms and raised prostate-specific antigen. Magnetic resonance imaging showed features consistent with prostate cancer, including low T2-signal intensity in the peripheral and transition zones with signs of extracapsular extension. Diffusion-weighted imaging showed high-signal intensity, with low apparent diffusion coefficient values, whereas dynamic contrast enhancement demonstrated a type 3 washout curve, similar to that found in prostate cancer. Transperineal sector-guided prostate biopsy confirmed nonspecific GP, and the patient was treated conservatively. We discuss and compare nonspecific, chronic GP as a radiologic mimic of prostate adenocarcinoma patient.

  17. Radiologic presentation of chronic granulomatous prostatitis mimicking locally advanced prostate adenocarcinoma

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    Su-Min Lee

    2016-06-01

    Full Text Available We present a case of nonspecific granulomatous prostatitis (GP, a clinical mimic of prostate adenocarcinoma. A 54-year-old man presented with lower urinary tract symptoms and raised prostate-specific antigen. Magnetic resonance imaging showed features consistent with prostate cancer, including low T2-signal intensity in the peripheral and transition zones with signs of extracapsular extension. Diffusion-weighted imaging showed high-signal intensity, with low apparent diffusion coefficient values, whereas dynamic contrast enhancement demonstrated a type 3 washout curve, similar to that found in prostate cancer. Transperineal sector-guided prostate biopsy confirmed nonspecific GP, and the patient was treated conservatively. We discuss and compare nonspecific, chronic GP as a radiologic mimic of prostate adenocarcinoma patient.

  18. Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer

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    Jill P Smith

    2010-03-01

    Full Text Available Jill P Smith1, Sandra I Bingaman1, David T Mauger2, Harold H Harvey1, Laurence M Demers3, Ian S Zagon41Departments of Medicine, 2Public Health Sciences, 3Pathology, and 4Neurosciences and Anatomy, Pennsylvania State University, College of Medicine, Hershey Medical Center, Hershey, PA, USABackground: Advanced pancreatic cancer carries the poorest prognosis of all gastrointestinal malignancies. Once the tumor has spread beyond the margins of the pancreas, chemotherapy is the major treatment modality offered to patients; however, chemotherapy does not significantly improve survival.Objective: Opioid growth factor (OGF; [Met5]-enkephalin is a natural peptide that has been shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The purpose of this study was to evaluate the effects of OGF biotherapy on subjects with advanced pancreatic cancer who failed chemotherapy.Methods: In a prospective phase II open-labeled clinical trial, 24 subjects who failed standard chemotherapy for advanced pancreatic cancer were treated weekly with OGF 250 μg/kg intravenously. Outcomes measured included clinical benefit, tumor response by radiographic imaging, quality of life, and survival.Results: Clinical benefit response was experienced by 53% of OGF-treated patients compared to historical controls of 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU, respectively. Of the subjects surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for OGF-treated patients was three times that of untreated patients (65.5 versus 21 days, p < 0.001. No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with OGF. Limitations: Measurements other than survival were not allowed in control patients, and clinical benefit comparisons were made to historical controls.Conclusion: OGF biotherapy improves the

  19. The combination of a nuclear HMGB1-positive and HMGB2-negative expression is potentially associated with a shortened survival in patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Takeda, Toru; Izumi, Hiroto; Kitada, Shohei; Uramoto, Hidetaka; Tasaki, Takashi; Zhi, Li; Guo, Xin; Kawatsu, Yuichiro; Kimura, Tomoko; Horie, Seichi; Nabeshima, Atsunori; Noguchi, Hirotsugu; Wang, Ke-Yong; Sasaguri, Yasuyuki; Kohno, Kimitoshi; Yamada, Sohsuke

    2014-10-01

    High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2- status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.

  20. 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

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

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    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.

  2. Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial.

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    Amélie Anota

    Full Text Available A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2 compared to gemcitabine alone (Arm 1 in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1. This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL as a secondary endpoint of this study.HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS.98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85], emotional functioning (0.35 [0.21-0.59] and pain (0.50 [0.31-0.81] than those of Arm 1.Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients' characteristics.Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM.

  3. miRNA-181b increases the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine in vitro and in nude mice by targeting BCL-2.

    Science.gov (United States)

    Cai, Baobao; An, Yong; Lv, Nan; Chen, Jianmin; Tu, Min; Sun, Jie; Wu, Pengfei; Wei, Jishu; Jiang, Kuirong; Miao, Yi

    2013-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease and is usually resistant to chemotherapy. MicroRNA‑181b (miR-181b) has been reported to be associated with chemoresistance in various types of cancer. In this study, we investigated the effects of miR-181b on the chemosensitivity of PDAC cells to gemcitabine and the underlying molecular events. miR-181b mimics and inhibitors were synthesized for transient gene transfection in vitro. Lentivirus carrying miR-181b mimics were used to infect PDAC cells for nude mouse xenograft assays by implanting infected PDAC cells into recipient mice. Cell viability was determined by MTT assays, while gene expression was assessed using qRT-PCR, western blot analysis and enzyme-linked immunosorbent assay (ELISA). miR-181b targeting BCL-2 expression was assessed by a dual-luciferase activity assay. The data showed that miRNA-181b expression sensitized PDAC cells to gemcitabine treatment. Although gemcitabine-resistant PDAC cell sublines (SW1990/GR and CFPAC-1/GR) expressed higher levels of miRNA-181b, gemcitabine induced higher levels of apoptosis in PDAC cells transfected with miRNA-181b mimics. The nude mouse xenograft assay data showed that miR-181b transfection also sensitized the cells to gemcitabine treatment in vivo. Molecularly, bioinformatics data predicted that miR-181b was able to bind to BCL-2 mRNA 3'UTR. The dual luciferase activity assay revealed that miRNA-181b downregulated BCL-2 expression. The results from western blot analysis showed a reduced BCL-2 expression following miR-181b transfection but an enhanced caspase-3 activity in miRNA-181b mimic-transfected PDAC cells. This study demonstrates that miRNA-181b sensitizes PDAC cells to gemcitabine by targeting BCL-2.

  4. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  5. Peripancreatic artery ligation and artery infusion chemotherapy for advanced pancreatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    纪宗正; 王永向; 陈熹; 吴涛

    2003-01-01

    Objective To develop a new treatment for advanced pancreatic carcinoma. Methods Twenty-nine patients with advanced pancreatic carcinoma (12 patients with liver metastasis at the same time) were randomly divided into two groups. In group A (n=11), patients underwent bilio-enterostomy and/or gastro-enterostomy combined with systemic chemotherapy after surgery. In group B (n=18), patients underwent bilio-enterostomy and/or gastro-enterostomy combined with peripancreatic arterial ligation and arterial infusion regional chemotherapy. Twenty-four patients were followed up for 3-18 months. The palliation of clinical symptoms, changes in carcinoma size by B ultrasound (BUS) and CT scan, survival period and serum carcinoembryonic antigen (CEA) were observed and compared between the two groups. Results Symptoms were alleviated in most patients in group B, and BUS and CT scan showed that tumor volume decreased in group B. The response rate was 66.7% in group B and 18.2% in group A (P0.05). Conclusion Peripancreatic arterial ligation combined with arterial infusion regional chemotherapy is effective against both pancreatic carcinoma and with liver metastases. It can alleviate clinical symptoms, postpone the growth rate of tumor and prolong the survival period.

  6. SU-E-J-154: Image Quality Assessment of Contrast-Enhanced 4D-CT for Pancreatic Adenocarcinoma in Radiotherapy Simulation

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    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.

  7. Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2.

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    Emily Yun-Chia Chang

    Full Text Available Prostaglandin reductase 2 (PTGR2 is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT and cystathionine gamma-lyase (CTH, two important providers of intracellular cysteine for the generation of glutathione (GSH, which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.

  8. Precursor lesions in pancreatic cancer: morphological and molecular pathology.

    Science.gov (United States)

    Scarlett, Christopher J; Salisbury, Elizabeth L; Biankin, Andrew V; Kench, James

    2011-04-01

    Pancreatic cancer has a dismal prognosis and is the fourth most common cause of cancer related death in Western societies. In large part this is due to its typically late presentation, usually as locally advanced or metastatic disease. Identification of the non-invasive precursor lesions to pancreatic cancer raises the possibility of surgical treatment or chemoprevention at an early stage in the evolution of this disease, when more amenable to therapeutic interventions. Precursor lesions to pancreatic ductal adenocarcinoma, in particular pancreatic intraepithelial neoplasia (PanIN), have been recognised under a variety of synonyms for over 50 years. Over the past decade our understanding of the morphology, biological significance and molecular aberrations of these lesions has grown rapidly and there is now a widely accepted progression model integrating the accumulated morphological and molecular observations. Further progress is likely to be accelerated by improved mouse models of pancreatic cancer and by insight into the cancer genome gained by the International Cancer Genome Consortium (ICGC), in which an Australian consortium is leading the pancreatic cancer initiative. This review also outlines the morphological and molecular features of the other two precursors of pancreatic ductal adenocarcinoma, i.e., intraductal papillary mucinous neoplasms and mucinous cystic neoplasms.

  9. Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma.

    Science.gov (United States)

    Togashi, Yosuke; Masago, Katsuhiro; Kubo, Takeshi; Fujimoto, Daichi; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Togashi, Kaori; Mishima, Michiaki

    2012-12-01

    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P area (P area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.

  10. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN - a randomized multicentre trial

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    Kraft Matthias

    2012-07-01

    Full Text Available Abstract Background Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia. Findings We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM kg. During treatment body-mass-index increased by 3,4 ± 1,4% under L-Carnitine and decreased (−1,5 ± 1,4% in controls (p  Conclusion While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.

  11. Intensity modulated radiation therapy and chemotherapy for locally advanced pancreatic cancer: Results of feasibility study

    Institute of Scientific and Technical Information of China (English)

    Yong-Rui Bai; Guo-Hua Wu; Wei-Jian Guo; Xu-Dong Wu; Yuan Yao; Yin Chen; Ren-Hua Zhou; Dong-Qin Lu

    2003-01-01

    AIM: To explore whether intensity modulated radiation therapy (IMRT) in combination with chemotherapy could increase radiation dose to gross tumor volume without severe acute radiation related toxicity by decreasing the dose to the surrounding normal tissue in patients with locally advanced pancreatic cancer.METHODS: Twenty-one patients with locally advanced pancreatic cancer were evaluated in this clinical trial,Patients would receive the dose of IMRT from 21Gy to 30Gy in 7 to 10 fractions within two weeks after conventional radiotherapy of 30Gy in 15 fractions over 3 weeks. The total escalation tumor dose would be 51, 54,57, 60Gy, respectively. 5-fluororacil (5-FU) or gemcitabine was given concurrently with radiotherapy during the treatment course.RESULTS: Sixteen patients who had completed the radiotherapy plan with doses of 51Gy (3 cases), 54Gy (3 cases), 57Gy (3 cases) and 60Gy (7 cases) were included for evaluation. The median levels of CA19-9 prior to and after radiotherapy were 716 U/ml and 255 U/ml respectively (P<0.001) in 13 patients who demonstrated high levels of CA19-9 before radiotherapy. Fourteen patients who suffered from pain could reduce at least 1/3-1/2 amount of analgesic intake and 5 among these patients got complete relief of pain. Ten patients improved in Kamofsky performance status (KPS). The median follow-up period was 8 months and one-year survival rate was 35 %. No patient suffered more than grade Ⅲ acute toxicities induced by radiotherapy.CONCLUSION: Sixty Gy in 25 fractions over 5 weeks with late course IMRT technique combined with concurrent 5-FU chemotherapy can provide a definitely palliative benefit with tolerable acute radiation related toxicity for patients with advanced pancreatic cancer.

  12. Chemoradiotherapy with twice-weekly administration of low-dose gemcitabine for locally advanced pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Hisato Igarashi; Tetsuhide Ito; Ken Kawabe; Terumasa Hisano; Yoshiyuki Arita; Toyoma Kaku; Ryoichi Takayanagi

    2008-01-01

    AIM:To evaluate the chemoradiotherapy for locally advanced pancreatic cancer utilizing low dose gemcitabine as a radiation sensitizer administered twice weekly.METHODS:We performed a retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2.After that,maintenance systemic chemotherapy with gemcitabine,at a dose of 1000 mg/m2,was administered weekly for 3 wk with 1-wk rest until disease progression or unacceptable toxicity developed.RESULTS:Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled.Three of those patients could not continue with the therapy;one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis during an early stage of the therapy.The median survival was 15.0 mo and the overall 1-year survival rate was 60%,while the median progression-free survival was 8.0 too.The subgroup which showed the reduction of tumor development,more than 50% showed a tendency for a better prognosis;however,other parameters including age,gender and performance status did not correlate with survival.The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 mo and 27.7 mo,respectively.CONCLUSION:Chemoradiotherapy with low-dose gemcitabine administered twice weekly could be effective to patients with locally advanced pancreatic cancer;however,patients developing liver metastases had a worse prognosis.Another chemoradiotherapy strategy might be needed for those patients,such as administrating one or two cycles of chemotherapy initially,followed by chemoradiotherapy for the cases with no distant metastases.

  13. The Problems of Radiofrequency Ablation as an Approach for Advanced Unresectable Ductal Pancreatic Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pezzilli, Raffaele, E-mail: raffaele.pezzilli@aosp.bo.it [Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy); Ricci, Claudio [Department of Surgery, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy); Serra, Carla [Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy); Casadei, Riccardo; Monari, Francesco; D’Ambra, Marielda [Department of Surgery, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy); Corinaldesi, Roberto [Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy); Minni, Francesco [Department of Surgery, S. Orsola-Malpighi Hospital, University of Bologna, Bologna (Italy)

    2010-07-01

    Advanced ductal pancreatic carcinoma (PC) remains a challenge for current surgical and medical approaches. It has recently been claimed that radiofrequency ablation (RFA) may be beneficial for patients with locally advanced or metastatic PC. Using the MEDLINE database, we found seven studies involving 106 patients in which PC was treated using RFA. The PC was mainly located in the pancreatic head (66.9%) with a median size of 4.6 cm. RFA was carried out in 85 patients (80.1%) with locally advanced PC and in 21 (19.9%) with metastatic disease. Palliative surgical procedures were carried out in 41.5% of the patients. The average temperature used was 90 °C (with a temperature range of 30–105 °C) and the ratio between the number of passes of the probe and the size of the tumor in centimeters was 0.5 (range of 0.36–1). The median postoperative morbidity and mortality were 28.3% and 7.5%, respectively; the median survival was 6.5 months (range of 1–33 months). In conclusion, RFA is a feasible technique: however, its safety and long-term results are disappointing; Thus, the RFA procedure should not be recommended in clinical practice for a PC patient.

  14. A complete response to S-1 plus cis-diamminedichloroplatinum in advanced-stage esophageal and gastric adenocarcinoma: a case report

    Directory of Open Access Journals (Sweden)

    Matsuno Yoritaka

    2012-07-01

    Full Text Available Abstract Background Complete remission from advanced-stage synchronous double primary (SDP esophageal and gastric adenocarcinoma by chemotherapy alone is rare. We report a case of advanced-stage SDP esophageal and gastric adenocarcinoma in which a complete response to treatment was obtained with S-1 and cis-diamminedichloroplatinum (CDDP. Case presentation The patient was a 74-year-old man referred to our hospital complaining of dysphagia. Gastrointestinal endoscopy was performed and advanced-stage SDP esophageal and gastric adenocarcinoma diagnosed. Computed tomography revealed multiple regional lymph node metastases in the mediastinum. Neoadjuvant chemotherapy with S-1 and CDDP for advanced esophageal and gastric cancer was planned. An endoscopy following two courses of chemotherapy revealed that the esophageal cancer had been replaced with a normal mucosal lesion and the gastric tumor with a scar lesion; the results of biopsies of both were negative for cancer. Computed tomography revealed that the multiple lymph node metastases had disappeared. We diagnosed a complete response to S-1 and CDDP in advanced-stage SDP esophageal and gastric cancer. The patient is still alive with no signs of recurrence 22 months after the disappearance of the original tumor and metastatic lesions without surgical treatment. Conclusion These results suggest that complete remission from advanced-stage esophageal and gastric cancer can be obtained with chemotherapy with S-1 plus CDDP.

  15. 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

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    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.

  16. An open label randomized multicentre phase IIIb trial comparing parenteral substitution versus best supportive nutritional care in subjects with pancreatic adenocarcinoma receiving 5-FU plus oxaliplatin as 2nd or higher line chemotherapy regarding clinical benefit - PANUSCO

    Directory of Open Access Journals (Sweden)

    Rötzer Ingeborg

    2009-11-01

    Full Text Available Abstract Background Pancreatic cancer is an extremely aggressive malignancy. Subjects are afflicted with a variety of disconcerting symptoms, including profound cachexia. Recent data indicate that the outcome of oncological patients suffering from cancer cachexia could be improved by parenteral nutrition and that parenteral nutrition results in an improvement of quality of life and in prolonged survival. Currently, there is no recommendation of routine use of parenteral nutrition. Furthermore, there is no clear recommendation for 2nd line therapy (or higher for pancreatic adenocarcinoma but often asked for. Methods/Design PANUSCO is an open label, controlled, prospective, randomized, multicentre phase IIIb trial with two parallel arms. All patients will be treated with 5-fluorouracil, folinic acid and oxaliplatin on an outpatient basis at the study sites. Additionally, all patients will receive best supportive nutritional care (BSNC. In the experimental group BSNC will be expanded with parenteral nutrition (PN. In contrast, patients in the control group obtain solely BSNC. Parenteral nutrition will be applied overnight and at home by experienced medical staff. A total of 120 patients are planned to be enrolled. Primary endpoint is the comparison of the treatment groups with respect to event-free survival (EFS, defined as the time from randomization till time to development of an event defined as either an impairment (change from baseline of at least ten points in EORTC QLQ-C30, functional domain total score or withdrawal due to fulfilling the special defined stopping criteria for chemotherapy as well as for nutritional intervention (NI or death from any cause (whichever occurs first. Discussion The aim of this clinical trial is to evaluate whether parenteral nutrition in combination with defined 2nd line or higher chemotherapy has an impact on quality of life for patients suffering from pancreatic adenocarcinoma. Trial registration Current

  17. PERIPANCREATIC ARTERIAL LIGATION COMBINED WITH ARTERIAL INFUSION REGIONAL CHEMOTHERAPY FOR TREATING PATIENTS WITH ADVANCED PANCREATIC CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To find out a new treatment method for advanced pancreatic carcinoma. Methods Twenty-nine patients with advanced pancreatic carcinoma and liver metastases were randomly divided into 2 groups.Group A (n=11) underwent bilio-enterostomy and/or gastro-enterostomy combined with systemic chemotherapy after operation;Group B(n=18) underwent bilio-enterostomy and/or gastro-enterostomy combined with peripancreatic arterial ligation and arterial infusion regional chemotherapy.The alleviation of clinical symptom,the change of carcinoma volume by BUS and CT scan,survival period and serum CEA were observed in two groups. Results The symptoms were alleviated apparently in most cases in Group B;BUS and CT scan showed that the tumor volume decreased apparently in Group B;The response rate was 67.7% in Group B,and 18.2% in Group A,respectively(P<0.01);the mean survival period was (4.8±0.6) months in Group A,and (12.5±1.2) months in Group B,respectively(P<0.01),there was significant difference between the two groups.The decrease of serum CEA was 54% in Group A and 60% in Group B,but the difference was not significant(P>0.05). Conclusion Peripancreatic arterial ligation combined with arterial infusion regional chmotherapy is believed to be effective against both pancreatic carcinoma and liver metastases,and it can alleviate the clinical symptoms,postpone the growth speed of tumor,and prolong the survival period.

  18. Outcome after neoadjuvant chemoradiation and correlation with nutritional status in patients with locally advanced pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Naumann, P.; Habermehl, D.; Welzel, T.; Combs, S.E. [University Clinic Heidelberg (Germany). Dept. of Radiation Oncology; Debus, J. [University Clinic Heidelberg (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum, Heidelberg (Germany)

    2013-09-15

    Background: Cancer patients commonly suffer from weight loss since rapid tumor growth can cause catabolic metabolism and depletion of energy stores such as abdominal fat. In locally advanced pancreatic cancer this is even more pronounced due to abdominal pain, fatigue, nausea or malnutrition. In the present article, we quantify this frequently observed weight loss and assess its impact on outcome and survival. Methods: Data on demographics, biometrics, toxicity and survival were collected for the last 100 patients treated with neoadjuvant chemoradiation for locally advanced pancreatic cancer at our department (45.0 Gy and boost up to 54.0 Gy plus concurrent and subsequent gemcitabine), and the subcutaneous fat area at the umbilicus level was measured by computer tomography before and after chemoradiation. Results: After chemoradiation, patients showed a highly statistically significant weight loss and reduction of the subcutaneous fat area. We could determine a very strong correlation of subcutaneous fat area to patient BMI. By categorizing patients according to their BMI based on the WHO classification as slender, normal, overweight and obese, we found improved but not statistically significant survival among obese patients. Accordingly, patients who showed less weight loss tended to survive longer. Conclusions: In this study, patients with pancreatic cancer lost weight during chemoradiation and their subcutaneous fat diminished. Changes in subcutaneous fat area were highly correlated with patients' BMI. Moreover, obese patients and patients who lost less weight had an improved outcome after treatment. Although the extent of weight loss was not significantly correlated with survival, the observed trend warrants greater attention to nutritional status in the future. (orig.)

  19. Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer

    Science.gov (United States)

    Ullenhag, Gustav J.; Mozaffari, Fariba; Broberg, Mats; Mellstedt, Håkan; Liljefors, Maria

    2017-01-01

    Purpose To assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination. Results A significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (pLenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study. Trial Registration ClinicalTrials.gov NCT01547260 PMID:28099502

  20. Comparing Concurrent Chemoradiotherapy to Chemotherapy Alone for Locally Advanced Unresectable Pancreatic Cancer

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    Park, Jeong Hoon; Kim, Woo Chul; Kim, Hun Jung; Gwak, Hee Keun [Inha University Hospital, Incheon (Korea, Republic of)

    2009-06-15

    Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced unresectable pancreatic cancer. However, the introduction of gemcitabine and the recognition of a benefit in patients with advanced disease stimulated the design of trials that compare chemotherapy alone to concurrent chemoradiation. Therefore, we evaluated role of CCRT for locally advanced unresectable pancreatic cancer. We carried out a retrospective analysis of treatment results for patients with locally advanced unresectable pancreatic cancer between January 2000 and January 2008. The radiation was delivered to the primary tumor and regional lymph nodes with a 1{approx}2 cm margin at a total dose of 36.0{approx}59.4 Gy (median: 54 Gy). The chemotherapeutic agent delivered with the radiation was 5-FU (500 mg/m{sup 2}). The patients who underwent chemotherapy alone received gemcitabine (1,000 mg/m{sup 2}) alone or gemcitabine with 5-FU. The follow-up period ranged from 2 to 38 months. The survival and prognostic factors were analyzed using Kaplan-Meier method and log-rank test, respectively. Thirty-four patients received concurrent chemoradiotherapy, whereas 21 patients received chemotherapy alone. The median survival time was 12 months for CCRT patients, compared to 11 months for chemotherapy alone patients (p=0.453). The median progression-free survival was 8 months for CCRT patients, compared to 5 months for chemotherapy alone patients (p=0.242). The overall response included 9 partial responses for CCRT and 1 partial response for chemotherapy alone. In total, 26% of patients from the CCRT group experienced grade 3{approx}4 bowel toxicity. In contract, no grade 3{approx}4 bowel toxicity was observed in the chemotherapy alone group. The significant prognostic factors of overall survival were lymph node status, high CA19-9, and tumor location. The response rate and progression-free survival were more favorable in the CCRT group, when compared with the chemotherapy alone group

  1. Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics.

    Science.gov (United States)

    Yee, Nelson S; Kazi, Abid A; Yee, Rosemary K

    2013-06-01

    Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

  2. Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

    Directory of Open Access Journals (Sweden)

    Maximilian Reichert

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN, and intraductal papillary mucinous neoplasm (IPMN is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized.

  3. [The first report from Sapporo Tsukisamu Hospital--chemotherapy and chemoradiotherapy for patients with advanced pancreatic cancer].

    Science.gov (United States)

    Yamamitsu, Susumu; Kimura, Hiromichi; Yamada, Yoshiyuki; Inui, Noriaki; Hiyama, Shigemi; Hirata, Koichi; Kimura, Yasutoshi; Koito, Kazumitsu; Shirasaka, Tetsuhiko

    2007-07-01

    The remedy, especially chemotherapy, for advanced pancreatic cancer is hardly ever successful in terms of efficacy rate and survival period, because it is virtually unable to contribute to the improvement of median survival time (MST). Thus,we devised a new intermittent dosage regimen utilizing the cell cycle difference of normal GI tract, bone marrow cell and pancreatic cancer cell, making use of 5-FU (-->S-1), CDDP and paclitaxel in March 2002. Ten patients with advanced pancreatic cancer (4 in Stage IVa and 6 in Stage IVb) were treated with this new regimen. As a result, an efficacy ratio of 50.0% and a 1-year survival ratio of 60.0% were achieved. However, 2-year survival ratio of 12.0% was low, and there was no 3-year survivor. The MST was 19 months as of December 31, 2006. All of the non-hematological toxicities were under grade 2. Eight patients had hematological toxicities over grade 3 and most of them were anemia and neutropenia. Only 2 cases had thrombocytopenia. Although adverse effects related to this regimen were clinically manageable, it was difficult to improve MST of patients with advanced pancreatic cancer with chemotherapy alone including this regimen. Hence, we devised another regimen with the joint use of radiotherapy along with the same chemotherapy regimen in January 2003. Twenty patients with advanced pancreatic cancer (Stage IV) were treated with this regimen. It is presently under way, and an efficacy ratio of 35.0%, 1-year survival ratio of 86.3% and 2-year survival ratio of 64.0% were obtained by May 2005, showing that this may contribute to the extension of survival time of Stage IV pancreatic cancer patients.

  4. 胰腺导管腺癌不同靶区勾画方法的稳定性研究%Stabilities of Different Strategies for Target Volume Delineation in Pancreatic Ductal Adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    李丹明; 穆庆霞; 孙新臣; 王沛沛

    2014-01-01

    Objective To compare the four various strategies [Radiation Therapy Oncology Group(RTOG),Oxford,Michigan and Selective Chemoradiation in Advanced Localized Pancreatic Cancer(SCALOP)]for target volume delineation in pancreatic ductal adenocarcinoma(PDAC). Methods Enhanced CT scanning was performed in 9 patients with pathologically proved PDAC, and planning target volumes(PTVs)were independently outlined by five radiotherapists according to the four different guidelines for target volume delineation.The size of PTVs,coefficient of vari-ance(COV),concordance index and Vintersection were compared quantificationally.Results The size of PTVs,Vintersection and concordance index were not significantly different between Ox-ford guideline and RTOG guideline(P>0.05),but were significantly different between RTOG or Oxford guidelines and Michigan or SCALOP guidelines(P0.05).Conclu-sion SCALOP and Michigan guidelines have better stability than RTOG and Oxford guidelines for target volume delineation in patients with PDAC.There are obvious differences in size of PTVs among the four various strategies.Further clinical evidence-based medical evidence is essen-tial to support the guideline that is beneficial for improving the survival of PDAC patients.%目的:研究4种[放射治疗肿瘤学组(RTOG)、牛津(Oxford)、密歇根(Michigan)和选择性放化疗协作组(SCALOP)]不同胰腺导管腺癌(PDAC)靶区勾画方法的差异。方法对9例病理确诊为 PDAC术后或未行手术的患者均行CT增强扫描,由5位医师在CT上根据4种不同的靶区定义独立勾画计划靶体积(PTVs)。比较9例患者的 RTOG、Oxford、Michigan和 SCALOP靶区勾画方法的 PTVs 情况,并以协方差(COV)、一致性指数(con-cordance index)和交集体积百分比(Vintersection)定量比较不同靶区勾画方法的勾画的稳定性。结果9例患者的 RTOG靶区勾画方法PTVs、Vintersection和 concordance index值与 Oxford

  5. Quality of Life in a Prospective, Multicenter Phase 2 Trial of Neoadjuvant Full-Dose Gemcitabine, Oxaliplatin, and Radiation in Patients With Resectable or Borderline Resectable Pancreatic Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Serrano, Pablo E. [Department of Surgery, University Health Network, University of Toronto, Toronto, ON (Canada); Herman, Joseph M. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Griffith, Kent A.; Zalupski, Mark M. [Center for Cancer Biostatistics, Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan (United States); Kim, Edward J. [Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan (United States); Bekaii-Saab, Tanios S. [Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio (United States); Ben-Josef, Edgar [Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan (United States); Dawson, Laura A. [Princess Margaret Cancer Center, University Health Network, Toronto, ON (Canada); Ringash, Jolie [Princess Margaret Cancer Center, University Health Network, Toronto, ON (Canada); Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON (Canada); Wei, Alice C., E-mail: alice.wei@uhn.ca [Department of Surgery, University Health Network, University of Toronto, Toronto, ON (Canada); Princess Margaret Cancer Center, University Health Network, Toronto, ON (Canada); Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON (Canada)

    2014-10-01

    Purpose: To determine the health-related quality of life (QOL) during and after neoadjuvant chemoradiation therapy and surgery for patients with pancreatic adenocarcinoma. Methods and Materials: Participants of a prospective, phase 2 multi-institutional trial treated with neoadjuvant chemoradiation followed by surgery completed QOL questionnaires (European Organization for Research and Treatment in Cancer Quality of Life Questionnaire version 3.0 [EORTC-QLQ C30], EORTC-Pancreatic Cancer module [EORTC-PAN 26], and Functional Assessment of Cancer Therapy Hepatobiliary and Pancreatic subscale [FACT-Hep]) at baseline, after 2 cycles of neoadjuvant therapy, after surgery, at 6 months from initiation of therapy, and at 6-month intervals for 2 years. Mean scores were compared with baseline. A change >10% was considered a minimal clinically important difference. Results: Of 71 participants in the trial, 55 were eligible for QOL analysis. Compliance ranged from 32% to 74%. The EORTC-QLQ C30 global QOL did not significantly decline after neoadjuvant therapy, whereas the Functional Assessment of Cancer Therapy global health measure showed a statistically, but not clinically significant decline (−8, P=.02). This was in parallel with deterioration in physical functioning (−14.1, P=.001), increase in diarrhea (+16.7, P=.044), and an improvement in pancreatic pain (−13, P=.01) as per EORTC-PAN 26. Because of poor patient compliance in the nonsurgical group, long-term analysis was performed only from surgically resected participants (n=36). Among those, global QOL returned to baseline levels after 6 months, remaining near baseline through the 24-month visit. Conclusions: The study regimen consisting of 2 cycles of neoadjuvant therapy was completed without a clinically significant QOL deterioration. A transient increase in gastrointestinal symptoms and a decrease in physical functioning were seen after neoadjuvant chemoradiation. In those patients who underwent surgical

  6. Therapeutic Evaluation on Advanced Pancreatic Cancer Treated by Integrative Chinese and Western Medicine Clinical Analysis of 56 Cases

    Institute of Scientific and Technical Information of China (English)

    刘鲁明; 吴良村; 林胜友; 杨维鸿; 郭勇; 徐颖扉; 舒琦瑾

    2003-01-01

    Objective: In comparison with chemotherapy, to evaluate therapeutic effcts on advanced pancreatic cancer treated by integrative Chinese and western medicine (ICWM) therapies. Methods: Based on the retrospective study of 56 patients with advanced pancreatic cancer,life table was applied to the analysis of patients' survival rate and χ2 test to the comparison of therapeutic response between ICWM and chemotherapy groups. Results: The results showed that 1-year survival rate in the ICWM group was 55.37%±3.24%; 2-year survival rate 34.61%±16.31%; 3-year survival rate 25.96%±24.64%; 5-year survival rate 25.96%±24.64%; and median survival period 16.3 months. However 1-year survival rate in the chemotherapy group was 21.95%±27.54%; 2-year survival rate 7.31%±27.54%; 3-year survival rate 0%; and median survival period 7.5 months. The therapeutic effects between two groups were significantly different (P=0.004). Further analysis suggested that the reduction of cancer mass in the ICWM group was more than that in chemotherapy group (P=0.049) and the improvement of advanced pancreatic cancer related-symptoms better than that of chemotherapy group (P=0.002). Conclusion: The ICWM comprehensive therapy is of important value in the treatment of advanced pancreatic cancer.

  7. Therapeutic Evaluation on Advanced Pancreatic Cancer Treated by Integrative Chinese and Western Medicine—Clinical Analysis of 56 Cases

    Institute of Scientific and Technical Information of China (English)

    LIULu-ming; WULiang-cun; 等

    2003-01-01

    Objective:In comparison with chemotherapy,to evaluate therapeutic effects on advanced pancreatic cancer treated by integrative Chinese and western medicine(ICWM) therapies.Methods:Based on the retrospective study of 56 patients with advanced pancreatic cancer,life table was applied to the anal-ysis of patients' survival rate and X2 test to the comparison of therapeutic response between ICWM and chemotherapy groups.Results:The results showed that 1-year survival rate 25.96%±24.64%; 5-year 37%±3.24%;2-year survival rate 34.61%±16.31%;3-year survival rate 25.96%±24.64%;5-year survival rate 25.96%±24.64%; and median survival period 16.3 months.However 1-year survival rate in the chemotherapy group was 21.95%±27.54%;2-year survival rate 7.31%±27.54%;3-year survival rate 0%; and median survival period 7.5months.The therapeutic effects between two groups were signifi-cantly different(P=0.004).Further analysis suggested that the reduction of cancer mass in the ICWM group was more than that in chemotherapy group(P=0.049) and the improvement of advanced pancreatic cancer related-symptoms better than that of chemotherapy group(P=0.002).Conclusion:The ICWM comprehensive therapy is of important value in the treatment of advanced pancreatic cancer.

  8. Gastric adenocarcinoma inducing portal hypertension: A rare presentation

    Institute of Scientific and Technical Information of China (English)

    Pradipta Ghosh; Katsumi Miyai; Mario Chojkier

    2007-01-01

    Advanced gastric cancer usually presents with symptoms due to direct extension into adjacent viscera, distant metastases from lymphatic or hematogenic dissemination and peritoneal seeding. However, portal hypertension as a presentation of metastatic gastric cancer is rare and usually seen in association with other malignancies, e.g. hepatocellular and pancreatic carcinoma. We report a case of signet ring adenocarcinoma of the stomach that presented with esophageal and duodenal varices and bleeding due to portal hypertensive gastropathy. Pagetoid spread of cancer cells likely caused early metastasis and the unusual presentation. We also discussed the pathophysiology of development of portal hypertension in association with malignancies.

  9. Prognostic Value of Baseline 18F-FDG PET/CT Functional Parameters in Patients with Advanced Lung Adenocarcinoma Stratified by EGFR Mutation Status.

    Directory of Open Access Journals (Sweden)

    Dalong Wang

    Full Text Available The study objective was to retrospectively analyze the metabolic variables derived from 18 F-fluorodeoxyglucose (18F-FDG positron emission tomography/computed tomography (PET/CT as predictors of progression-free survival (PFS and overall survival (OS in advanced lung adenocarcinoma stratified by epidermal growth factor receptor (EGFR mutation status. A total of 176 patients (91, EGFR mutation; 85, wild-type EGFR who underwent 18F-FDG PET/CT before treatment were enrolled. The main 18F-FDG PET/CT-derived variables: primary tumor maximum standardized uptake value (SUVmaxT, primary tumor total lesion glycolysis (TLGT, the maximum SUVmax of all selected lesions in whole body determined using the Response Evaluation Criteria In Solid Tumors (RECIST 1.1 criteria (SUVmaxWBR, and whole-body total TLG determined using the RECIST 1.1 criteria (TLGWBR were measured. Survival analysis regarding TLGWBR, and other factors in advanced lung adenocarcinoma patients stratified using EGFR mutation status, were evaluated. The results indicated that high TLGWBR (≥259.85, EGFR wild-type, and high serum LDH were independent predictors of worse PFS and OS in all patients with advanced lung adenocarcinoma. Among patients with wild-type EGFR, only TLGWBR retained significance as an independent predictor of both PFS and OS. Among patients with the EGFR mutation, high serum LDH level was an independent predictor of worse PFS and OS, and high TLGWBR (≥259.85 was an independent predictor of worse PFS but not worse OS. In conclusion, TLGWBR is a promising parameter for prognostic stratification of patients with advanced lung adenocarcinoma and EGFR status; however, it cannot be used to further stratify the risk of worse OS for patients with the EGFR mutation. Further prospective studies are needed to validate our findings.

  10. Survival of patients with advanced pancreatic cancer after iodine125 seeds implantation brachytherapy

    Science.gov (United States)

    Han, Quanli; Deng, Muhong; Lv, Yao; Dai, Guanghai

    2017-01-01

    Abstract Background: Brachytherapy with iodine125-labeled seeds (125I-seeds) implantation is increasingly being used to treat tumors because of its positional precision, minimal invasion, least damage to noncancerous tissue due to slow and continuous release of radioactivity and facilitation with modern medical imaging technologies. This study evaluates the survival and pain relief outcomes of the 125I-seeds implantation brachytherapy in advanced pancreatic cancer patients. Methods: Literature search was carried out in multiple electronic databases (Google Scholar, Embase, Medline/PubMed, and Ovid SP) and studies reporting I125 seeds implantation brachytherapy in pancreatic cancer patients with unresectable tumor were selected by following predetermined eligibility criteria. Random effects meta-analysis was performed to achieve inverse variance weighted effect size of the overall survival rate after the intervention. Sensitivity and subgroups analyses were also carried out. Results: Twenty-three studies (824 patients’ data) were included in the meta-analysis. 125I-seeds implantation brachytherapy alone was associated with 8.98 [95% confidence interval (CI): 6.94, 11.03] months (P < 0.00001) overall survival with 1-year survival of 25.7 ± 9.3% (mean ± standard deviation; SD) and 2-year survival was 17.9 ± 8.6% (mean ± SD). In stage IV pancreatic cancer patients, overall survival was 7.13 [95% CI: 4.75, 9.51] months (P < 0.00001). In patients treated with 125I-seeds implantation along with 1 or more therapies, overall survival was 11.75 [95% CI: 9.84, 13.65] months (P < 0.00001) with 1-year survival of 47.4 ± 22.75% (mean ± SD) and 2-year survival was 16.97 ± 3.1% (mean ± SD). 125I-seeds brachytherapy was associated with relief of pain in 79.7 ± 9.9% (mean ± SD) of the patients. Conclusions: Survival of pancreatic cancer patients after 125I-seeds implantation brachytherapy is found to be 9 months

  11. An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review.

    Science.gov (United States)

    Vodopivec, Danica Maria; Rubio, Jose Enrique; Fornoni, Alessia; Lenz, Oliver

    2012-01-01

    Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia in patients with a malignancy. When these laboratory abnormalities develop rapidly, clinical complications such as cardiac arrhythmias, acute renal failure, seizures, or death may occur. TLS is caused by rapid release of intracellular contents by dying tumor cells, a condition that is expected to be common in hematologic malignancies. However, TLS rarely occurs with solid tumors, and here we present the second chemotherapy-induced TLS in a patient with advanced gastric adenocarcinoma to be reported in the literature. We also provide information regarding the total cases of TLS in solid tumors reported from 1977 to present day. Our methodology involved identifying key articles from existing reviews of the literature and then using search terms from these citations in MEDLINE to find additional publications. We relied on a literature review published in 2003 by Baeksgaard et al., where they gathered all total 45 cases reported from 1977 to 2003. Then, we looked for new reported cases from 2004 to present day. All reports (case reports, brief reports, letters to editor, correspondence, reviews, journals, and short communications) identified through these searches were reviewed and included.

  12. An Unusual Presentation of Tumor Lysis Syndrome in a Patient with Advanced Gastric Adenocarcinoma: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Danica Maria Vodopivec

    2012-01-01

    Full Text Available Tumor lysis syndrome (TLS is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia in patients with a malignancy. When these laboratory abnormalities develop rapidly, clinical complications such as cardiac arrhythmias, acute renal failure, seizures, or death may occur. TLS is caused by rapid release of intracellular contents by dying tumor cells, a condition that is expected to be common in hematologic malignancies. However, TLS rarely occurs with solid tumors, and here we present the second chemotherapy-induced TLS in a patient with advanced gastric adenocarcinoma to be reported in the literature. We also provide information regarding the total cases of TLS in solid tumors reported from 1977 to present day. Our methodology involved identifying key articles from existing reviews of the literature and then using search terms from these citations in MEDLINE to find additional publications. We relied on a literature review published in 2003 by Baeksgaard et al., where they gathered all total 45 cases reported from 1977 to 2003. Then, we looked for new reported cases from 2004 to present day. All reports (case reports, brief reports, letters to editor, correspondence, reviews, journals, and short communications identified through these searches were reviewed and included.

  13. 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.

  14. Importance of performance status for treatment outcome in advanced pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Stefan Boeck; Axel Hinke; Ralf Wilkowski; Volker Heinemann

    2007-01-01

    Despite progress in the treatment of advanced and metastatic pancreatic cancer (PC), the outcome of this disease remains dismal for the majority of patients.Given the moderate efficacy of treatment, prognostic factors may help to guide treatment decisions. Several trials identified baseline performance status as an important prognostic factor for survival. Unfit patients with a Karnofsky performance status (KPS) below 70% only have a marginal benefit from chemotherapy with gemcitabine (Gem) and may often benefit more from optimal supportive care. Once, however, the decision is taken to apply chemotherapy, KPS may be used to select either mono- or combination chemotherapy. Patients with a good performance status (KPS = 90%-100%) may have a significant and clinically relevant survival benefit from combination chemotherapy. By contrast, patients with a poor performance status (KPS ≤ 80%) have no advantage from intensified therapy and should rather receive single-agent treatment.

  15. Advances in researches on the immune dysregulation and therapy of severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Xi-ping ZHANG; Han-qing CHEN; Fang LIU; Jie ZHANG

    2009-01-01

    During the development and progression of severe acute pancreatitis (SAP), conspicuous immune dysregulation develops, which is mainly manifested as excessive immune response in the early stage and immunosuppression in the late stage.This process involves complex changes in a variety of immune molecules and cells, such as cytokines, complements, lymphocytes,and leukocytes. With the gradual deepening of studies on the development and progression of SAP, the role of immune dysregulation in the pathogenesis of SAP has attracted more and more attention. In this article, we review the advances in research on the immune dysregulation in SAP and the immunotherapy of this disease through exploring the formation of excessive immune response and immune suppression as well as their mutual transformation.

  16. Adjuvant and neoadjuvant treatment in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies,ranking 4th among causes for cancer-related death in the Western world including the United States.Surgical resection offers the only chance of cure,but only 15 to 20 percent of cases are potentially resectable at presentation.Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy.Currently there is no consensus around the world on what constitutes "standard"adjuvant therapy for pancreatic cancer.This controversy derives from several studies,each fraught with its own limitations.Standards of care also vary somewhat with regard to geography and economy,for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe.Regardless of the efforts in adjuvant and neoadjuvant improved therapy,the major goal to combat pancreatic cancer is to find diagnostic markers,identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients.In this review,authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.

  17. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer.

    Science.gov (United States)

    Peixoto, Renata D'Alpino; Speers, Caroline; McGahan, Colleen E; Renouf, Daniel J; Schaeffer, David F; Kennecke, Hagen F

    2015-08-01

    Due to differences in natural history and therapy, clinical trials of patients with advanced pancreatic cancer have recently been subdivided into unresectable locally advanced pancreatic cancer (LAPC) and metastatic disease. We aimed to evaluate prognostic factors in LAPC patients who were treated with first-line chemotherapy and describe patterns of disease progression. Patients with LAPC who initiated first-line palliative chemotherapy, 2001-2011 at the BC Cancer Agency were included. A retrospective chart review was conducted to identify clinicopathologic variables, treatment, and subsequent sites of metastasis. Kaplan-Meier and Cox-regression survival analyses were performed. A total of 244 patients were included in this study. For the majority of patients (94.3%), first-line therapy was single-agent gemcitabine. About 144 (59%) patients developed distant metastatic disease and the most frequent metastatic sites included peritoneum/omentum (42.3%), liver (41%), lungs (13.9%), and distant lymph nodes (9%). Median overall survival (OS) for the entire cohort was 11.7 months (95% CI, 10.6-12.8). Development of distant metastases was associated with significantly inferior survival (HR 3.56, 95% CI 2.57-4.93), as was ECOG 2/3 versus 0/1 (HR 1.69, 95% CI 1.28-2.23), CA 19.9 > 1000 versus ≤ 1000 (HR 1.59, 95% CI 1.19-2.14) and female gender, (HR 1.57, 95% CI 1.19-2.08). In this population-based study, 41% of LAPC patients treated with first-line chemotherapy died without evidence of distant metastases. Prognostic factors for LAPC were baseline performance status, elevated CA 19.9, gender, and development of distant metastasis. Results highlight the heterogeneity of LAPC and the importance of locoregional tumor control.

  18. Síndrome de Fournier secundária a adenocarcinoma de próstata avançado: relato de caso Fournier's syndrome secondary to advanced prostatic adenocarcinoma: case report

    Directory of Open Access Journals (Sweden)

    Rodrigo Rocha Batista

    2010-06-01

    Full Text Available A Síndrome de Fournier é uma fasciite necrotizante rapidamente progressiva que acomete a genitália e região perineal. Mesmo com os avanços na terapêutica, a morbidade e a mortalidade desta afecção permanecem elevadas. É relatado caso de paciente masculino, 70 anos, com diagnóstico de adenocarcinoma de próstata avançado. Há um dia com dor e aumento de volume escrotal associado a febre. Ao exame físico, paciente séptico com gangrena gasosa do pênis e escroto; ao toque retal, lesão ulcero-vegetante em parede anterior do reto estendendo-se de 3 a 7 cm da borda anal. Realizado desbridamento cirúrgico, com identificação de fístula reto-escrotal transtumoral. Estudo histo-patológico da lesão retal confirmou infiltração por adenocarcinoma de próstata. Recebeu alta hospitalar no vigésimo dia de internação, atualmente em acompanhamento oncológico ambulatorial.Fournier's syndrome is a rapidly progressive necrotizing fasciitis affecting the genitalia and perineal region. Even with the advances in therapy, morbidity and mortality of this disease remain high. We report the case of male patient, 70 years old, diagnosed with advanced adenocarcinoma of the prostate. A day with pain and swelling near scrotum associated with fever. The physical examination revealed septic patient with gas gangrene of the penis and scrotum; on digital rectal examination, a vegetative and ulcerated lesion on the anterior wall of the rectum extending from 3 to 7 cm from the anal edge. Performed surgical debridement, with identification of scrotal-rectal fistula transtumoral. Histo-pathological study of the lesion confirmed rectal infiltration by adenocarcinoma of prostate. Was discharged from the hospital on the twentieth day of hospitalization, outpatient cancer currently monitoring.

  19. Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer

    Science.gov (United States)

    Bournet, Barbara; Gayral, Marion; Torrisani, Jérôme; Selves, Janick; Cordelier, Pierre; Buscail, Louis

    2014-01-01

    Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wild-type Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarcinoma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion (S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials. PMID:25152579

  20. Ressecção alargada para o adenocarcinoma colorretal localmente invasivo: relato de caso e revisão da literatura Enlarged resection for locally advanced colorectal adenocarcinoma: case report and literature review

    Directory of Open Access Journals (Sweden)

    Sergio Henrique Couto Horta

    2009-03-01

    Full Text Available O câncer colorretal localmente invasivo, que acomete por contiguidade estruturas adjacentes e sem metástases à distância, ocorre de 5 a 18% dos casos. São adequadamente tratados com ressecção do tumor e órgãos comprometidos em monobloco e margens livres. É relatado o caso de paciente de 27 anos, masculino, portador de adenocarcinoma de retossigmóide com extensa invasão para bexiga e ceco. Tratado com colectomia total, cistectomia radical em monobloco e ileostomia. O trânsito urinário foi reconstituído com reservatório ileal e anastomose com a uretra prostática. O estudo anátomo-patológico da peça cirúrgica revelou adenocarcinoma moderadamente diferenciado, invasão perineural e invasão da parede da bexiga (T4, N0. Realizou no pós-operatório quimioterapia adjuvante, 6 ciclos, com 5-Fluorouracil e ácido folínico. Após 36 meses de seguimento, o paciente encontra-se livre de doença neoplásica, função urinária preservada, porém com ejaculação retrógrada.The locally advanced colorectal cancer compromises adjacent structures and do not disseminate distant metastasis, occur in 5 to 18% of patients. It is properly treated with tumour resection as well as other compromised organs in an "en bloc" resection with free margins. We report a 27 year old, male patient with colorectal adenocarcinoma invading the urinary bladder and cecum. He was treated with total colectomy associated with radical cistectomy and ileostomy. The urinary transit was established building an ileal reservatory anastomosed to the urethra. The tumour histopathologic study showed adenocarcinoma moderate differentiated, invading urinary bladder (T4N0. Postoperative treatment was 5-fluorouracil and folinic acid chemotherapy. After 36 months of outcome, patient is improving and preserves urinary function but has ejaculatory dysfunction.

  1. ERCP in acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Jijo V Cherian; Joye Varghese Selvaraj; Rajesh Natrayan; Jayanthi Venkataraman

    2007-01-01

    BACKGROUND:The role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of acute pancreatitis has evolved over years since its introduction in 1968. Its importance in diagnosing the etiology of pancreatitis has steadily declined with the advent of less invasive diagnostic tools. The therapeutic implications of ERCP in acute pancreatitis are many fold and are directed towards management of known etiological factors or its related complications. This article highlights the current status of ERCP in acute pancreatitis. DATA SOURCES:An English literature search using PubMed database was conducted on ERCP in acute pancreatitis, the etiologies and complications of pancreatitis amenable to endotherapy and other related subjects, which were reviewed. RESULTS: ERCP serves as a primary therapeutic modality for management of biliary pancreatitis in speciifc situations, pancreatitis due to microlithiasis, speciifc types of sphincter of Oddi dysfunction, pancreas divisum, ascariasis and malignancy. In recurrent acute pancreatitis and smoldering pancreatitis it has a deifnite therapeutic utility. Complications of acute pancreatitis including pancreatic-duct disruptions or leaks, benign pancreatic-lfuid collections and pancreatic necrosis can be beneifcially dealt with. Intraductal ultrasound and pancreatoscopy during ERCP are useful in detecting pancreatic malignancy. CONCLUSIONS:The role of ERCP in acute pancreatitis is predominantly therapeutic and occasionally diagnostic. Its role in the management continues to evolve and advanced invasive procedures should be undertaken only in centers dedicated to pancreatic care.

  2. Paclitaxel-Based Chemotherapy for Advanced Pancreatic Cancer after Gemcitabine-Based Therapy Failure: A Case Series of 5 Patients

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    Hisato Igarashi

    2011-11-01

    Full Text Available Background/Objectives: Gemcitabine (GEM is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. Results: The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. Conclusion: Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.

  3. Coexistent adenocarcinoma and microcystic adenoma of the pancreas.

    Science.gov (United States)

    Posniak, H V; Olson, M C; Demos, T C

    1991-01-01

    A case with coexistent pancreatic adenocarcinoma and microcystic adenoma is presented. These diagnoses were suspected on the basis of their computed tomography (CT) appearances and confirmed with CT-guided fine-needle aspiration.

  4. The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

    Science.gov (United States)

    Ahmed, Sunjida; Bradshaw, Azore-Dee; Gera, Shweta; Dewan, M. Zahidunnabi; Xu, Ruliang

    2017-01-01

    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. PMID:28067794

  5. S-1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro-esophageal junction adenocarcinoma patients: a pilot study.

    Science.gov (United States)

    Li, Yu Hong; Qiu, Miao Zhen; Xu, Jian Ming; Sun, Guo Ping; Lu, Hui Shan; Liu, Yun Peng; Zhong, Mei Zuo; Zhang, He Long; Yu, Shi Ying; Li, Wei; Hu, Xiao Hua; Wang, Jie Jun; Cheng, Ying; Zhou, Jun Tian; Guo, Zeng Qing; Guan, Zhon Gzhen; Xu, Rui Hua

    2015-10-27

    The safety and efficacy of S-1 plus cisplatin in Chinese advanced gastric cancer patients in first line setting is unknown. In this pilot study, patients with advanced gastric or gastro-esophageal junction adenocarcinoma were enrolled and randomly assigned in a 1:1 ratio to receive S-1 plus cisplatin (CS group) or 5-FU plus cisplatin (CF group). The primary endpoint was time to progression (TTP). Secondary end points included overall survival (OS) and safety. This study was registered on ClinicalTrials. Gov, number NCT01198392. A total of 236 patients were enrolled. Median TTP was 5.51 months in CS group compared with 4.62 months in CF group [hazard ratio (HR) 1.028, 95% confidential interval (CI) 0.758-1.394, p = 0.859]. Median OS was 10.00 months and 10.46 months in CS and CF groups (HR 1.046, 95%CI 0.709-1.543, p = 0.820), respectively. The most common adverse events in both groups were anemia, leukopenia, neutropenia, nausea, thrombocytopenia, vomiting, anorexia and diarrhea. We find that S-1 plus cisplatin is an effective and tolerable option for advanced gastric or gastro-esophageal junction adenocarcinoma patients in China.

  6. Sesamin Ameliorates Advanced Glycation End Products-Induced Pancreatic β-Cell Dysfunction and Apoptosis

    Directory of Open Access Journals (Sweden)

    Xiang Kong

    2015-06-01

    Full Text Available Advanced glycation end products (AGEs, the direct modulators of β-cells, have been shown to cause insulin-producing β-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked β-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg and orally treated with sesamin (160 mg/kg for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and β-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 μM and then exposed to AGEs (200 mg/L for 24 h. Insulin secretion, β-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced β-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67phox and p22phox, and reduced NADPH oxidase activity. These results suggest that sesamin protects β-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.

  7. Sesamin Ameliorates Advanced Glycation End Products-Induced Pancreatic β-Cell Dysfunction and Apoptosis.

    Science.gov (United States)

    Kong, Xiang; Wang, Guo-Dong; Ma, Ming-Zhe; Deng, Ru-Yuan; Guo, Li-Qun; Zhang, Jun-Xiu; Yang, Jie-Ren; Su, Qing

    2015-06-09

    Advanced glycation end products (AGEs), the direct modulators of β-cells, have been shown to cause insulin-producing β-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS) production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked β-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg) and orally treated with sesamin (160 mg/kg) for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and β-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 μM) and then exposed to AGEs (200 mg/L) for 24 h. Insulin secretion, β-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced β-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67(phox) and p22(phox), and reduced NADPH oxidase activity. These results suggest that sesamin protects β-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.

  8. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

    Science.gov (United States)

    Jensen, Robert T.; Berna, Marc J.; Bingham, David B; Norton, Jeffrey A.

    2008-01-01

    Pancreatic endocrine tumors (PETs) can occur in as part of four inherited disorders including: Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1(NF-1) [von Recklinghausen’s disease] and the tuberous sclerosis complex (TSC). The relative frequency with which patients with these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization, medical and surgical treatment of the PETs in these patients. The study of the PETs in these disorders has not only provided insights into the possible pathogenesis of sporadic PETs, but have also presented a number of unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore the study of PETs in these uncommon disorders has provided valuable insights that in many cases are applicable to the general group of patients with sporadic PETs. In this article these areas are briefly reviewed as well as the current state of knowledge of the PETs in these disorders and the controversies that exist in their management are briefly summarized and discussed. PMID:18798544

  9. Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells

    Institute of Scientific and Technical Information of China (English)

    Essam M Abdelalim; Mohamed M Emara

    2015-01-01

    Pluripotent stem cells (PSCs) are able to differentiate intoseveral cell types, including pancreatic β cells. Differentiationof pancreatic β cells depends on certain transcriptionfactors, which function in a coordinated way duringpancreas development. The existing protocols for in vitrodifferentiation produce pancreatic β cells, which are nothighly responsive to glucose stimulation except after theirtransplantation into immune-compromised mice and allowingseveral weeks for further differentiation to ensurethe maturation of these cells in vivo . Thus, although thesubstantial improvement that has been made for the differentiationof induced PSCs and embryonic stem cellstoward pancreatic β cells, several challenges still hinderingtheir full generation. Here, we summarize recent advancesin the differentiation of PSCs into pancreatic β cells anddiscuss the challenges facing their differentiation as wellas the different applications of these potential PSC-derivedβ cells.

  10. Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

    Institute of Scientific and Technical Information of China (English)

    Mariangela Torniai; Silvia Rinaldi; Francesca Morgese; Giulia Ricci; Azzurra Onofri; Christian Groh; Rossana Berardi

    2016-01-01

    Neuroendocrine tumors (NETs) represent a spectrum of rare neoplasms arising in different organism sites. Depending on the site of onset, they also can be distinguished using lab exams (secretingvs. nonsecreting), clinical symptoms (functioningvs. nonfunctioning), behavioral, morphological characteristics (tumor cells’ architectural growth patterns, mitotic and Ki-67 index, presence of necrosis), and grade of cellular differentiation. The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) neuroendocrine neoplasms. The scientiifc literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases, selecting principal and more recent research articles, clinical trials, and updated guidelines. Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs. The pathogenesis of NETs has been the subject of increased interest in recent years. Many driver mutations pathway genes have been identiifed as important factors in the carcinogenesis process and, therefore, as potential targets for new anticancer therapies. Activating mutations have been shown in epidermal growth factor receptor, stem cell factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, basic-ifbroblastic growth factor, transforming growth factor, insulin-like growth factor-1, and their receptors. Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this ifeld such as everolimus. New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.

  11. 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

  12. State of the art biological therapies in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one ofthe most lethal malignancies with a five-year survivalrate of approximately 5%. Several target agents havebeen tested in PDAC, but almost all have failed todemonstrate efficacy in late phase clinical trials, despitethe better understanding of PDAC molecular biologygenerated by large cancer sequencing initiatives in thepast decade. Eroltinib (a small-molecule tyrosine-kinaseinhibitor of epidermal growth factor receptor) plusgemcitabine is the only schedule with a biological agentapproved for advanced pancreatic cancer, but it hasresulted in a very modest survival benefit in unselectedpatients. In our work, we report a summary of the mainclinical trials (closed and ongoing) that refer to biologicaltherapy evaluation in pancreatic cancer treatment.

  13. Chromodomain-helicase-DNA binding protein 5, 7 and pronecrotic mixed lineage kinase domain-like protein serve as potential prognostic biomarkers in patients with resected pancreatic adenocarcinomas

    Institute of Scientific and Technical Information of China (English)

    Crystal S Seldon; Lauren E Colbert; William A Hall; Sarah B Fisher; David S Yu; Jerome C Landry

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomainhelicase-DNA binding protein 5, chromodomain-helicaseDNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation,and should be validated in future studies.

  14. Hereditary pancreatitis: current perspectives

    Directory of Open Access Journals (Sweden)

    Raphael KL

    2016-07-01

    Full Text Available Kara L Raphael, Field F Willingham Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Abstract: Hereditary pancreatitis (HP is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. Keywords: pancreatic cancer, chronic pancreatitis, idiopathic pancreatitis, pancreatitis, familial pancreatitis, genetic mutations

  15. Danish Pancreatic Cancer Database

    DEFF Research Database (Denmark)

    Fristrup, Claus; Detlefsen, Sönke; Palnæs Hansen, Carsten

    2016-01-01

    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......, and survival. The results are published annually. CONCLUSION: The Danish Pancreatic Cancer Database has registered data on 2,217 patients with microscopically verified ductal adenocarcinoma of the pancreas. The data have been obtained nationwide over a period of 4 years and 2 months. The completeness...

  16. Prognostic potential of initial CT changes for progression-free survival in gefitinib-treated patients with advanced adenocarcinoma of the lung: a preliminary analysis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yu-Cheng; Hsu, Hsian-He; Chang, Wei-Chou; Ko, Kai-Hsiung; Hsu, Yi-Chih [Tri-Service General Hospital, National Defense Medical Center, Department of Radiology, Taipei (China); Tung, Ho-Jui [Asia University, Department of Healthcare Administration, Taichung (China); Huang, Tsai-Wang; Chang, Hung [Tri-Service General Hospital, National Defense Medical Center, Division of Thoracic Surgery, Department of Surgery, Taipei (China); Ho, Ching-Liang [Tri-Service General Hospital, National Defense Medical Center, Division of hematology-oncology, Department of internal Medicine, Taipei (China)

    2015-06-01

    We aimed to determine whether initial tumour responses measured during short-term follow-up computed tomography (CT) examinations after baseline examinations would correlate with clinical outcomes in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR)-targeted therapy. A total of 86 gefitinib-treated patients with advanced adenocarcinoma of the lung were retrospectively reviewed. All patients underwent baseline and short-term follow-up CT examinations. The new response criteria (NRC) by Lee et al. were used for the response evaluations. A Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses were used to evaluate correlations between the initial tumour changes and progression-free and overall survival (PFS, OS). Better separation and smaller p values were observed for both PFS and OS when good and poor disease responses (as defined by NRC) were compared after excluding tumours with characteristic morphologies. Early tumour changes correlated with PFS in a size-dependent manner. Moreover, a stronger association was observed between size changes and PFS when characteristic morphology was also considered. Initial changes in tumour size during short-term post-treatment CT examinations could act as a potential prognostic imaging surrogate for PFS in gefitinib-treated patients with advanced adenocarcinoma of the lung. (orig.)

  17. Acute pancreatitis

    Science.gov (United States)

    ... its blood vessels. This problem is called acute pancreatitis. Acute pancreatitis affects men more often than women. Certain ... pancreatitis; Pancreas - inflammation Images Digestive system Endocrine glands Pancreatitis, acute - CT scan Pancreatitis - series References Forsmark CE. Pancreatitis. ...

  18. [Autoimmune pancreatitis].

    Science.gov (United States)

    Beyer, G; Menzel, J; Krüger, P-C; Ribback, S; Lerch, M M; Mayerle, J

    2013-11-01

    Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease.

  19. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

    Energy Technology Data Exchange (ETDEWEB)

    Thorek, Daniel L.J., E-mail: dthorek1@jhmi.edu [Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, MD (United States); Kramer, Robin M. [Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center (MSKCC), Weill Cornell Medical College, The Rockefeller University, New York, NY (United States); Chen, Qing; Jeong, Jeho; Lupu, Mihaela E. [Department of Medical Physics, MSKCC, New York, NY (United States); Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve [Department of Medicine, MSKCC, New York, NY (United States); Ulmert, David [Molecular Pharmacology and Chemistry Program, MSKCC, New York, NY (United States); Department of Surgery (Urology), Skåne University Hospital, Malmö (Sweden); Zanzonico, Pat; Deasy, Joseph O.; Humm, John L. [Department of Medical Physics, MSKCC, New York, NY (United States); Russell, James, E-mail: russellj@mskcc.org [Department of Medical Physics, MSKCC, New York, NY (United States)

    2015-10-01

    Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

  20. Long-term results of intraoperative electron beam radiation therapy for nonmetastatic locally advanced pancreatic cancer

    Science.gov (United States)

    Chen, Yingtai; Che, Xu; Zhang, Jianwei; Huang, Huang; Zhao, Dongbing; Tian, Yantao; Li, Yexiong; Feng, Qinfu; Zhang, Zhihui; Jiang, Qinglong; Zhang, Shuisheng; Tang, Xiaolong; Huang, Xianghui; Chu, Yunmian; Zhang, Jianghu; Sun, Yuemin; Zhang, Yawei; Wang, Chengfeng

    2016-01-01

    Abstract To assess prognostic benefits of intraoperative electron beam radiation therapy (IOERT) in patients with nonmetastatic locally advanced pancreatic cancer (LAPC) and evaluate optimal adjuvant treatment after IOERT. A retrospective cohort study using prospectively collected data was conducted at the Cancer Hospital of the Chinese Academy of Medical Sciences, China National Cancer Center. Two hundred forty-seven consecutive patients with nonmetastatic LAPC who underwent IOERT between January 2008 and May 2015 were identified and included in the study. Overall survival (OS) was calculated from the day of IOERT. Prognostic factors were examined using Cox proportional hazards models. The 1-, 2-, and 3-year actuarial survival rates were 40%, 14%, and 7.2%, respectively, with a median OS of 9.0 months. On multivariate analysis, an IOERT applicator diameter < 6 cm (hazards ratio [HR], 0.67; 95% confidence interval [CI], 0.47–0.97), no intraoperative interstitial sustained-release 5-fluorouracil chemotherapy (HR, 0.46; 95% CI, 0.32–0.66), and receipt of postoperative chemoradiotherapy followed by chemotherapy (HR, 0.11; 95% CI, 0.04–0.25) were significantly associated with improved OS. Pain relief after IOERT was achieved in 111 of the 117 patients, with complete remission in 74 and partial remission in 37. Postoperative complications rate and mortality were 14.0% and 0.4%, respectively. Nonmetastatic LAPC patients with smaller size tumors could achieve positive long-term survival outcomes with a treatment strategy incorporating IOERT and postoperative adjuvant treatment. Chemoradiotherapy followed by chemotherapy might be a recommended adjuvant treatment strategy for well-selected cases. Intraoperative interstitial sustained-release 5-fluorouracil chemotherapy should not be recommended for patients with nonmetastatic LAPC. PMID:27661028

  1. High-dose Helical Tomotherapy With Concurrent Full-dose Chemotherapy for Locally Advanced Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Jee Suk [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Wang, Michael L.C. [Department of Radiation Oncology, National Cancer Centre (Singapore); Koom, Woong Sub; Yoon, Hong In; Chung, Yoonsun [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Song, Si Young [Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Seong, Jinsil, E-mail: jsseong@yuhs.ac [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-08-01

    Purpose: To improve poor therapeutic outcome of current practice of chemoradiotherapy (CRT), high-dose helical tomotherapy (HT) with concurrent full-dose chemotherapy has been performed on patients with locally advanced pancreatic cancer (LAPC), and the results were analyzed. Methods and Materials: We retrospectively reviewed 39 patients with LAPC treated with radiotherapy using HT (median, 58.4 Gy; range, 50.8-59.9 Gy) and concomitant chemotherapy between 2006 and 2009. Radiotherapy was directed to the primary tumor with a 0.5-cm margin without prophylactic nodal coverage. Twenty-nine patients (79%) received full-dose (1000 mg/m{sup 2}) gemcitabine-based chemotherapy during HT. After completion of CRT, maintenance chemotherapy was administered to 37 patients (95%). Results: The median follow-up was 15.5 months (range, 3.4-43.9) for the entire cohort, and 22.5 months (range, 12.0-43.9) for the surviving patients. The 1- and 2-year local progression-free survival rates were 82.1% and 77.3%, respectively. Eight patients (21%) were converted to resectable status, including 1 with a pathological complete response. The median overall survival and progression-free survival were 21.2 and 14.0 months, respectively. Acute toxicities were acceptable with no gastrointestinal (GI) toxicity higher than Grade 3. Severe late GI toxicity ({>=}Grade 3) occurred in 10 patients (26%); 1 treatment-related death from GI bleeding was observed. Conclusion: High-dose helical tomotherapy with concurrent full-dose chemotherapy resulted in improved local control and long-term survival in patients with LAPC. Future studies are needed to widen the therapeutic window by minimizing late GI toxicity.

  2. Autoimmune pancreatitis: A review

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the proposed diagnostic criteria and treatment algorithms.

  3. Chronic Pancreatitis and Neoplasia: Correlation or Coincidence

    Directory of Open Access Journals (Sweden)

    G. N. Zografos

    1997-01-01

    Full Text Available Any link between pancreatic carcinoma and chronic pancreatitis could reflect the malignant potential of a chronic inflammatory process. Four patients with ductal adenocarcinomas had a long history of pancreatic pain (median duration 5 years and showed clearcut evidence of chronic pancreatitis “downstream” of the tumour. Four were alcoholics and two heavy smokers. These four cases arose within a surgical series of approximately 250 patients with chronic pancreatitis, giving an incidence of 1.6 per cent. The incidence and anatomical distribution of carcinoma and chronic pancreatitis could possibly be consistent with a casual relationship.

  4. 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.

  5. Inhibition of the mammalian target of rapamycin (mTOR in advanced pancreatic cancer: results of two phase II studies

    Directory of Open Access Journals (Sweden)

    Zhang Yujian

    2010-07-01

    Full Text Available Abstract Background The phosphoinositide 3-kinase (PI3K/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop. The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models. Methods Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN. Results Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively. One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2. Grade 4 toxicity: hyponatremia (n = 1, Grade 3: diarrhea (n = 1, cholangitis (n = 3, hyperglycemia (n = 1, fatigue (n = 1. Grade 2: pneumonia (n = 2, dehydration (n = 2, nausea (n = 2, neutropenia (n = 1, mucositis (n = 2

  6. Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Wang Y

    2016-06-01

    Full Text Available Yuan Wang,1 Guo-fang Hu,1 Qian-qian Zhang,1 Ning Tang,1 Jun Guo,2 Li-yan Liu,2 Xiao Han,2 Xia Wang,2 Zhe-hai Wang2 1School of Medicine and Life Sciences, Shandong Academy of Medical Sciences, University of Jinan, 2Shandong Cancer Hospital, Shandong University, Jinan, Shandong, People’s Republic of China Background: Pancreatic cancer is considered as a chemoresistant neoplasm with extremely dismal prognosis. Gemcitabine is recommended as the standard agent for locally advanced or metastatic pancreatic cancer. A series of trials have been conducted to improve the outcome of advanced pancreatic cancer with other anticancer drugs in combination with gemcitabine. Unfortunately, the designers of the clinical trials failed to improve the poor prognosis of patients with advanced pancreatic cancer. Erlotinib was the first additional drug that improved the overall survival of patients with advanced pancreatic cancer with gemcitabine. We performed this systematic review and meta-analysis to explore the efficacy and safety of the combination of gemcitabine with erlotinib (GemErlo for patients with advanced pancreatic cancer using the currently available evidence. Methods: PubMed/MEDLINE, EMBASE, the Cochrane Library, and relevant abstracts of major conferences were comprehensively searched. Data results on objective response rate, disease control rate, and 1-year survival were pooled by using MetaAnalyst with a random-effects model. Results on progression-free survival and overall survival were only summarized descriptively. Results: A total of 24 studies with 1,742 patients with locally advanced or metastatic pancreatic cancer treated with GemErlo were included. Combined objective response rate was 14.4% (95% CI: 11.6%–17.7%, disease control rate was 55.0% (95% CI: 51.5%–58.5%, and 1-year survival rate was 28.5% (95% CI: 24.0%–33.4%. Progression-free survival ranged from 2.63 to 9.6 months, and overall survival varied from 6 to 10 months. As

  7. Comparative Study of Gemcitabine Plus Cisplatin and Gemcitabine Plus Fluorouracil in the Treatment of Advanced Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    YongqionShu; LiankeLiu; LinxiangLiu; PuwenHuang; KoihuoLu; YongmeiYin

    2004-01-01

    OBJECTIVE To compare the efficacy and toxicity of gemcitabine plus cisplatin and gemcitabine plus fluorouracil in the treatment of advanced pancreatic cancer. METHODS Sixty patients with advanced pancreatic cancer were randomly divided into a GP group (gemcitabine + cisplatin, 30 cases) and a GF group (gemcitabine + fluorouracil, 30 cases). All patients were treated with gemcitabine at a dose of 1,000mg/m2 (diluted in 100ml saline solution over 30 min) once a week for 3 consecutive weeks. The GP Group was followed by 40mg cisplatin via intravenous drip on days 15,16,17. Group GF was followed by 500mg/m2 5-Fu (diluted in 5% glucose-saline (GS) 500ml, intravenously, over 6 hr) every day for five subsequent days.RESULTS In the GP group, eight cases (32.0%) were PR and MR, the median survival time was 8.7 months, the Clinical Beneficial Rate (CBR) was 57.7%, and the CA19-9 decreased by over 50% in 13 vases (48.1%). In the GF group, 11 cases (45.8%) were PR and MR, the survival time was 10.1 months, the CBR was 82.1%, and CA19-9 decreased by over 50% in 15 cases(53.6%). There was a significant difference in the CBR between the two groups (P<0.05). The main toxicities in both groups were leucopenia and thrombocytopenia with no significant difference. CONCLUSIONS The treatment given to either the GP or GF group is a feasible and well-tolerated chemotherapy regimen for treating advanced pancreatic cancer with improved therapeutic efficacy and few side effects. The median survival period is long and the CBR is high, especially with the GF regimen.

  8. GEMMs as preclinical models for testing pancreatic cancer therapies

    Directory of Open Access Journals (Sweden)

    Aarthi Gopinathan

    2015-10-01

    Full Text Available Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs, the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

  9. Prospective small bowel mucosal assessment immediately after chemoradiotherapy of unresectable locally advanced pancreatic cancer using capsule endoscopy: a case series.

    Science.gov (United States)

    Yamashina, Takeshi; Takada, Ryoji; Uedo, Noriya; Akasaka, Tomofumi; Hanaoka, Noboru; Takeuchi, Yoji; Higashino, Koji; Ioka, Tatsuya; Ishihara, Ryu; Teshima, Teruki; Nishiyama, Kinji; Iishi, Hiroyasu

    2016-01-01

    In this case series, three consecutive patients with unresectable locally advanced pancreatic cancer (ULAPC) underwent capsule endoscopy (CE) before and after chemoradiotherapy (CRT) to evaluate duodenal and jejunal mucosa, and to examine the relationship between CE findings and dose distribution. CE after CRT showed duodenitis and proximal jejunitis in all three patients. The most inflamed region was the third part of the duodenum, and in dose distribution, this was the closest region to the center of irradiation. This case series shows that CE can safely diagnose acute duodenitis and proximal jejunitis caused by CRT for ULAPC, and that dose distribution is possible to predict the degree of duodenal and jejunal mucosal injuries.

  10. How fibrosis influences imaging and surgical decisions in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Mert eErkan

    2012-10-01

    Full Text Available Our understanding of pancreatic ductal adenocarcinoma is shifting away from a disease of malignant ductal cells-only, towards a complex system where tumor evolution is a result of interaction of cancer cells with their microenvironment. This change has led to intensification of research focusing on the fibrotic stroma of pancreatic ductal adenocarcinoma. Pancreatic stellate cells are the main fibroblastic cells of the pancreas which are responsible for producing the desmoplasia in chronic pancreatitis and pancreatic ductal adenocarcinoma. Clinically, the effect of desmoplasia is two-sided; on the negative side it is a hurdle in the diagnosis of pancreatic ductal adenocarcinoma because the fibrosis in cancer resembles that of chronic pancreatitis. It is also believed that pancreatic stellate cells and pancreatic fibrosis are partially responsible for the therapy resistance in pancreatic cancer. On the positive side, a fibrotic pancreas is safer to operate on compared to a fatty and soft pancreas which is prone for postoperative pancreatic fistula. In this review the impact of pancreatic fibrosis on diagnosis of pancreatic cancer and surgical decisions are discussed from a clinical point of view.

  11. Erlotinib-associated interstitial lung disease in advanced pancreatic carcinoma: a case report and literature review.

    Science.gov (United States)

    Macerelli, Marianna; Mazzer, Micol; Foltran, Luisa; Cardellino, Giovanni Gerardo; Aprile, Giuseppe

    2015-07-24

    The combination of erlotinib and gemcitabine is a recognized option for patients with metastatic pancreatic cancer whose common adverse events such as skin rash, diarrhea, or fatigue are usually easily manageable. Interstitial lung disease (ILD) is a life-threatening toxicity reported in patients with non-small-cell lung cancers treated with epidermal growth factor receptor-tyrosine kinase inhibitors or gemcitabine. This side effect is extremely rare in patients with pancreatic cancer. We report fatal treatment-related ILD that occurred in a 67-year-old patient with metastatic pancreatic cancer. Risk factors and pathophysiology of ILD need further investigation but caution is highly recommended for patients with an underlying pulmonary disease when using erlotinib in monotherapy or combination therapy.

  12. Impact of histological subtype on survival in patients with locally advanced cervical cancer that were treated with definitive radiotherapy: adenocarcinoma/adenosquamous carcinoma versus squamous cell carcinoma

    Science.gov (United States)

    Kuroda, Hiromasa; Kimura, Tadashi

    2017-01-01

    Objective To compare the survival outcomes of patients with cervical squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) among patients with locally advanced cervical cancer that were treated with definitive radiotherapy. Methods The baseline characteristics and outcome data of patients with locally advanced cervical cancer who were treated with definitive radiotherapy between November 1993 and February 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of AC/ASC histology. Results The patients with AC/ASC of the cervix exhibited significantly shorter overall survival (OS) (p=0.004) and progression-free survival (PFS) (p=0.002) than the patients with SCC of the cervix. Multivariate analysis showed that AC/ASC histology was an independent negative prognostic factor for PFS. Among the patients who displayed AC/ASC histology, larger tumor size, older age, and incomplete response to radiotherapy were found to be independent prognostic factors. PFS was inversely associated with the number of poor prognostic factors the patients exhibited (the estimated 1-year PFS rates; 100.0%, 77.8%, 42.8%, 0.0% for 0, 1, 2, 3 factors, respectively). Conclusion Locally advanced cervical cancer patients with AC/ASC histology experience significantly worse survival outcomes than those with SCC. Further clinical studies are warranted to develop a concurrent chemoradiotherapy (CCRT) protocol that is specifically tailored to locally advanced cervical AC/ASC. PMID:28028992

  13. Postmenopausal bleeding and vaginal nodules as the first presenting sign of adenocarcinoma of the gallbladder.

    Science.gov (United States)

    Triolo, O; Antico, F; Mancuso, A; Salimbeni, V; Nicotina, P A

    2005-01-01

    Vaginal submucosal nodules were observed in a 67-year-old woman, with ultrasonographic features of an advanced uterine neoplasm. On biopsy, light microscopy suggested that the lesions might be metastatic foci from an extragenital cancer, with a prevalent tubular growth pattern. Parallel immunohistochemical reactions revealed a diffuse, strong CA 19-9 positivity in both the cell membrane and cytoplasm. Subsequently, high serum levels of such tumor marker were also found, and an extragenital cancer was suspected of pancreatic or biliary origin. A mass in the gallbladder fossa was then detected by computed tomography and a primary gallbladder adenocarcinoma was confirmed on ultrasound-guided biopsy.

  14. Locally advanced adenocarcinoma of the rectum presenting with necrotising fasciitis of the perineum: successful management with early aggressive surgery and multimodal therapy.

    Science.gov (United States)

    Ferreira, Luís; Alexandrino, Henrique; Soares Leite, Júlio; Castro Sousa, Francisco

    2015-12-16

    Colorectal cancer is a common malignant neoplasm and its treatment usually involves surgery associated, in some cases, depending on the staging, with chemoradiotherapy. Necrotising fasciitis of the perineum is a highly lethal infection of the perineum, perirectal tissues and genitals, requiring emergency surgical debridement, broad-spectrum antibiotics and control of sepsis. We present the case of a 59-year-old man with necrotising fasciitis of the perineum as the first clinical manifestation of locally advanced adenocarcinoma of the rectum, in which successful management consisted of early and aggressive surgical debridement, followed by multimodal therapy with curative intent. 2 years and 6 months after surgery the patient is well, with no evidence of local or systemic relapse.

  15. Frequency and Significance of Abnormal Pancreatic Imaging in Patients with BRCA1 and BRCA2 Genetic Mutations

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    Elie Chahla

    2016-01-01

    Full Text Available Objective. Pancreatic adenocarcinoma is typically diagnosed in advanced stages resulting in a significant reduction in the number of patients who are candidates for surgical resection. Although the majority of cases are believed to occur sporadically, about 10% show familial clustering and studies have identified an increased frequency of BRCA germline mutations. The role of screening for pancreatic adenocarcinoma in these populations is unclear. Our study aims to identify the abnormal pancreatic imaging findings in BRCA1 and BRCA2 mutation carriers. Methods. A retrospective review of patient medical records with known BRCA1 and BRCA2 mutations was conducted. Data was collected and all available abdominal imaging studies were reviewed. Results. A total of 66 patients were identified, 36 with BRCA1 and 30 with BRCA2 mutations. Only 20/66 (30% had abdominal imaging (14 BRCA1 and 6 BRCA2 patients. Of those patients with abdominal imaging, abnormal pancreatic imaging findings were detected in 7/20 (35% cases. Conclusion. Our study shows a high incidence of abnormal pancreatic imaging findings in patients with BRCA genetic mutations (35%. Larger studies are needed to further define the role of pancreatic cancer screening and the significance of abnormal imaging findings in BRCA1 and BRCA2 mutation carriers.

  16. Treatment for locally advanced pancreatic cancer%局部晚期胰腺癌的治疗进展

    Institute of Scientific and Technical Information of China (English)

    王梦; 杨继元

    2013-01-01

    局部晚期胰腺癌目前治疗的主要手段是放化疗联合姑息性手术的综合治疗,目的在于延长患者生命的同时提高其生活质量.吉西他滨是目前的标准治疗,以其为基础的联合方案的疗效已得到肯定,与靶向药物联合亦有一定的疗效.新的化疗药物和靶向药物的涌现,为局部晚期胰腺癌的治疗提供了更多的途径.%Combined therapy consisting of radiotherapy,chemotherapy and palliative surgery is the primary management for locally advanced pancreatic cancer,with the purpose of prolonging survival and improving life quality.Gemcitabine is the standard chemotherapy at present.Gemcitabine-based combinations show a definite effect,and the combination with targeted drugs also has a certain degree of efficacy.The development of new chemotherapy drugs and targeted drugs provides more ways for the teatment of locally advanced pancreatic cancer.

  17. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... alcohol abuse over many years. Repeated episodes of acute ... chronic pancreatitis. Genetics may be a factor in some cases. ...

  18. Hereditary Pancreatitis

    Science.gov (United States)

    ... alcohol is a known risk factor for both acute and chronic pancreatitis. Therefore it is recommended that all HP patients ... Pancreatitis Patient Info Animated Pancreas Patient Pancreatic Cancer Chronic Pancreatitis Acute Pancreatitis Research Research Grant Application Research History Grant ...

  19. Pancreatitis - discharge

    Science.gov (United States)

    Chronic pancreatitis - discharge; Pancreatitis - chronic - discharge; Pancreatic insufficiency - discharge; Acute pancreatitis - discharge ... You were in the hospital because you have pancreatitis. This is a swelling of the pancreas. You ...

  20. A practical approach to the diagnosis of autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Luca Frulloni; Antonio Amodio; Anna Maria Katsotourchi; Italo Vantini

    2011-01-01

    Autoimmune pancreatitis is a disease characterized by specific pathological features, different from those of other forms of pancreatitis, that responds dramatically to steroid therapy. The pancreatic parenchyma may be diffusely or focally involved with the possibility of a low-density mass being present at imaging, mimicking pancreatic cancer. Clinically, the most relevant problems lie in the diagnosis of autoimmune pancreatitis and in distinguishing autoimmune pancreatitis from pancreatic cancer. Since in the presence of a pancreatic mass the probability of tumour is much higher than that of pancre-atitis, the physician should be aware that in focal autoimmune pancreatitis the first step before using steroids is to exclude pancreatic adenocarcinoma. In this review, we briefly analyse the strategies to be followed for a correct diagnosis of autoimmune pancreatitis.

  1. Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis

    Science.gov (United States)

    Wang, Yuan; Hu, Guo-fang; Zhang, Qian-qian; Tang, Ning; Guo, Jun; Liu, Li-yan; Han, Xiao; Wang, Xia; Wang, Zhe-hai

    2016-01-01

    Background Pancreatic cancer is considered as a chemoresistant neoplasm with extremely dismal prognosis. Gemcitabine is recommended as the standard agent for locally advanced or metastatic pancreatic cancer. A series of trials have been conducted to improve the outcome of advanced pancreatic cancer with other anticancer drugs in combination with gemcitabine. Unfortunately, the designers of the clinical trials failed to improve the poor prognosis of patients with advanced pancreatic cancer. Erlotinib was the first additional drug that improved the overall survival of patients with advanced pancreatic cancer with gemcitabine. We performed this systematic review and meta-analysis to explore the efficacy and safety of the combination of gemcitabine with erlotinib (GemErlo) for patients with advanced pancreatic cancer using the currently available evidence. Methods PubMed/MEDLINE, EMBASE, the Cochrane Library, and relevant abstracts of major conferences were comprehensively searched. Data results on objective response rate, disease control rate, and 1-year survival were pooled by using MetaAnalyst with a random-effects model. Results on progression-free survival and overall survival were only summarized descriptively. Results A total of 24 studies with 1,742 patients with locally advanced or metastatic pancreatic cancer treated with GemErlo were included. Combined objective response rate was 14.4% (95% CI: 11.6%–17.7%), disease control rate was 55.0% (95% CI: 51.5%–58.5%), and 1-year survival rate was 28.5% (95% CI: 24.0%–33.4%). Progression-free survival ranged from 2.63 to 9.6 months, and overall survival varied from 6 to 10 months. As for the toxicity profile, the most common adverse events (AEs) were hematologic reactions, skin rash, and gastrointestinal reactions. Other severe AEs, which had low incidence, included treatment-induced death and interstitial lung disease. Conclusion Our study showed that GemErlo is associated with reasonable activity in treating

  2. Possible Involvement of Pancreatic Fatty Infiltration in Pancreatic Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Mika Hori

    2016-03-01

    Full Text Available Pancreatic cancer is difficult to diagnose in its early stage and is one of the most lethal human cancers. Thus, it is important to clarify its major risk factors, predictive factors and etiology. Here, we focus on fatty infiltration of the pancreas and suggest that it could be a risk factor for pancreatic cancer. Fatty infiltration of the pancreas is observed as ectopic adipocytes infiltrating the pancreatic tissue and is positively correlated with obesity and the prevalence of diabetes mellitus, which are risk factors for pancreatic cancer. However, whether fatty infiltration is a major risk factor for pancreatic cancer has not been established. Recent clinical studies show there is a positive correlation between fatty infiltration of the pancreas and pancreatic precancerous lesions or ductal adenocarcinomas. Animal experimental studies also show an association between fatty infiltration of the pancreas and pancreatic precancerous lesions or ductal adenocarcinomas development. Syrian golden hamsters, which are sensitive to chemical carcinogens in the pancreas, develop fatty infiltration of the pancreas with age. The combination of a high-fat diet and a chemical carcinogen that induces a K-ras mutation increases the severity of fatty infiltration of the pancreas. Thus, fatty infiltration of the pancreas is suggested to promote pancreatic carcinogenesis via a K-ras activating mutation. It is assumed that increased expression of adipokines and of inflammatory and proliferation-associated factors elicited by fatty infiltration of the pancreas may contribute to pancreatic precancerous lesions or ductal adenocarcinomas development. Accumulating evidence suggests that in addition to suppression of Ras activation, methods to modulate fatty infiltration in the pancreas can be considered as a strategy for preventing pancreatic cancer.

  3. Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma – CapRI: study protocol [ISRCTN62866759

    Directory of Open Access Journals (Sweden)

    Schmitz-Winnenthal H

    2005-04-01

    Full Text Available Abstract After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation. Design The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrolment. Discussion The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers.

  4. 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 managem...

  5. Proteomics portrait of archival lesions of chronic pancreatitis.

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    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.

  6. Skeletal Muscle Depletion Predicts the Prognosis of Patients with Advanced Pancreatic Cancer Undergoing Palliative Chemotherapy, Independent of Body Mass Index.

    Directory of Open Access Journals (Sweden)

    Younak Choi

    Full Text Available Body composition has emerged as a prognostic factor in cancer patients. We investigated whether sarcopenia at diagnosis and loss of skeletal muscle during palliative chemotherapy were associated with survival in patients with pancreatic cancer.We retrospectively reviewed the clinical outcomes of pancreatic cancer patients receiving palliative chemotherapy between 2003 and 2010. The cross-sectional area of skeletal muscle at L3 by computed tomography was analyzed with Rapidia 3D software. We defined sarcopenia as a skeletal muscle index (SMI< 42.2 cm2/m2 (male and < 33.9 cm2/m2 (female using ROC curve.Among 484 patients, 103 (21.3% patients were sarcopenic at diagnosis. Decrease in SMI during chemotherapy was observed in 156 (60.9% male and 65 (40.6% female patients. Decrease in body mass index (BMI was observed in 149 patients (37.3%, with no gender difference. By multivariate analysis, sarcopenia (P< 0.001, decreasedBMI and SMI during chemotherapy (P = 0.002, P = 0.004, respectively were poor prognostic factors for overall survival (OS. While the OS of male patients was affected with sarcopenia (P< 0.001 and decreased SMI (P = 0.001, the OS of female patients was influenced with overweight at diagnosis (P = 0.006, decreased BMI (P = 0.032 and decreased SMI (P = 0.014. Particularly, while the change of BMI during chemotherapy did not have impact on OS within the patients with maintained SMI (P = 0.750, decrease in SMI was associated with poor OS within the patients with maintained BMI (HR 1.502; P = 0.002.Sarcopenia at diagnosis and depletion of skeletal muscle, independent of BMI change, during chemotherapy were poor prognostic factors in advanced pancreatic cancer.

  7. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    Science.gov (United States)

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  8. Republished: recent advances in autoimmune pancreatitis: type 1 and type 2.

    Science.gov (United States)

    Kamisawa, Terumi; Chari, Suresh T; Lerch, Markus M; Kim, Myung-Hwan; Gress, Thomas M; Shimosegawa, Tooru

    2014-01-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

  9. [Chronic pancreatitis, acute pancreatitis].

    Science.gov (United States)

    Mabuchi, T; Katada, N; Nishimura, D; Hoshino, H; Shimizu, F; Suzuki, R; Sano, H; Kato, K

    1998-11-01

    MRCP has been recognized as a safe and noninvasive diagnostic method. In the present study we evaluated the usefulness of MRCP in diagnosis of chronic and acute pancreatitis. Two-dimensional fast asymmetric spin-echo (FASE) MRCP was performed in 40 patients with chronic pancreatitis and 13 with acute pancreatitis. In 29 patients (72.5%) with chronic pancreatitis and 9 (66.7%) with acute pancreatitis, main pancreatic duct (MPD) was visualized entirely. MRCP could demonstrate the characteristic findings of chronic pancreatitis such as dilatation and irregularity of MPD in most cases. In acute pancreatitis, MRCP indicated that MPD was normal in diameter, but irregular in configuration compared with that of the control group. MRCP may facilitate the diagnosis of chronic and acute pancreatitis.

  10. Multimodality Treatment by FOLFOX plus HIFU in a Case of Advanced Pancreatic Carcinoma. A Case Report

    Directory of Open Access Journals (Sweden)

    Dobromir Dimitrov

    2015-01-01

    Full Text Available Context Pancreatic cancer is one of the most aggressive malignant diseases in which the survival rate has not improved in the past 40 years. Case report A fifty-one-year-old male patient with inoperable metastatic pancreatic cancer and low response to chemotherapy with gemcitabine as single therapy underwent palliative high intensity focused ultrasound (HIFU ablation. Continuing chemotherapy with folinic acid, oxaliplatin and 5-fluorouracil (FOLFOX was made. Tools, provided by the European Organization for Research and Treatment of Cancer (EORTC were used to evaluate his quality of life. The Global Health Status improved from 25 to 42 out of 100 and the body mass index (BMI increased from 14.9 to 18.1 kg/m2. Measured by the visual analog scale, the pain was reduced from 7 to 2 out of 10. Twelve months after the HIFU ablation, CT revealed decreased size of the tumor and liver lesions. Conclusion FOLFOX plus interventional, physical destruction of the primary tumor by HIFU sufficiently improved the quality of life, reduced pancreatic pain and provided better survival in this case.

  11. Trajectory of chemotherapy for patients with EGFR wild-type advanced pulmonary adenocarcinoma: a single-institution retrospective study

    Science.gov (United States)

    Minami, Seigo; Ogata, Yoshitaka; Ihara, Shouichi; Yamamoto, Suguru; Komuta, Kiyoshi

    2017-01-01

    Background Pulmonary adenocarcinoma, recently benefited by new cytotoxic and molecularly targeted drugs, has been classified by driver mutations, such as EGFR mutations. The aim of this study was to research the proportions of patients treated with first- to third-line chemotherapy and to find influential factors for the introduction of chemotherapy and survival benefit from chemotherapy. Materials and methods Data were collected retrospectively on patients who met the following criteria: adenocarcinoma, diagnosed between June 2007 and March 2015 at our hospital, stage IIIB or IV, and EGFR wild type. A nonchemotherapy group of patients who did not receive chemotherapy was compared with a chemotherapy group of patients who received it. The patients who had received first- to third-line chemotherapy between June 2007 and November 2015 at our hospital were also analyzed. Results During the study period, 46 patients did not receive chemotherapy, while 148, 89, and 48 received first-, second- and third-line chemotherapy, respectively. As predictive factors for unlikely chemotherapy, multivariate logistic analysis detected Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, hemoglobin <13.2 g/dL, creatinine clearance (Ccr) <50.4 mL/min, and CRP ≥0.53 mg/dL. As factors predicting shorter survival after chemotherapy, multivariate Cox proportional-hazard analyses detected age ≥75 years, ECOG PS ≥2, lower lymphocyte counts, and higher CRP for the first line; female, higher neutrophil counts, lower lymphocyte counts, reduced Ccr, hyponatremia, and shorter interval between first- and second-line chemotherapy for the second line; and age ≥75 years, body mass index <18.5 kg/m2, higher neutrophil counts, lower lymphocyte counts, hyponatremia, higher lactate dehydrogenase, and higher CRP for the third line. Conclusion Approximately 76% of patients were treated with first-line chemotherapy. Of those patients, 61% and 34% proceeded to second- and third

  12. Revising You the Staging for Pancreatic Cancer in 2012

    Directory of Open Access Journals (Sweden)

    Muhammad Wasif Saif

    2012-03-01

    Full Text Available In 2010, there were an estimated 43,140 new cases of pancreatic ductal adenocarcinoma and 36,800 deaths from pancreatic cancer in the United States [1]. This represents the 10th most common cancer diagnosis but the 4th most common cause of cancer-related death among men and women (6% of all cancer-related deaths, highlighting the disproportionate mortality associated with this diagnosis [2]. Why is Staging so Important? Sadly, only 20% patients are “resectable” at the time of diagnosis [3]. Pancreatic cancer is “resectable” if the tumor is confined to the pancreas without the encasement of adjacent surrounding major vessels, or distant metastases. Even among those patients who undergo resection for pancreatic cancer and have tumor-free margins, the 5-year survival rate after resection is 10-25% and the median survival is 15-19 months [3]. “Locally advanced pancreatic cancer” is defined as the tumor that has a local invasion: arterial (celiac trunk, hepatic artery, superior mesenteric artery or venous (portal vein, superior mesenteric vein but not metastasized, and represents about 25% of pancreatic cancer cases at presentation [4]. Locally advanced stage is associated with a median survival of 6-10 months. The vast majority of these patients develop metastatic disease within the first year of therapy. The tumor is considered “advanced” when it has metastasized to other organs, such as the liver or distant areas of the abdomen. Approximately 45% to 55% of patients are diagnosed at this stage. The prognosis of patients with advanced disease remains extremely poor, with a median survival of 6 months [5].

  13. Acute Exposure to a Precursor of Advanced Glycation End Products Induces a Dual Effect on the Rat Pancreatic Islet Function

    Directory of Open Access Journals (Sweden)

    Ghada Elmhiri

    2014-01-01

    Full Text Available Aim. Chronic diseases are the leading cause of death worldwide. Advanced glycation end products, known as AGEs, are a major risk factor for diabetes onset and maintenance. Methylglyoxal (MG, a highly reactive metabolite of glucose, is a precursor for the generation of endogenous AGEs. Methods. In this current study we incubated in vitro pancreatic islets from adult rats in absence or presence of MG (10 μmol/l with different concentrations of glucose and different metabolic components (acetylcholine, epinephrine, potassium, forskolin, and leucine. Results. Different effects of MG on insulin secretion were evidenced. In basal glucose stimulation (5.6 mM, MG induced a significant (P<0.05 increase of insulin secretion. By contrast, in higher glucose concentrations (8.3 mM and 16.7 mM, MG significantly inhibited insulin secretion (P<0.05. In the presence of potassium, forskolin, and epinephrine, MG enhanced insulin secretion (P<0.05, while when it was incubated with acetylcholine and leucine, MG resulted in a decrease of insulin secretion (P<0.05. Conclusion. We suggest that MG modulates the secretion activity of beta-cell depending on its level of stimulation by other metabolic factors. These results provide insights on a dual acute effect of MG on the pancreatic cells.

  14. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

    Science.gov (United States)

    Stathopoulos, George P; Boulikas, Teni; Vougiouka, Maria; Rigatos, Sotirios K; Stathopoulos, John G

    2006-05-01

    The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

  15. Intermittent Chemotherapy and Erlotinib for Nonsmokers or Light Smokers with Advanced Adenocarcinoma of the Lung: A Phase II Clinical Trial

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    Matjaz Zwitter

    2011-01-01

    Full Text Available Background. Intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs. This hypothesis was tested in a Phase II clinical trial. Patients and Methods. Eligible patients were nonsmokers or light smokers, chemo-naïve, with metastatic adenocarcinoma of the lung. Treatment: 4 to 6 cycles of gemcitabine 1250 mg/m2 on days 1 and 4, cisplatin 75 mg/m2 on day 2, and erlotnib 150 mg daily on days 5–15, followed by erlotinib as maintenance. Results. 24 patients entered the trial. Four pts had grade 3 toxicity. Complete remission (CR and partial remission (PR were seen in 5 pts and 9 pts, respectively (response rate 58%. Median time to progression (TTP was 13.4 months and median overall survival (OS was 23 months. When compared to patients with negative or unknown status of EGFR mutations, 8 patients with EGFR gene activating mutations had significantly superior experience: 4 CR and 4 PR, with median TTP 21.5 months and OS 24.2 months (P  <  .05. Conclusions. Intermittent schedule with gemcitabine, cisplatin and erlotinib has mild toxicity. For patients who are positive for EGFR gene activating mutations, this treatment offers excellent response rate, time to progression and survival.

  16. Updates on Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Ojas Vyas

    2014-05-01

    Full Text Available Pancreatic adenocarcinoma remains a therapeutic challenge. The American Cancer Society estimates that in 2014 about 46,420 people will be diagnosed with pancreatic cancer and about 39,590 people will die of pancreatic cancer in the United States [1]. The incidence of pancreatic carcinoma has markedly increased over the past several decades and it now ranks as the fourth leading cause of cancer-related death in the United States. Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood. Although progress in the development of new cytotoxic and biological drugs for the treatment of pancreatic cancer continues, the outcome remains grim. Many organizations and associations have taken an effort to improve knowledge, understanding and outcome of patients with pancreatic cancer. Pancreas Club, since its founding in 1966, is aimed to promote the interchange of ideas between physicians and scientists focused on pancreas throughout the world in an informal “club” atmosphere. We attended the 48th Annual Meeting of Pancreas Club in Chicago and reviewed many interesting posters and oral presentations. Here we discuss a few selected abstracts.

  17. 进展期胰腺癌化疗中的肠外营养支持%The application of the parenteral nutritional support in the advanced pancreatic carcinoma patients under chemotherapy

    Institute of Scientific and Technical Information of China (English)

    刘建东; 才又红; 张绍军; 张军; 杨家祥

    2001-01-01

    Objectives  To explore the effects of parenteral nutrition on advanced pancreatic carcinoma patients under chemotherapy.  Methods  From Jun. 1995 to Jun. 1998, we treated 33 cases of advanced pancreatic carcinoma with combined chemotherapy. of which, 21 cases had histologically documented and 12 cases had exfoliative cytologically documented adenocarcinoma of the pancreas. Clinical staging: Ⅲ 26 cases, Ⅳ 7 cases. Thirty three cases of advanced pancreatic carcinoma patients were randomly divided into 2 groups. (1)treatment group (2) control group. The two groups received combined chemotherapy. The regimen was 5 FU+CF+MMC+DDP or EPI. The control group, 9 men and 6 women had a median age of 60.3 years, received combined chemotherapy and routine treatment; and the treatment group, 11 men and 7 women had a median age of 59.5 years,received the parenteral nutritional support for mean 12.8 days in the combined chemotherapy period. Results  Treatment group was superior to control group. Serum prealbumin, transferrin concentration, total lymphocyte count, natural killer cells activity and IL-2R+cells (CD25)percentage of peripheral blood increased significantly (P<0.05,P<0.01,P<0.05,respectively). However, no significant difference was observed in the respone rate (CR+PR) and the median swrvival time between the two groups. But after biliary drainage operation, received chemotherapy and TPN, the patients survival time increasad significantly. Conclusions  The parenteral nutrition support was effective in maintaining the nutritional and immune status in the advanced pancreatic carcinoma petients receiving chemotherapy.%目的探讨进展期胰腺癌化疗中的肠外营养支持对病人营养、免疫状态及肿瘤疗效的影响。方法 33例病人均给予联合化疗(FCMP/A),随机分为治疗组(肠外营养),对照组(常规治疗)。检验两组病人的营养、免疫状态,肿瘤治疗的有效率、生存期。结果治疗组

  18. Hepatic artery pseudoaneurysm after surgical treatment for pancreatic cancer: Minimally invasive angiographic techniques as the preferred treatment

    Directory of Open Access Journals (Sweden)

    Sucandy Iswanto

    2014-01-01

    Full Text Available Background: Delayed intra-abdominal bleeding related to hepatic artery pseudoaneurysm is a potentially lethal complication after pancreaticoduodenectomy for pancreatic cancer. Locally advanced tumors, which result in vessel erosion or extensive operative skeletonization, may contribute to weakness of the arterial wall. Reoperation is often technically difficult with high rate of mortality; therefore, alternative less invasive options are ideal. Aims: The study was to present an alternative endovascular treatment of a large hepatic artery pseudoaneurysm after pancreatic resection for locally advanced multicystic adenocarcinoma. Materials and Methods: Transcatheteric mesenteric angiography with deployment of detachable coils in the pseudoaneurysm sac was utilized to manage the hepatic artery pseudoaneurysm. Results: Completion angiography confirmed cessation of contrast enhancement in the pseudoaneurysm sac with preservation of normal antegrade hepatic artery flow. Conclusion: Minimally invasive angiographic technique is the preferred treatment for hepatic artery pseudoaneurysm after pancreatic resections.

  19. Intensity-Modulated and Image-Guided Radiotherapy in Patients with Locally Advanced Inoperable Pancreatic Cancer after Preradiation Chemotherapy

    Directory of Open Access Journals (Sweden)

    M. Sinn

    2014-01-01

    Full Text Available Background. Radiotherapy (RT in patients with pancreatic cancer is still a controversial subject and its benefit in inoperable stages of locally advanced pancreatic cancer (LAPC, even after induction chemotherapy, remains unclear. Modern radiation techniques such as image-guided radiotherapy (IGRT and intensity-modulated radiotherapy (IMRT may improve effectiveness and reduce radiotherapy-related toxicities. Methods. Patients with LAPC who underwent radiotherapy after chemotherapy between 09/2004 and 05/2013 were retrospectively analyzed with regard to preradiation chemotherapy (PRCT, modalities of radiotherapy, and toxicities. Progression-free (PFS and overall survival (OS were estimated by Kaplan-Meier curves. Results. 15 (68% women and 7 men (median age 64 years; range 40–77 were identified. Median duration of PRCT was 11.1 months (range 4.3–33.0. Six patients (27% underwent conventional RT and 16 patients (73% advanced IMRT and IGRT; median dosage was 50.4 (range 9–54 Gray. No grade III or IV toxicities occurred. Median PFS (estimated from the beginning of RT was 5.8 months, 2.6 months in the conventional RT group (conv-RT, and 7.1 months in the IMRT/IGRT group (P=0.029; median OS was 11.0 months, 4.2 months (conv-RT, and 14.0 months (IMRT/IGRT; P=0.141. Median RT-specific PFS for patients with prolonged PRCT > 9 months was 8.5 months compared to 5.6 months for PRCT 9 months group, with 19.0 months compared to 8.5 months in the PRCT  <  9 months group (P=0.049. Conclusions. IGRT and IMRT after PRCT are feasible and effective options for patients with LAPC after prolonged preradiation chemotherapy.

  20. Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma.

    Science.gov (United States)

    Bria, Emilio; Pilotto, Sara; Amato, Eliana; Fassan, Matteo; Novello, Silvia; Peretti, Umberto; Vavalà, Tiziana; Kinspergher, Stefania; Righi, Luisella; Santo, Antonio; Brunelli, Matteo; Corbo, Vincenzo; Giglioli, Eliana; Sperduti, Isabella; Milella, Michele; Chilosi, Marco; Scarpa, Aldo; Tortora, Giampaolo

    2015-05-20

    Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

  1. Class III β-tubulin in advanced NSCLC of adenocarcinoma subtype predicts superior outcome in a randomized trial

    DEFF Research Database (Denmark)

    Vilmar, Adam Christian; Santoni-Rugiu, Eric; Sørensen, Jens Benn

    2011-01-01

    Platinum-based doublets are the cornerstone of treatment in advanced non-small-cell lung cancer (NSCLC) and often include vinorelbine or taxanes. A predictive biomarker is greatly needed to select chemotherapy-sensitive patients for these microtubule-interfering agents. Class III β-tubulin (TUBB3......) has been shown of value in NSCLC, but evidence is not uniform. Accordingly, we explored the predictive role of TUBB3 in advanced NSCLC....

  2. Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: a multicenter prospective study

    Institute of Scientific and Technical Information of China (English)

    Xiao-Dong Zhang; Cheng-Ye Guo; Lin Shen; Mao-Lin Jin; Yong-Qian Shu; Jun Liang; Feng-Chun Zhang; Xue-Zhen Ma; Jian-Jin Huang; Li Chen; Gen-Ming Shi; Wei-Guo Cao

    2012-01-01

    Objective:To evaluate the efficacy and toxicity of the combination regimen of paclitaxel,cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China.Methods:The patients were treated with paclitaxel 150 mg/m2 on d1; fractionated cisplatin 15 mg/m2 and continuous infusion 5-FU 600 mg/(m2·d) intravenously on d1-d5 of a 21-d cycle until disease progression or unacceptable toxicities.Results:Seventy-five patients have been enrolled,among which,41 received PCF regimen as the first-line therapy (group A) and 34 received the regimen as the second-line therapy (group B) with the median age of 59 years old and Karnofsky performance status (KPS) score ≥80.Toxicities were analyzed in all 75 patients.Seventy-one patients were evaluable for efficacy.The median overall survival (mOS) was 12.0 months (95% CI:7.9-16.2 months) in group A and 7.3 months (95% CI:4.3-10.3 months) in group B,respectively.The median progression-free survival (mPFS) was 5.7 months (95% CI:4.1-7.2 months) and 5.0 months (95% CI:3.1-6.9 months),respectively.The response rate (CR+PR) was 40% (16/40; 95% CI:24.9-56.7%) in group A and 22.6% (7/31; 95% CI:9.6-41.1%) in group B.Major grade 3 or 4 adverse events include neutropenia (41.3%),febrile neutropenia (9.3%),nausea/anorexia (10.7%),and vomiting (5.3%).There was no treatment-related death.Conclusions:The combination chemotherapy with PCF is active and tolerable as first-line and second-line therapy in Chinese patients with advanced gastric and EGJ adenocarcinoma.The response and survival of PCF are same as those of DCF,but the tolerance is much better.

  3. Biomarkers and Pharmacogenetics in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Xunhai Xu

    2011-07-01

    Full Text Available Appropriate identification and validation of biomarkers as well as pharmacogenetics are important in formulating patient-oriented, individualized chemotherapy or biological therapy in cancer patients. These markers can be especially valuable in pancreatic cancer, where high mortality and complex disease biology are frequently encountered. Recently, several advances have been made to further our knowledge in this specific area of pancreatic cancer. In the 2011 American Society of Clinical Oncology (ASCO Annual Meeting, researchers have presented several interesting results in biomarkers development: the identifications of 9 single nucleotide polymorphisms (SNPs that is associated with positive efficacy of gemcitabine (Abstract #4022; the introduction of circulating tumor cells as a prognostic markers in pancreatic adenocarcinoma (Abstract #e14657; the re-affirmation of plasma cytidine deaminase (CDA as a positive predictive markers for gemcitabine efficacy, as well as the postulations that CDA*3 as a potential genotype marker to predict gemcitabine responses (Abstract #e14645; and finally the retrospective tumor tissues analysis in the Arbeitsgemeinschaft Internistische Onkologie (AIO trial in an attempt for epidermal growth factor receptor (EGFR pathway biomarker identifications (Abstract #4047

  4. IQGAP1 in rectal adenocarcinomas

    DEFF Research Database (Denmark)

    Holck, Susanne; Nielsen, Hans Jørgen; Hammer, Emilie;

    2015-01-01

    Treatment of rectal adenocarcinoma includes total mesorectal excision, which is preceded by radiochemotherapy (RCT) in cases of advanced disease. The response to RCT varies from total tumor regression to no effect but this heterogeneous response is unexplained. However, both radiation and treatme...

  5. 胰管结石的治疗进展%Advance in pancreatic duct calculi

    Institute of Scientific and Technical Information of China (English)

    王恺; 邵江华

    2009-01-01

    胰管结石在我国的发病率有逐年升高的趋势.目前治疗手段主要有非手术治疗及手术治疗2种.非手术治疗方法主要有内镜下取石和/或体外震波碎石后取石,手术治疗方法分为胰管引流减压术及胰腺切除术2大类.具体的治疗方法或手术方式的选择需遵循个体化的原则.%The morbidity of pancreatic duct calculus is increasing every year in China. Currently the main therapeutic methods include non-surgical treatment and surgical treatment. Non-surgical treatments contain endoscopic calculus extracting and / or extracorporeal shock wave lithotripsy. Surgical treatment has two categories: drainage of the pancreatic duct decompression and pancreatectomy. Concrete treatment or surgical options should follow the strategy of individual.

  6. Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies.

    Science.gov (United States)

    Maksimenko, Andrei; Caron, Joachim; Mougin, Julie; Desmaële, Didier; Couvreur, Patrick

    2015-03-30

    Gemcitabine is currently the most effective agent against advanced pancreatic cancer. However, the major therapeutic hurdles using gemcitabine include rapid inactivation by blood deaminases and fast development of cell chemoresistance, induced by down-regulation of deoxycytidine kinase or nucleoside transporters. To overcome the above drawbacks we designed recently a novel nanomedicine strategy based on squalenoyl prodrug of 5'-monophosphate gemcitabine (SQdFdC-MP). This amphiphilic conjugate self-organized in water into unilamellar vesicles with a mean diameter of 100 nm. In this study the antitumor efficacy of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models have been investigated. Cell viability assays showed that SQdFdC-MP NAs displayed higher antiproliferative and cytotoxic effects, particularly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC-MP NAs decreased significantly the growth (∼70%) of human MiaPaCa2 xenografts, also preventing tumor cell invasion, whereas native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. These results correlated with a reduction of Ki-67 antigen and the induction of apoptosis mediated by caspase-3 activation in tumor cells. These findings demonstrated the feasibility of utilizing SQdFdC-MP NAs to make tumor cells more sensitive to gemcitabine and thus providing an efficient new therapeutic alternative for pancreatic adenocarcinoma.

  7. Phenotyping of peripheral blood mononuclear cells of patients with advanced heavily pre-treated adenocarcinoma of the stomach and gastro-esophageal junction.

    Science.gov (United States)

    Kuehnle, Marie-Cristine; Attig, Sebastian; Britten, Cedrik M; Schulze-Bergkamen, Henning; Lordick, Florian; von Wichert, Goetz; Thuss-Patience, Peter; Stein, Alexander; Schuler, Martin; Bassermann, Florian; Sahin, Ugur; Türeci, Ozlem

    2014-12-01

    Immunotherapeutic approaches are emerging as promising new treatment options for patients with solid cancers. The host immune system in cancer patients is dysfunctional due to a number of reasons. The level of immunosuppression is variable at the time of diagnosis and depends on the particular cancer entity, stage, and prior anti-cancer therapies. For many cancer entities, the immune alterations of the respective patient population have not been further characterized even though a patient's immunophenotype may be prognostic for the course of the disease or predictive for clinical/biological response to immunotherapy. In this study, we used flow cytometry to determine the phenotype of peripheral blood mononuclear cells (PBMCs) from 30 patients with heavily pre-treated, advanced adenocarcinoma of the stomach and gastro-esophageal junction. The frequencies and activation status of relevant immune effector populations were determined in PBMCs and compared to those of healthy individuals. This report provides comprehensive immune phenotyping data of a patient population with a high medical need.

  8. Class III β-tubulin in advanced NSCLC of adenocarcinoma subtype predicts superior outcome in a randomized trial

    DEFF Research Database (Denmark)

    Vilmar, Adam Christian; Santoni-Rugiu, Eric; Sørensen, Jens Benn

    2011-01-01

    Platinum-based doublets are the cornerstone of treatment in advanced non-small-cell lung cancer (NSCLC) and often include vinorelbine or taxanes. A predictive biomarker is greatly needed to select chemotherapy-sensitive patients for these microtubule-interfering agents. Class III ß-tubulin (TUBB3...

  9. Bone and brain metastases from ampullary adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Ioannis A Voutsadakis; Stergios Doumas; Konstantinos Tsapakidis; Maria Papagianni; Christos N Papandreou

    2009-01-01

    Ampullary carcinoma is the second most common cancer of the peri-ampullary area after pancreatic carcinoma and metastasizes mostly intra-abdominally and to the liver. Extra-abdominal metastases are less frequent. In this report we describe the case of a patient with resected adenocarcinoma of the ampulla of Vater who developed skeletal metastases in the lower extremity and brain metastases. We briefly discuss aspects of this comparatively rare gastrointestinal malignancy.

  10. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report.

    LENUS (Irish Health Repository)

    Duffy, M J

    2012-02-01

    Pancreatic ductal adenocarcinoma is one of the most difficult malignancies to diagnose and treat. The aim of this article is to review how tumor markers can aid the diagnosis and management of patients with this malignancy. The most widely used and best validated marker for pancreatic cancer is CA 19-9. Inadequate sensitivity and specificity limit the use of CA 19-9 in the early diagnosis of pancreatic cancer. In non-jaundiced patients, however, CA 19-9 may complement other diagnostic procedures. In patients with resectable pancreatic cancer, presurgical and postresection CA 19-9 levels correlate with overall survival. In advanced disease, elevated pretreatment levels of CA 19-9 are associated with adverse patient outcome and thus may be combined with other factors for risk stratification. Most, but not all, reports indicate that serial levels of CA 19-9 correlate with response to systemic therapy. Use of CA 19-9 kinetics in conjunction with imaging is therefore recommended in monitoring therapy. Although several potential serum and tissue markers for pancreatic cancer are currently undergoing evaluation, none are sufficiently validated for routine clinical use. CA 19-9 thus remains the serum pancreatic cancer marker against which new markers for this malignancy should be judged.

  11. Glufosfamide administered using a 1-hour infusion given as first-line treatment for advanced pancreatic cancer. A phase II trial of the EORTC-new drug development group.

    Science.gov (United States)

    Briasoulis, E; Pavlidis, N; Terret, C; Bauer, J; Fiedler, W; Schöffski, P; Raoul, J L; Hess, D; Selvais, R; Lacombe, D; Bachmann, P; Fumoleau, P

    2003-11-01

    The activity of glufosfamide (beta-D-glucopyranosyl-N,N'-di-(2-chloroethyl)-phosphoric acid diamide) against pancreatic cancer was investigated in a multicentre, phase II clinical study. Chemotherapy-nai;ve patients with advanced or metastatic disease were treated with glufosfamide (5 g/m(2)) using a 1-h intravenous (i.v.) infusion every 3 weeks. Patients were randomised between active-hydration and normal fluids to evaluate the nephroprotective effect of forced diuresis. Patients experiencing >0.4 mg/dl (>35 micromol/l) increase in serum creatinine compared with their baseline value were taken off treatment for safety reasons. The evaluation of response was according to the Response evaluation criteria in solid tumours (RECIST). Blood sampling was performed for pharmacokinetic analyses. 35 patients from 13 institutions were registered over a 13-month period. A total of 114 treatment cycles (median 3, range 1-8) were administered to 34 patients; 18 patients were allocated to the hydration arm. Overall haematological toxicity was mild. Metabolic acidosis occurred in 2 patients treated in the active-hydration arm, grade 3 hypokalaemia was recorded in 5 patients and grade 3 hypophosphataemia in 4 patients. One patient had a grade 4 increase in serum creatinine level, concomitantly to disease progression. Active-hydration did not show a nephroprotective effect and the plasma pharmacokinetics (Pk) of glufosfamide was not significantly influenced by hydration. Two confirmed partial remissions (PR) were reported (response rate 5.9%, 95% Confidence Interval (CI) 0.7-19.7%) and 11 cases obtained disease stabilisation (32.4%). An extra mural review panel confirmed all of the responses. Median overall survival was 5.3 months (95% CI 3.9-7.1) and time to progression (TTP) was 1.4 months (95% CI 1.3-2.7). In conclusion, glufosfamide administered using a 1-h infusion every 3 weeks has a modest activity in advanced pancreatic adenocarcinoma. Haematological toxicity is

  12. Analysis of clinical factors associating with improvement of TNM staging accuracy in pancreatic head adenocarcinoma%胰头癌肿瘤分期影响因素分析

    Institute of Scientific and Technical Information of China (English)

    徐威; 李敬东; 赵国刚; 田云鸿

    2011-01-01

    Objective To explore possible clinical factors contributing to improvement of TNM staging accuracy in pancreatic head adenocarcinoma (PHA). Methods The retrospective study was conducted on 121 consecutive cases of PHA surgically treated from January 2004 to December 2010 in Affiliated Hospital of North Sichuan Medical College. Univariate and multivariate analysis using ordinal logistic regression explored clinical factors relating to postoperative tumor staging (Ptnm staging). Cross-validation was done to test discriminant accuracy of multivariate analysis results when compared with preoperatively radiologically TNM staging evaluation. Results Altogether 121 cases of potentially-resectable PHA entered the study. Preoperatively radiologically TNM staging evaluation revealed as followed: unidentified: 28 cases (23.1%), IA 9 cases (7.4%),IB 45 cases (37.2%), HA 18 cases (14.9%),IIB 15 case