Graham W. Donald

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. Cancer Prev Res; 6(10); 1064–73. ©2013 AACR.

Baicalein--an intriguing therapeutic phytochemical in pancreatic cancer.

Despite advances in therapy for many of the most common cancers, advances which have led to corresponding improvements in survival rates, progress on the pancreatic cancer front have been slow and mortality rates remain startlingly high. New therapeutic strategies are needed. Phytochemicals are naturally occurring, plant-based substances that have garnered much interest in the research world for their anti-cancer properties, both as therapeutics and as components of the diet for chemoprevention. One particularly ubiquitous group of phytochemicals is the polyphenolic flavonoids. Baicalein, one such flavonoid, which has been widely studied in several malignancies, shows potent activity against pancreatic adenocarcinoma in both in vitro and in vivo studies. The mechanisms by which baicalein accomplishes this have recently been elucidated, and is through an induction of apoptosis in pancreatic cancer cells that are fiercely resistant to cell death. Compounds such as baicalein, offer promise in dietary chemoprevention, as chemotherapeutic adjuvants, or as targeted therapy.

Locally Advanced Pancreatic Cancer: Association Between Prolonged Preoperative Treatment and Lymph-Node Negativity and Overall Survival

IMPORTANCE Treatment of patients with locally advanced/borderline resectable (LA/BR) pancreatic ductal adenocarcinoma (PDAC) is not standardized. OBJECTIVE To (1) perform a detailed survival analysis of our institutions experience with patients with LA/BR PDAC who were downstaged and underwent surgical resection and (2) identify prognostic biomarkers that may help to guide a decision for the use of adjuvant therapy in this patient subgroup. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of 49 consecutive patients from a single institution during 1992-2011 with American Joint Committee on Cancer stage III LA/BR PDAC who were initially unresectable, as determined by staging computed tomography and/or surgical exploration, and who were treated and then surgically resected. MAIN OUTCOMES AND MEASURES Clinicopathologic variables and prognostic biomarkers SMAD4, S100A2, and microRNA-21 were correlated with survival by univariate and multivariate Cox proportional hazard modeling. RESULTS All 49 patients were deemed initially unresectable owing to vascular involvement. After completing preoperative chemotherapy for a median of 7.1 months (range, 5.4-9.6 months), most (75.5%) underwent a pylorus-preserving Whipple operation; 3 patients (6.1%) had a vascular resection. Strikingly, 37 of 49 patients were lymph-node (LN) negative (75.5%) and 42 (85.7%) had negative margins; 45.8% of evaluable patients achieved a complete histopathologic (HP) response. The median overall survival (OS) was 40.1 months (range, 22.7-65.9 months). A univariate analysis of HP prognostic biomarkers revealed that perineural invasion (hazard ratio, 5.5; P=.007) and HP treatment response (hazard ratio, 9.0; P=.009) were most significant. Lymph-node involvement, as a marker of systemic disease, was also significant on univariate analysis (P=.05). Patients with no LN involvement had longer OS (44.4 vs 23.2 months, P=.04) than LN-positive patients. The candidate prognostic biomarkers, SMAD4 protein loss (P=.01) in tumor cells and microRNA-21 expression in the stroma (P=.05), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P=.004). CONCLUSIONS AND RELEVANCE Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.

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.

CXCR2: a target for pancreatic cancer treatment?

Introduction: Pancreatic cancer, a leading cause of cancer deaths worldwide, is very aggressive and has minimally effective treatment options. For those who have no surgical options, medical treatments are limited. The chemokine receptor CXCR2 has become the subject of much interest recently because of multiple studies indicating its involvement in cancer and inflammatory conditions. Research now indicates that CXCR2 and its ligands are intimately involved in tumor regulation and growth and that inhibition of its function shows promising results in multiple cancer types, including pancreatic cancer. Areas covered: In this study, the authors review basic molecular and structural details of CXCR2, as well as the known functions of CXCR2 and several of its ligands in inflammation and cancer biology with specific attention to pancreatic cancer. Then the future possibilities and questions remaining for pharmacological intervention against CXCR2 in pancreatic cancer are explored. Expert opinion: Many current inhibitory strategies already exist for targeting CXCR2 in vitro as well as in vivo. Clinically speaking, CXCR2 is an exciting potential target for pancreatic cancer; however, CXCR2 is functionally important for multiple processes and therapeutic options would benefit from further work toward understanding of these roles as well as structural and target specificity.

Endoscopic Transgastric Necrosectomy for Infected Necrotizing Pancreatitis

For decades, treatment of severe acute pancreatitis and pancreatic necrosis incorporated aggressive pancreatic debridement via an open necrosectomy.1 The indications for surgical intervention included confirmed or suspected nonviable pancreatic parenchyma, infection within that necrotic collection, or both. This approach often resulted in poor outcomes due to precipitation of a systemic inflammatory response with subsequent organ failure as a result of gross disturbance of an infected necrotic collection.2 In the 1990s, it became apparent that this approach was not required for most patients with sterile pancreatic necrosis.3 However, patients presenting to the hospital with infected pancreatic necrosis—as evidenced by a positive culture from a pancreatic aspirate or gas in the pancreatic phlegmon identified by CT scan—often were promptly taken to the operating room because of the perception that delay in operative intervention with drainage would result in an extremely high mortality rate. Despite advances in critical care, open necrosectomy has both substantial complication rates and mortality rates, in some series as high as 92% and 58%, respectively.4,5 However, the treatment of necrotizing pancreatitis is rapidly evolving. Numerous studies over the past decade have investigated less-invasive methods for addressing this highly fatal disease process and the less-than-satisfactory historical surgical management. These studies have evaluated procedures ranging from percutaneous drainage of infected necrotic collections, to video-assisted retroperitoneal debridement, to transgastric endoscopic drainage, and various combinations of these modalities. The general consensus is that similar and possibly reduced complication and mortality rates can be achieved by several means other than open necrosectomy. On the forefront of these efforts are authors from the Dutch Pancreatitis Study Group, who in this issue of JAMA report the results of the PENGUIN (Pancreatitis Endoscopic Transgastric vs Primary Necrosectomy in Patients with Infected Pancreatic Necrosis) trial.6 In 2010, this research group reported results of the PANTER (Pancreatitis, Necrosectomy vs Step up approach) trial, a randomized controlled study in which 88 patients with infected pancreatic necrosis were treated with either a “step-up” approach (consisting of percutaneous drainage followed by video-assisted retroperitoneal debridement if necessary) or open necrosectomy.7 Although there was no difference in overall mortality between patients in the 2 treatment groups, those in the step-up intervention group had significantly fewer complications, and more importantly, 35% of patients were adequately treated with percutaneous drainage alone. In their continued efforts to improve the operative management of patients with infected pancreatic necrosis, Bakker et al6 now report results of a well-designed randomized controlled trial comparing minimally invasive techniques against surgery in 22 patients with infected necrotizing pancreatitis. This trial demonstrates that, compared with surgical debridement, a less invasive approach of natural orifice transluminal endoscopic surgery (NOTES), using transoral endoscopic drainage of infected and necrotic pancreatic collections, significantly reduced the overall inflammatory state and also resulted in lower rates of new-onset multiorgan failure. The primary clinical end point for this trial was serum levels of IL-6, a surrogate for the overall inflammatory state.8 Although the difference in IL-6 levels between the NOTES group and the surgical group was statistically significant and scientifically compelling, IL-6 has limited utility as a clinical decision-making tool. A clinical composite outcome that included major complications and death also occurred less frequently among patients in the endoscopic group. This group also experienced a lower incidence of pancreatic fistula, which follows given the route of debridement in the 2 groups. The authors also report that 2 patients who were randomized to the endoscopic group subsequently underwent surgical necrosectomy. Because of the prespecified intention-to-treat approach, these patients remained in the endoscopic group in the primary analysis and essentially did not benefit from endoscopic treatment for infected pancreatic necrosis. Additional sensitivity analyses could have been conducted with inclusion of these patients in the surgery group or with eliminating these 2 patients from the analysis. Because of sample size and small numbers of outcome events, these analyses may have attenuated the differences in the composite clinical score, although it seems likely that a significant effect would have remained. The authors are appropriately circumspect in describing their findings as preliminary because the results may have been more robust if the trial recruitment period had been longer and more patients had been enrolled. The PANTER trial demonstrated the advantages of percutaneous drainage as the initial treatment in patients with infected pancreatic necrosis. This has become the standard surgical approach in many large centers. Data from the report by Rodriguez et al9 suggest that it may now be acceptable and preferred to perform drainage procedures earlier and, if possible, to delay more invasive interventions for at least a month. The trial results reported by Bakker et al6 imply that endoscopic drainage, even if performed relatively earlier, will lead to fewer complications and less morbidity than open or even video-assisted necrosectomy. Although similar findings have been reported in case series,10 larger trials with more robust clinical end points (such as ongoing trials in the Netherlands, ISRCTN09186711) are needed to clearly establish the utility of endoscopic drainage in patients with infected pancreatic necrosis.