Cataloging formal medical student surgical funding opportunities: A retrospective characterization.

Representation of female surgical residents has slowly increased, but underrepresented in medicine (URiM) representation remains disappointingly low. National residency matching reports suggest that meaningful research experience improves surgical residency match success - therefore, formal funding opportunities and early mentorship for URiM medical students. In this study, we catalog medical student (MS) funding opportunities (funding type, eligibility by year, mission, compensation, length of commitment, number of awardees, and dollar investment amount per student) from 7 surgical departments (general surgery, thoracic surgery, vascular surgery, plastic surgery, otorhinolaryngology, orthopedic surgery, neurosurgery) within 196 US medical schools and 20 professional surgical educational organizations through manually searching web pages. We recorded 146 surgical funding opportunities from medical school surgical departments and 16 surgical funding opportunities from professional organizations. Overall, we find that medical institutions' surgical departments and professional surgical educational organizations may not be effectively utilizing recruitment strategies in MS funding opportunities.

Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.

Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.

Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar-to-Ductal Metaplasia of Pancreatic Cells.

BACKGROUND AND AIMS: Animal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation. METHODS: The efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area. RESULTS: Lipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice. CONCLUSION: Our data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.

A Prognostic Scoring System for the Prediction of Metastatic Recurrence Following Curative Resection of Pancreatic Neuroendocrine Tumors.

BACKGROUND: Patients with early-stage pancreatic neuroendocrine tumors (PNETs) may develop metastatic recurrences despite undergoing potentially curative pancreas resections. We sought to identify factors predictive of metastatic recurrences and develop a prognostication strategy to predict recurrence-free survival (RFS) in resected PNETs. METHODS: Patients with localized PNETs undergoing surgical resection between 1989 and 2015 were identified. Univariate and multivariate analysis were used to identify potential predictors of post-resection metastasis. A score-based prognostication system was devised using the identified factors. The bootstrap model validation methodology was utilized to estimate the external validity of the proposed prognostication strategy. RESULTS: Of the 140 patients with completely resected early-stage PNETs, overall 5- and 10-year RFS were 84.6% and 67.1%, respectively. The median follow-up was 56 months. Multivariate analysis identified tumor size > 5 cm, Ki-67 index 8-20%, lymph node involvement, and high histologic grade (G3, or Ki-67 > 20%) as independent predictors of post-resection metastatic recurrence. A scoring system based on these factors stratified patients into three prognostic categories with distinct 5-year RFS: 96.9%, 54.8%, and 33.3% (P < 0.0001). The bootstrap model validation methodology projected our proposed prognostication strategy to retain a high predictive accuracy even when applied in an external dataset (validated c-index of 0.81). CONCLUSIONS: The combination of tumor size, LN status, grade, and Ki-67 was identified as the most highly predictive indicators of metastatic recurrences in resected PNETs. The proposed prognostication strategy may help stratify patients for adjuvant therapies, enhanced surveillance protocols and future clinical trials.

Factors associated with general surgery residents' desire to leave residency programs: a multi-institutional study.

IMPORTANCE: General surgical residency continues to experience attrition. To date, work hour amendments have not changed the annual rate of attrition. OBJECTIVE: To determine how often categorical general surgery residents seriously consider leaving residency. DESIGN, SETTING, AND PARTICIPANTS: At 13 residency programs, an anonymous survey of 371 categorical general surgery residents and 10-year attrition rates for each program. Responses from those who seriously considered leaving surgical residency were compared with those who did not. MAIN OUTCOMES AND MEASURES: Factors associated with the desire to leave residency. RESULTS: The survey response rate was 77.6%. Overall, 58.0% seriously considered leaving training. The most frequent reasons for wanting to leave were sleep deprivation on a specific rotation (50.0%), an undesirable future lifestyle (47.0%), and excessive work hours on a specific rotation (41.4%). Factors most often cited that kept residents from leaving were support from family or significant others (65.0%), support from other residents (63.5%), and perception of being better rested (58.9%). On univariate analysis, older age, female sex, postgraduate year, training in a university program, the presence of a faculty mentor, and lack of Alpha Omega Alpha status were associated with serious thoughts of leaving surgical residency. On multivariate analysis, only female sex was significantly associated with serious thoughts of leaving residency (odds ratio, 1.2; 95% CI, 1.1-1.3; P = .003). Eighty-six respondents were from historically high-attrition programs, and 202 respondents were from historically low-attrition programs (27.8% vs 8.4% 10-year attrition rate, P = .04). Residents from high-attrition programs were more likely to seriously consider leaving residency (odds ratio, 1.8; 95% CI, 1.0-3.0; P = .03). CONCLUSIONS AND RELEVANCE: A majority of categorical general surgery residents seriously consider leaving residency. Female residents are more likely to consider leaving. Thoughts of leaving seem to be associated with work conditions on specific rotations rather than with overall work hours and are more prevalent among programs with historically high attrition rates.

Nonfunctional pancreatic neuroendocrine tumors <2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival.

BACKGROUND: The optimal surgical management of small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial. We sought to identify (1) clinicopathologic factors associated with survival in NF-PNETs and (2) preoperative tumor characteristics that can be used to determine which lesions require resection and lymph node (LN) harvest. METHODS: The records of all 116 patients who underwent resection for NF-PNETs between 1989 and 2012 were reviewed retrospectively. Preoperative factors, operative data, pathology, surgical morbidity, and survival were analyzed. RESULTS: The overall 5- and 10-year survival rates were 83.9 and 72.8 %, respectively. Negative LNs (p = 0.005), G1 or G2 histology (p = 0.033), and age <60 years (p = 0.002) correlated with better survival on multivariate analysis. The 10-year survival rate was 86.6 % for LN-negative patients (n = 73) and 34.1 % for LN-positive patients (n = 32). Tumor size ≥2 cm on preoperative imaging predicted nodal positivity with a sensitivity of 93.8 %. Positive LNs were found in 38.5 % of tumors ≥2 cm compared to only 7.4 % of tumors <2 cm. CONCLUSIONS: LN status, a marker of systemic disease, was a highly significant predictor of survival in this series. Tumor size on preoperative imaging was predictive of nodal disease. Thus, it is reasonable to consider parenchyma-sparing resection or even close observation for NF-PNETs <2 cm.

Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells.

Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be an intriguing therapeutic strategy in PaCa.

High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model.

There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, for example, weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a high-fat, high-calorie diet (HFCD; ∼4,535 kcal/kg; 40% of calories from fats) or control diet (∼3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared with control animals, mice fed with the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor I (IGF-I). The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results show that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemopreventive strategies targeting obesity-associated pancreatic cancer development.

Perioperative antibiotics for surgical site infection in pancreaticoduodenectomy: does the SCIP-approved regimen provide adequate coverage?

INTRODUCTION: The Joint Commission Surgical Care Improvement Project (SCIP) includes performance measures aimed at reducing surgical site infections (SSI). One measure defines approved perioperative antibiotics for general operative procedures. However, there may be a subset of procedures not adequately covered with the use of approved antibiotics. We hypothesized that piperacillin-tazobactam is a more appropriate perioperative antibiotic for pancreaticoduodenectomy (PD). METHODS: In collaboration with hospital epidemiology and the Division of Infectious Diseases, we retrospectively reviewed records of 34 patients undergoing PD between March and May 2008 who received SCIP-approved perioperative antibiotics and calculated the SSI rate. After changing our perioperative antibiotic to piperacillin-tazobactam, we prospectively reviewed PDs performed between June 2008 and March 2009 and compared the SSI rates before and after the change. RESULTS: For 34 patients from March through May 2008, the SSI rate for PD was 32.4 per 100 cases. Common organisms from wound cultures were Enterobacter and Enterococcus (50.0% and 41.7%, respectively), and these were cefoxitin resistant. From June 2008 through March 2009, 106 PDs were performed. During this period, the SSI rate was 6.6 per 100 surgeries, 80% lower than during March through May 2008 (relative risk, 0.204; 95% confidence interval [CI], 0.086-0.485; P = .0004). CONCLUSION: Use of piperacillin-tazobactam as a perioperative antibiotic in PD may reduce SSI compared with the use of SCIP-approved antibiotics. Continued evaluation of SCIP performance measures in relationship to patient outcomes is integral to sustained quality improvement.

The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo.

OBJECTIVES: The flavonoid quercetin holds promise as an antitumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown. METHODS: The antiproliferative effects of quercetin alone or in combination with gemcitabine were tested in 2 human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet. RESULTS: Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared with quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation. CONCLUSIONS: Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells.

Scutellaria baicalensis (SB) and SB-derived polyphenols possess anti-proliferative activities in several cancers, including pancreatic cancer (PaCa). However, the precise molecular mechanisms have not been fully defined. SB extract and SB-derived polyphenols (wogonin, baicalin, and baicalein) were used to determine their anti-proliferative mechanisms. Baicalein significantly inhibited the proliferation of PaCa cell lines in a dose-dependent manner, whereas wogonin and baicalin exhibited a much less robust effect. Treatment with baicalein induced apoptosis with release of cytochrome c from mitochondria, and activation of caspase-3 and -7 and PARP. The general caspase inhibitor zVAD-fmk reversed baicalein-induced apoptosis, indicating a caspase-dependent mechanism. Baicalein decreased expression of Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, presumably through a transcriptional mechanism. Genetic knockdown of Mcl-1 resulted in marked induction of apoptosis. The effect of baicalein on apoptosis was significantly attenuated by Mcl-1 over-expression, suggesting a critical role of Mcl-1 in this process. Our results provide evidence that baicalein induces apoptosis in pancreatic cancer cells through down-regulation of the anti-apoptotic Mcl-1 protein.

Invasive intraductal papillary mucinous neoplasm versus sporadic pancreatic adenocarcinoma: a stage-matched comparison of outcomes.

BACKGROUND: Although invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas is thought to be more indolent than sporadic pancreatic adenocarcinoma (PAC), the natural history remains poorly defined. The authors compared survival and identify prognostic factors after resection for invasive IPMN versus stage-matched PAC. METHODS: The Surveillance, Epidemiology, and End Results database (1991-2005) was used to identify 729 patients with invasive IPMN and 8082 patients with PAC who underwent surgical resection. RESULTS: Patients with resected invasive IPMN experienced improved overall survival when compared with resected PAC (median survival, 21 vs 14 months; P<.001). Stratification by nodal status demonstrated no difference in survival among lymph node-positive patients; however, median survival of resected, lymph node-negative, invasive IPMN was significantly improved compared with lymph node-negative PAC (34 vs 18 months; P<.001). On multivariate analysis, PAC histology was an adverse predictor of overall survival (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.50) compared with invasive IPMN. For patients with invasive IPMN, positive lymph nodes (HR, 1.98; 95% CI, 1.50-2.60), high tumor grade (HR, 1.74; 95% CI, 1.31-2.31), tumor size>2 cm (HR, 1.50; 95% CI, 1.04-2.19), and age>66 years (HR, 1.33; 95% CI, 1.03-1.73) were adverse predictors of survival. CONCLUSIONS: Although lymph node-negative invasive IPMN showed improved survival after resection compared with lymph node-negative PAC, the natural history of lymph node-positive invasive IPMN mimicked that of lymph node-positive PAC. The authors also identified adverse predictors of survival in invasive IPMN to guide discussions regarding use of adjuvant therapies and prognosis after resection of invasive IPMN.

Impact of tumor grade on prognosis in pancreatic cancer: should we include grade in AJCC staging?

BACKGROUND: AJCC staging of pancreatic cancer (PAC) is used to determine prognosis, yet survival within each stage shows wide variation and remains unpredictable. We hypothesized that tumor grade might be responsible for some of this variation and that the addition of grade to current AJCC staging would provide improved prognostication. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1991-2005) was used to identify 8082 patients with resected PAC. The impact of grade on overall and stage-specific survival was assessed using Cox regression analysis. Variables in the model were age, sex, tumor size, lymph node status, and tumor grade. RESULTS: For each AJCC stage, survival was significantly worse for high-grade versus low-grade tumors. On multivariate analysis, high tumor grade was an independent predictor of survival for the entire cohort (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.31-1.48) as well as for stage I (HR 1.28, 95% CI 1.07-1.54), stage IIA (HR 1.43, 95% CI 1.26-1.61), stage IIB (HR 1.38, 95% CI 1.27-1.50), stage III (HR 1.28, 95% CI 1.02-1.59), and stage IV (HR 1.58, 95% CI 1.21-2.05) patients. The addition of grade to staging results in a statistically significant survival discrimination between all stages. CONCLUSIONS: Tumor grade is an important prognostic variable of survival in PAC. We propose a novel staging system incorporating grade into current AJCC staging for pancreas cancer. The improved prognostication is more reflective of tumor biology and may impact therapy decisions and stratification of future clinical trials.

Pancreatic surgery.

PURPOSE OF REVIEW: Surgery of the pancreas is evolving as the understanding of pancreatic disease improves. This report reviews the work published over the last year related to pancreatic surgery and the diseases addressed by surgical techniques. RECENT FINDINGS: Obesity is an important risk factor for many diseases of the pancreas, including pancreatic adenocarcinoma. Recent evidence suggests that obese patients with pancreatic cancer appear to have more advanced disease at the time of diagnosis and a worse outcome following resection. The issues surrounding adjuvant treatment for pancreatic cancer with chemotherapy and/or radiation therapy continue to be evaluated. Cystic lesions of the pancreas remain a vexing treatment dilemma, but as we learn more about their natural history, more thoughtful recommendations for management become possible. Resection of pancreatic endocrine neoplasms is often appropriate, even in the face of metastatic disease. Minimally invasive approaches to the drainage of infected pancreatic necrosis are beginning to gain acceptance. The pain of chronic pancreatitis may be lessened by operative intervention and possibly radiation. SUMMARY: Each year more is learned about the natural history of pancreatic lesion. For those dedicated to the study and treatment of this gland, several new advances help the clinician with treatment decisions.

Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer.

Angioinvasion is critical for metastasis with urokinase-type plasminogen activator receptor (uPAR) and tumor hypoxia-activated hypoxia-inducible factor 1 (HIF-1) as key players. Transcriptional control of uPAR expression by HIF has never been reported. The aim of the present study, therefore, was to test whether tumor hypoxia-induced HIF expression may be linked to transcriptional activation of uPAR and dependent angioinvasion. We used human pancreatic cancer cells and a model of parental and derived HIF-1beta-deficient mouse liver cancer cell lines and performed Northern blot analysis, nuclear runoff assays, electrophoretic mobility shift assay, polymerase chain reaction-generated deletion mutants, luciferase assays, Matrigel invasion assays, and in vivo angioinvasion assays in the chorioallantoic membrane of fertilized chicken eggs. Urokinase-type plasminogen activator receptor promoter analysis resulted in four putative HIF binding sites. Hypoxia strongly induced de novo transcription of uPAR mRNA. With sequential deletion mutants of the uPAR promoter, it was possible to identify one HIF binding site causing a nearly 200-fold increase in luciferase activity. Hypoxia enhanced the number of invading tumor cells in vitro and in vivo. In contrast, HIF-1beta-deficient cells failed to upregulate uPAR expression, to activate luciferase activity, and to invade on hypoxia. Taken together, we show for the first time that uPAR is under transcriptional control of HIF and that this is important for hypoxia-induced metastasis.

Utilization of parenteral nutrition following pancreaticoduodenectomy: is routine jejunostomy tube placement warranted?

INTRODUCTION: Complications following pancreaticoduodenectomy (PD) often necessitate nutritional support. This study analyzes the utilization of parenteral nutrition (TPN) during the surgical admission as evidence for or against routine jejunostomy placement. METHODS: The California Cancer Registry (1994-2003) was linked to the California Inpatient File; PD for adenocarcinoma was performed in 1,873 patients. TPN use and enterostomy tube placement were determined and preoperative characteristics predictive of TPN use during the surgical admission were identified. RESULTS: Fourteen percent of patients received TPN, 23% underwent enterostomy tube placement, and 63% received no supplemental nutritional support. TPN was associated with longer hospital stay (18 vs. 13 days, P < 0.0001). The Charlson Comorbidity Index (CCI) > or = 3 had nearly two-fold greater odds of receiving TPN (odds ratio [OR] = 1.85, P < 0.005). CONCLUSION: Approximately 1 in 6 patients undergoing PD received TPN, which was associated with prolonged hospital stay. CCI > or = 3 was associated with increased odds of TPN utilization. Selected jejunostomy placement in patients with high CCI is worthy of consideration.

Evaluation of the guidelines for management of pancreatic branch-duct intraductal papillary mucinous neoplasm.

BACKGROUND & AIMS: The 2006 Sendai Consensus Guidelines recommend surgical resection for all suspected branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) greater than 3 cm irrespective of symptoms, and those less than 3 cm with worrisome features. We aimed to evaluate the surgical characteristics of these guidelines retrospectively in pathologically confirmed cases of BD-IPMN. METHODS: IPMNs resected at our institution (1995-2006) were classified as main-duct predominant or branch-duct (BD) predominant based on preoperative imaging and postoperative histology. Resected BD-IPMNs were classified histologically: low risk (adenoma, borderline) and high risk (carcinoma in situ or invasive cancer). Clinical data (presence of symptoms, mural nodule, dilated pancreatic duct, and cyst size) were correlated with pathology. RESULTS: Between 1995 and 2006, there were 204 patients who underwent surgical resection of pancreatic cysts. Sixty-one patients had IPMN including 31 with BD-IPMN. A total of 74.2% (23 of 31) of BD-IPMNs would have been recommended for surgical resection including 69.2% (18 of 26) of low-risk lesions and 100% (5 of 5) of high-risk lesions. All 8 cases of BD-IPMN that would have been recommended for nonsurgical management were low-risk lesions. The positive predictive value of the guidelines is 21.7% (95% confidence interval, 9.7%-41.9%). The negative predictive value is 100% (95% confidence interval, 67.6%-100.0%). Between 2000 and 2007, 351 patients with likely BD-IPMN were evaluated but not resected. CONCLUSIONS: Implementation of the Consensus Guidelines to our single-institution, referral-based, surgical BD-IPMN population would have recommended resection of all histologically high-risk lesions. All lesions recommended for nonsurgical management were histologically low-risk lesions. For presumed BD-IPMNs less than 3 cm, the application of the Consensus Guidelines may reduce the resection rate for low-risk lesions.

Expression analysis of the prostaglandin E2 production pathway in human pancreatic cancers.

OBJECTIVES: There is strong evidence for an important role of cyclooxygenase (COX) 2 and COX-2-generated PGE2 during pancreatic tumorigenesis. Cyclooxygenase 2 has therefore become a potential chemotherapeutic target for pancreatic cancer. However, recent studies raised concerns regarding the safety of selective COX-2 inhibitors. Although the benefits of COX-2 inhibition may eventually outweigh the associated cardiovascular risks, there are a number of alternative targets for inhibiting the formation of PGE2 in human tumors that may prove less harmful to the patient. This study aimed at analyzing the expression of various proteins involved in the generation of PGE2 in human pancreatic cancers. METHODS AND RESULTS: Real-time polymerase chain reaction and Western blot analyses demonstrated overexpression of cytoplasmic phospholipase A2, COX-2, cytoplasmic prostaglandin E synthase, and microsomal prostaglandin E synthases 1 and 2 in most human pancreatic cancers when compared with matched normal pancreas. Immunohistochemistry revealed expression of these proteins predominantly by pancreatic cancer cells. Variable expression of these proteins was also confirmed in several human pancreatic cancer cell lines. CONCLUSIONS: Our studies demonstrated for the first time that various proteins involved in the generation of PGE2 are overexpressed in human pancreatic cancers. These proteins may represent potentially novel targets for the therapy of pancreatic cancers.

Mononuclear cell-derived interleukin-1 beta confers chemoresistance in pancreatic cancer cells by upregulation of cyclooxygenase-2.

BACKGROUND: Pancreatic cancer is a very aggressive malignancy and efficient therapeutic options are still largely lacking. The importance of interactions between tumor cells and surrounding stromal elements, eg, mononuclear cells, for chemoresistance have been increasingly recognized. In addition, cyclooxygenase-2 is thought to be an important mediator of chemoresistance in several malignancies. The aim of this study was to explore the role of mononuclear cells in pancreatic cancer chemoresistance. METHODS: Human histiocytic lymphoma U937 cells were differentiated into macrophage-like cells. The effect of U937-conditioned medium on drug-induced pancreatic cancer cell apoptosis was measured by enzyme-linked immunosorbent assay. The contributions of interleukin-1beta and cyclooxygenase-2 were evaluated by specific receptor antagonists and inhibitors. The importance of the extracellular signal-regulated kinase (ERK1/2) pathway also was determined. RESULTS: U937-conditioned culture medium protected pancreatic cancer cells from drug-induced apoptosis. This protective effect was abolished by an interleukin-1 receptor antagonist and cyclooxygenase-2 inhibitor. U937-conditioned medium and interleukin-1beta stimulated expression of cyclooxygenase-2 and prostaglandin E(2) production in pancreatic cancer cells, which was mediated by activation of the ERK1/2 pathway. Transfection of pancreatic cancer cells with cyclooxygenase-2 increased resistance to drug-induced cell death. CONCLUSIONS: Mononuclear cells protect pancreatic cancer cells from drug-induced apoptosis in vitro by interleukin-1beta-mediated expression of cyclooxygenase-2 and production of prostaglandins. This study highlights the importance of tumor-host interactions in pancreatic cancers and may provide the basis for novel therapeutic approaches to sensitize pancreatic cancers to chemotherapeutic agents.