Patrick B. White

Intraductal papillary mucinous neoplasms: Predictors of malignant and invasive pathology

Objective:Determine whether size and other preoperative parameters predict malignant or invasive intraductal papillary mucinous neoplasia (IPMN). Summary Background Data:From 1991 to 2006, 150 patients underwent 156 operations for IPMN. Methods:Prospectively collected, retrospective review of a single academic institutions experience. All preoperative parameters including a detailed radiologic-based classification of IPMN type, location, distribution, size, number, cytology, and mural nodularity were correlated with IPMN pathology. Results:Malignant IPMN was present in 32% of cases, whereas 19% of cases were invasive. IPMN type and main pancreatic duct diameter were significant predictors of malignant IPMN (P < 0.001). Side-branch lesion number was negatively associated with invasive IPMN (P = 0.03). Side-branch size, location, and distribution did not predict IPMN pathology. The presence of mural nodules was associated with malignant and invasive IPMN (P < 0.001; P < 0.02). Atypical cytopathology was significantly associated with malignant and invasive IPMN (P < 0.001; P < 0.001). Multivariate analysis demonstrated mural nodularity and atypical cytopathology were predictive of malignancy and/or invasion in branch-type IPMN. Conclusions:To lower the rate of invasive pathology, surgery should be recommended for fit patients with main-duct IPMN and for branch-duct IPMN with mural nodularity or positive cytology irrespective of location, distribution, or size.

CT vs MRCP: optimal classification of IPMN type and extent.

IntroductionIntraductal papillary mucinous neoplasms (IPMNs) of the pancreas are being diagnosed with increased frequency. CT scanning commonly serves as the primary imaging modality before surgery. We hypothesized MRCP provides better characterization of IPMN type/extent, which more closely matches actual pathology.MethodsOf 214 patients treated with IPMN (1991–2006), 30 had both preoperative CT and MRCP. Of these, 18 met imaging study criteria. Independent readers performed retrospective, blinded analyses using standardized criteria for IPMN type and extent.ResultsA ductal connection was detected on 73% of MRCP scans and only 18% of CT. IPMN type was classified differently in seven (39%); four (22%) of which were read on CT as having main duct involvement where this was not appreciated on MRCP or found on surgical pathology. MRCP showed multifocal disease in 13(72%) versus only 9(50%) on CT. A different disease distribution was seen in 9(50%). Finally, 101 branch lesions were identified on MRCP compared to 46 on CT.ConclusionsCT falls short of MRCP in detecting a ductal connection, estimating main duct involvement, and identification of small branch duct cysts. These factors influence diagnostic accuracy, cancer risk stratification and operative strategy. MRCP should be employed for optimal management of patients with IPMN.

Pancreatic Cancer in Obesity: Epidemiology, Clinical Observations, and Basic Mechanisms

Obesity, now a worldwide epidemic, causes myriad medical problems. One of the most significant obesity-related problems is the well-recognized relationship between obesity and various malignancies, including pancreatic cancer. Pancreatic cancer is a devastating disease--the annual death rate nearly approximates its incidence. While surgical extirpation provides the best chance at long term survival, systemic therapy is largely ineffective: even those patients undergoing successful operative resection have only approximately 20% 5-year survival. These poor outcomes are largely a consequence of poor understanding of tumor biology. Clearly, identification of novel treatment strategies is of paramount importance; investigation of pancreatic cancer biology from the novel aspect of obesity offers the potential to identify unique therapeutic targets. This manuscript reviews the epidemiology, clinical findings, and putative basic science mechanisms underlying obesity-related pancreatic cancer.

An unusual case of late gastrointestinal bleeding after pancreatoduodenectomy

With more widespread application of and improved outcomes from pancreatoduodenectomy, late complications of this procedure are appearing more commonly in the clinical setting. Presented here is an unusual case of hemobilia secondary to cavernous portal vein transformation one year following pylorus-sparing pancreatoduodenectomy. Common and unusual causes of gastrointestinal bleeding following pancreatoduodenectomy are discussed.

Abstract 510: Do adipocytes in the tumor microenvironment influence the growth of pancreatic cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: Pancreatic cancer develops more frequently and progresses more rapidly in obesity. The mechanisms influencing this association are incompletely understood. Using our murine model of pancreatic cancer in diet-induced obesity, we hypothesized that changes in the immune profile and tumor microenvironment may contribute to accelerated pancreatic cancer growth in obesity. Methods: Thirty male C57BL/6J mice were studied. At 5 weeks of age, 20 mice were fed high fat diet (60% fat; HFD) and 10 were fed low fat (10% fat) diet. At 19 weeks of age all mice were inoculated in the flank with 2.5 x105 Pan02 murine pancreatic cancer cells. After 5 weeks of tumor growth, spleens and tumors were collected, splenic flow cytometry evaluated lymphocyte population, proliferation was determined by PCNA staining, and tumor infiltrating lymphocytes (TIL), both B and T, were scored by immunohistochemistry. Intratumoral adipocyte volume was assessed by H&E staining. Studentss t-test and Pearsons correlation were applied where appropriate. P value <0.05 was accepted as statistically significant. Results: Mice were segregated into overweight (OW – heavier than the mean body weight of the HFD mice – 35.5g, n=15) and lean (<35.5g, n=14). OW mice were significantly heavier (37.3±0.2g vs. 33.9±0.3g, p<0.001). Tumors were twice as large in OW mice as in lean mice (1.23±0.2g vs. 0.6±0.1g; p=0.001). The peripheral lymphocyte profile was similar in both OW and lean animals (T cells: 51.2±2.5% vs. 49.2±2.3%, p=0.59; B cells: 32.9±1.0% vs. 32.0±1.9%, p=0.73). TIL were observed in similar numbers in both OW and lean groups (T cell: 1.31±0.18 vs. 1.54±0.16, p=0.35; B cell: 0.63±0.08 vs. 0.91±0.15, p=0.33). Tumor proliferation as measured by PCNA was similar in both groups (139±18 OW vs. 143±14 lean, p=0.85). Interestingly, adipocyte volume was significantly greater in the OW tumor microenvironment than in the lean tumors (3.7%±0.7 vs. 2.2%±0.3, p<0.05). Conclusions: These results demonstrate that: 1) tumor weight was significantly greater in OW mice; 2) peripheral and tumor infiltrating lymphocyte profile was similar in OW and lean animals; and 3) adipocyte volume was significantly greater in the tumor microenvironment of OW mice. We conclude that obesity accelerates the growth of pancreatic cancer, and adipocytes in the tumor microenvironment may directly influence tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 510. doi:10.1158/1538-7445.AM2011-510

Abstract 466: Does body weight influence tumor-infiltrating B cells in murine pancreatic cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: We have developed a murine model of pancreatic cancer in congenitally obese (LepOb and LepDb) mice where tumors grow larger, metastasize, and decrease survival. Obese mice also had altered splenic T and B cells as well as downregulation of B cell and immunoglobulin genes and reduced numbers of B cells in the tumors. The question remained, however, whether alterations in tumor-infiltrating lymphocytes were a reflection of body weight or leptin metabolism. Therefore, we designed an experiment to determine whether diet-induced weight gain would alter systemic and tumor-infiltrating lymphocytes. Methods: Thirty lean C57 female mice were fed either a control 10% fat (n=10) or a 60% fat diet (n=20) starting at 6 weeks of age. At 11 weeks, all mice were inoculated with 2.5x105 PAN02 murine pancreatic cancer cells. After 6 weeks tumors that developed in 18 mice, the spleen (n=12), and the sera were harvested. Mice were categorized as Lean or Overweight if they weighed less or more than the mean final weight of the 60% fat animals (23.1g). Tumors in Lean (n=10) and Overweight (n=8) mice were sectioned and stained for B and T cells. Two observers blinded to animal weight graded cell density on a scale of 0-4 in 10 high-powered fields. Flow cytometry was performed on the spleen from Lean and Overweight mice for B, T, activated T and B (ACT), natural killer (NK) cells, and macrophages (MACRO). Serum leptin was measured. ANOVA and Students t-test were applied. Results: Tumors were larger (1.33 vs. 0.54g, p=0.03) and leptin levels were higher (3.1 vs. 1.4ng/ml, p=0.05) in Overweight mice. Mean tumor-infiltrating lymphocyte (TIL) scores and spleen lymphocyte data are presented in the table. Conclusion: The data suggest that 1) both B and T cells are present in the pancreatic cancer microenvironment and 2) TIL and splenic lymphocyte populations do not differ between lean and overweight mice. We conclude that obesity, as opposed to overweight, is required to alter systemic and tumor microenvironment lymphocyte populations. View this table: Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 466.