المؤلفون: Flick KF; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Soufi M; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Yip-Schneider MT; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA.; Walther Oncology Center, Indianapolis, IN, USA.; Indiana University Simon Cancer Center, Indianapolis, IN, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Simpson RE; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Colgate CL; Center for Outcomes Research in Surgery, Indiana University School of Medicine, Indianapolis, IN, USA., Nguyen TK; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Ceppa EP; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., House MG; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Zyromski NJ; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Nakeeb A; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA., Schmidt CM; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN, USA. maxschmi@iupui.edu.; Walther Oncology Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Simon Cancer Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. maxschmi@iupui.edu.

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2021 Nov; Vol. 25 (11), pp. 2902-2907. Date of Electronic Publication: 2021 Mar 26.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4626 (Electronic) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Pancreaticoduodenectomy*/adverse effects , Surgeons*, Decompression ; Gastric Emptying ; Humans ; Intubation, Gastrointestinal/adverse effects ; Postoperative Complications/epidemiology ; Postoperative Complications/etiology ; Prospective Studies ; Retrospective Studies

مستخلص: Background: The decision to routinely leave a nasogastric tube after pancreatoduodenectomy remains controversial. We sought to determine the impact of immediate nasogastric tube removal versus early nasogastric tube removal (<24 h) on postoperative outcomes.
Methods: A retrospective review of our institution's prospective ACS-NSQIP database identified patients that underwent pancreatoduodenectomy from 2015 to 2018. Outcomes were compared among patients with immediate nasogastric tube removal versus early nasogastric tube removal.
Results: A total of 365 patients were included in primary analysis (no nasogastric tube, n = 99; nasogastric tube removed <24 h, n = 266). Thirty-day mortality and infectious, renal, cardiovascular, and pulmonary morbidity were similar in comparing those with no nasogastric tube versus early nasogastric tube removal on univariable and multivariable analyses (P > 0.05). Incidence of delayed gastric emptying (11.1 versus 13.2%) was similar between groups. Patients with no nasogastric tube less frequently required nasogastric tube reinsertion (n = 4, 4%) compared to patients with NGT <24 h (n = 39, 15%) (OR = 3.83, 95% CI [1.39-10.58]; P = 0.009).
Conclusion: Routine gastric decompression can be safely avoided after uneventful pancreaticoduodenectomy.
(© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

المؤلفون: Flick KF; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Schmidt CM; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Department of Biochemistry/Molecular Biology, Indiana University Simon Cancer Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Walther Oncology Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA. maxschmi@iupui.edu., Colgate CL; Center for Outcomes Research in Surgery, Indiana University School of Medicine, Indianapolis, IN, USA., Yip-Schneider MT; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA.; Walther Oncology Center, Indianapolis, IN, USA.; Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Sublette CM; Indiana University School of Medicine, Indianapolis, IN, USA., Maatman TK; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Soufi M; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Ceppa EP; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., House MG; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Zyromski NJ; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Nakeeb A; Department of Surgery, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2021 May; Vol. 25 (5), pp. 1253-1260. Date of Electronic Publication: 2020 Jun 24.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4626 (Electronic) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Nomograms* , Patient Discharge*, Humans ; Logistic Models ; Pancreaticoduodenectomy/adverse effects ; Risk Factors

مستخلص: Background: In patients undergoing pancreatoduodenectomy, non-home discharge is common and often results in an unnecessary delay in hospital discharge. This study aimed to develop and validate a preoperative prediction model to identify patients with a high likelihood of non-home discharge following pancreatoduodenectomy.
Methods: Patients undergoing pancreatoduodenectomy from 2013 to 2018 were identified using an institutional database. Patients were categorized according to discharge location (home vs. non-home). Preoperative risk factors, including social determinants of health associated with non-home discharge, were identified using Pearson's chi-squared test and then included in a multiple logistic regression model. A training cohort composed of 80% of the sampled patients was used to create the prediction model, and validation carried out using the remaining 20%. Statistical significance was defined as P < 0.05.
Results: Seven hundred sixty-six pancreatoduodenectomy patients met the study criteria for inclusion in the analysis (non-home, 126; home, 640). Independent predictors of non-home discharge on multivariable analysis were age, marital status, mental health diagnosis, functional health status, dyspnea, and chronic obstructive pulmonary disease. The prediction model was then used to generate a nomogram to predict likelihood of non-home discharge. The training and validation cohorts demonstrated comparable performances with an identical area under the curve (0.81) and an accuracy of 84%.
Conclusion: A prediction model to reliably assess the likelihood of non-home discharge after pancreatoduodenectomy was developed and validated in the present study.

المؤلفون: Yip-Schneider MT; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 129, Indianapolis, IN, 46202, USA.; Walther Oncology Center, Indianapolis, IN, USA.; Indiana University Simon Cancer Center, Indianapolis, IN, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Simpson R; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 129, Indianapolis, IN, 46202, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Carr RA; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 129, Indianapolis, IN, 46202, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Wu H; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 129, Indianapolis, IN, 46202, USA.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA., Fan H; Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, 1050 Wishard Blvd. RG5118, Indianapolis, IN, 46202, USA., Liu Z; Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Biostatistics, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA., Korc M; Indiana University Simon Cancer Center, Indianapolis, IN, USA.; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Zhang J; Indiana University Simon Cancer Center, Indianapolis, IN, USA. JZ21@iu.edu.; Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, 1050 Wishard Blvd. RG5118, Indianapolis, IN, 46202, USA. JZ21@iu.edu., Schmidt CM; Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 129, Indianapolis, IN, 46202, USA. maxschmi@iupui.edu.; Walther Oncology Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Simon Cancer Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Indiana University Health Pancreatic Cyst and Cancer Early Detection Center, Indianapolis, IN, USA. maxschmi@iupui.edu.; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. maxschmi@iupui.edu.

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2019 May; Vol. 23 (5), pp. 966-974. Date of Electronic Publication: 2018 Sep 13.

نوع المنشور: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4626 (Electronic) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Amino Acids, Branched-Chain/*blood , Biomarkers, Tumor/*blood , Leptin/*blood , Pancreatic Intraductal Neoplasms/*blood , Pancreatic Intraductal Neoplasms/*pathology , Retinol-Binding Proteins, Plasma/*metabolism, Adult ; Aged ; Case-Control Studies ; Cross-Sectional Studies ; Diagnosis, Differential ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Pancreatic Cyst/blood ; Pancreatic Cyst/diagnosis ; Pancreatic Cyst/pathology ; Pancreatic Intraductal Neoplasms/diagnosis ; Precancerous Conditions/blood ; Precancerous Conditions/diagnosis ; Precancerous Conditions/pathology ; Prospective Studies ; Sex Factors

مستخلص: Background: The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN.
Methods: Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology.
Results: Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p = 0.0086). Leptin levels were positively correlated with BMI (r = 0.65, p < 0.0001) and were higher in females (p < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p = 0.011). No significant differences in RBP-4 levels were observed.
Conclusions: Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.

المؤلفون: Holcomb BK; Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St., Building R3, Rm. 541C, Indianapolis, IN 46202, USA., Yip-Schneider MT, Waters JA, Beane JD, Crooks PA, Schmidt CM

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2012 Jul; Vol. 16 (7), pp. 1333-40. Date of Electronic Publication: 2012 May 23.

نوع المنشور: Evaluation Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4626 (Electronic) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Antimetabolites, Antineoplastic/*pharmacology , Deoxycytidine/*analogs & derivatives , Drug Resistance, Neoplasm/*drug effects , NF-kappa B/*antagonists & inhibitors , Pancreatic Neoplasms/*drug therapy , Sesquiterpenes/*pharmacology, Animals ; Antimetabolites, Antineoplastic/therapeutic use ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Drug Resistance, Neoplasm/physiology ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mice ; Mice, Nude ; NF-kappa B/metabolism ; Pancreatic Neoplasms/pathology ; Gemcitabine

مستخلص: Introduction: Gemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-κB) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-κB suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine.
Methods: BxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-κB pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model.
Results: Gemcitabine induced NF-κB activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-κB inhibitor IκBα in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-κB. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-κB activity in vivo.
Conclusions: DMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-κB suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-κB activity in vivo, thus supporting the evaluation of NF-κB-targeted agents to complement gemcitabine-based therapies.

المؤلفون: Holcomb B; Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Yip-Schneider MT, Matos JM, Dixon J, Kennard J, Mahomed J, Shanmugam R, Sebolt-Leopold J, Schmidt CM

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2008 Feb; Vol. 12 (2), pp. 288-96. Date of Electronic Publication: 2007 Nov 30.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1091-255X (Print) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Adenocarcinoma/*drug therapy , Adenocarcinoma/*genetics , Antimetabolites, Antineoplastic/*administration & dosage , Antineoplastic Agents/*administration & dosage , Chromones/*administration & dosage , Curcumin/*administration & dosage , Deoxycytidine/*analogs & derivatives , Enzyme Inhibitors/*administration & dosage , Morpholines/*administration & dosage , Pancreatic Neoplasms/*drug therapy , Pancreatic Neoplasms/*genetics, Blotting, Western ; Cell Proliferation/drug effects ; Deoxycytidine/administration & dosage ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Electrophoretic Mobility Shift Assay ; Humans ; MAP Kinase Signaling System/drug effects ; NF-kappa B/drug effects ; NF-kappa B/physiology ; Proto-Oncogene Proteins c-akt/drug effects ; Proto-Oncogene Proteins c-akt/physiology ; Tumor Cells, Cultured ; Gemcitabine

مستخلص: Introduction: Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-kappaB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies.
Materials and Methods: PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay.
Results: Each agent dose-dependently decreased proliferation. All cells decreased NF-kappaB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-kappaB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine.
Conclusions: These results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

المؤلفون: Schmidt CM; Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. maxschmi@iupui.edu, Yip-Schneider MT, Ralstin MC, Wentz S, DeWitt J, Sherman S, Howard TJ, McHenry L, Dutkevitch S, Goggins M, Nakeeb A, Lillemoe KD

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2008 Feb; Vol. 12 (2), pp. 243-9. Date of Electronic Publication: 2007 Nov 20.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1091-255X (Print) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Carcinoma, Pancreatic Ductal/*diagnosis , Carcinoma, Pancreatic Ductal/*metabolism , Carcinoma, Papillary/*diagnosis , Carcinoma, Papillary/*metabolism , Dinoprostone/*metabolism , Pancreatic Cyst/*metabolism , Pancreatic Neoplasms/*diagnosis , Pancreatic Neoplasms/*metabolism, Adenocarcinoma/diagnosis ; Adenocarcinoma/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Papillary/pathology ; Diagnosis, Differential ; Enzyme-Linked Immunosorbent Assay ; Humans

مستخلص: Current management of intraductal papillary mucinous neoplasm (IPMN) according to recently published International Consensus Guidelines depends upon distinguishing it from mucinous cystic neoplasms (MCNs). We have previously shown that prostaglandin E(2) (PGE(2)) is increased in pancreatic cancer tissue over normal controls. Thus, we hypothesized that PGE(2) level in pancreatic fluid differentiates IPMN and MCN and is a biomarker of IPMN dysplasia. Pancreatic fluid was collected in 65 patients at the time of endoscopy (EUS or ERCP) or operation (OR) and analyzed by PGE(2) enzyme-linked immunosorbent assay (ELISA). PGE(2) level was correlated with surgical pathologic diagnosis and dysplastic stage. Mean PGE(2) level (pg/microl) in IPMNs (2.2 +/- 0.6) was greater than in MCNs (0.2 +/- 0.1) (p < 0.05). Mean PGE(2) level of IPMN by dysplastic stage was 0.1 +/- 0.01 (low grade), 1.2 +/- 0.6 (medium grade), 4.4 +/- 0.9 (high grade), and 5.0 +/- 2.3 (invasive). Among invasive IPMN, PGE(2) level dropped in advanced cases with pancreatic ductal obstruction by tumor (0.3 +/- 0) vs non-obstructed (8.6 +/- 2.9). PGE(2) level may help in distinguishing IPMN from MCN in patients with known mucinous lesions. PGE(2) level may also be an indicator of malignant progression of IPMN before ductal obstruction by tumor. Prospective evaluation will be necessary to evaluate the clinical role of PGE(2) level in pancreatic fluid.

المؤلفون: Wentz SC; Department of Surgery, Indiana University School of Medicine, 1044 W Walnut St R4-039, Indianapolis, IN 46202, USA., Wu H, Yip-Schneider MT, Hennig M, Klein PJ, Sebolt-Leopold J, Schmidt CM

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2008 Jan; Vol. 12 (1), pp. 30-7. Date of Electronic Publication: 2007 Nov 07.

نوع المنشور: Comparative Study; Journal Article

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1091-255X (Print) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Benzamides/*therapeutic use , Carcinoma, Hepatocellular/*prevention & control , Chemoprevention/*methods , Diphenylamine/*analogs & derivatives , Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors , Liver Neoplasms, Experimental/*prevention & control , Transforming Growth Factor alpha/*metabolism, Alkylating Agents/toxicity ; Animals ; Apoptosis/drug effects ; Benzamides/administration & dosage ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation/drug effects ; Diethylnitrosamine/toxicity ; Diphenylamine/administration & dosage ; Diphenylamine/therapeutic use ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Follow-Up Studies ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Immunohistochemistry ; Ki-67 Antigen/metabolism ; Liver Neoplasms, Experimental/metabolism ; Liver Neoplasms, Experimental/pathology ; Mice ; Mice, Transgenic

مستخلص: Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p<0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p<0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

المؤلفون: Yip-Schneider MT; Departments of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA, Wiesenauer CA, Schmidt CM

المصدر: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [J Gastrointest Surg] 2003 Mar-Apr; Vol. 7 (3), pp. 354-63.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier B.V Country of Publication: United States NLM ID: 9706084 Publication Model: Print Cited Medium: Print ISSN: 1091-255X (Print) Linking ISSN: 1091255X NLM ISO Abbreviation: J Gastrointest Surg Subsets: MEDLINE

مواضيع طبية MeSH: Phosphoinositide-3 Kinase Inhibitors* , Protein Serine-Threonine Kinases*, Anti-Inflammatory Agents, Non-Steroidal/*pharmacology , Chromones/*pharmacology , Morpholines/*pharmacology , Pancreatic Neoplasms/*drug therapy , Signal Transduction/*drug effects , Sulindac/*pharmacology, Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Drug Combinations ; Flow Cytometry ; Humans ; Phosphorylation ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Sulindac/therapeutic use ; Tumor Cells, Cultured

مستخلص: Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 micromol/L) and/or LY294002 (1 to 100 micromol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 micromol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent assay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac.