Faculty Bibliography

BACKGROUND:The management of incidental pancreatic cysts is not well established because of lack of information on their natural history. International Consensus Guidelines advocate observation of asymptomatic patients with small lesions, despite limited data to support this approach. METHODS:To characterize clinical outcomes in a cohort of asymptomatic patients with incidental pancreatic cysts who underwent endoscopic ultrasound (EUS) evaluation+/-fine needle aspiration (FNA). RESULTS:Overall, 317 patients underwent EUS for evaluation of pancreatic cysts from 1995 to 2005. A total of 97/317 (31%) had asymptomatic, incidentally discovered pancreatic cysts; of 97 asymptomatic patients, 93 were contacted. Of these patients, 71/93 (76%) had lesions<3 cm and benign EUS features. All were followed without operative therapy. The mean follow-up was 44 months (range, 6-123). A total of 69/71 (97%) were alive and free of symptoms of pancreatic disease; 2 patients died of unrelated causes. Among these 71 patients with lesions<3 cm, FNA was performed in 33 patients and cytology was negative for malignant cells in all. Overall, 45/71 patients had either follow-up cross-sectional imaging or EUS. All of them had stable lesions. Surveillance studies were performed with a mean follow-up of 28 months (range, 4-120). The 22 patients with lesions >3 cm and/or concerning EUS features underwent resection. Pathologic analysis revealed that 2/22 patients had adenocarcinoma and that 60% had premalignant lesions. CONCLUSION/CONCLUSIONS:Endoscopic ultrasound is helpful in evaluation of patients with small incidental pancreatic cystic lesions. Asymptomatic cysts with benign radiographic and/or endosonographic features may safely be followed clinically and with serial imaging.

The immunogenic nature of cancer can be explored to distinguish pancreatic cancer from related non-cancer conditions. We describe a liquid-based microarray approach followed by statistical analysis and confirmation for discovery of auto-immune biomarkers for pancreatic cancer. Proteins from the Panc-1 pancreatic cancer cell line were fractionated using a 2-D liquid separation method into over 1052 fractions and spotted onto nitrocellulose coated glass slides. The slides were hybridized with 37 pancreatic cancer sera, 24 chronic pancreatitis sera and 23 normal sera to detect elevated levels of reactivity against the proteins in spotted fractions. The response data obtained from protein microarrays was first analyzed by Wilcoxon Rank-Sum Tests to generate two lists of fractions that positively responded to the cancer sera and showed p-values less than 0.02 in the pairwise comparison between cancer specimens and normal and chronic pancreatitis specimens. The top 3 fractions with the lowest correlations were combined in receiver operating characteristic analyses. The area-under-the-curve (AUC) values are 0.813 and 0.792 for cancer vs. normal and cancer vs. pancreatitis respectively. Outlier-Sum statistics were then applied to the microarray data to determine the existence of outliers exclusive in cancer sera. The selected fractions were identified by LC-MS/MS. We further confirmed the occurrence of outliers with three proteins among cancer samples in a confirmation experiment using a separate dataset of 165 serum samples containing 48 cancer sera and 117 non-cancer controls. Phosphoglycerate kinase 1 (PGK1) elicited greater reactivity in 20.9% (10 in 48) of the samples in the cancer group, while no outlier was present in the non-cancer groups.

While several aberrant signaling pathways have been attributed to the formation and progression of pancreatic cancer, there is mounting evidence for the increased role of the Hedgehog (Hh) pathway in multiple aspects of pancreatic tumor development. The Hh pathway is a signaling cascade that plays an important role in cell patterning of multiple tissues and organs, including the development of the gastrointestinal system. While normal pancreatic tissue exhibits little Hh pathway activity, patients with pancreatic adenocarcinoma show high levels of Hh pathway signaling in both the tumor epithelia and the surrounding mesenchyme. Several recent studies have focused on this paracrine activation of Hh signaling in the tumor microenvironment and have provided evidence for how activation of this pathway may play roles in mediating cellular proliferation, metastasis, and resistance to therapy. Together, these findings present new insights into how modulation of this pathway may allow us to target multiple aspects of pancreatic tumor biology.

PURPOSE/OBJECTIVE:To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. PATIENTS AND METHODS/METHODS:We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m(2) intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m(2) intravenously on Days 1 and 8 or capecitabine 1500 mg/m(2) orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m(2) orally in divided doses) day 1 to treatment completion. RESULTS:Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >or=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. CONCLUSIONS:A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

An empirical model was developed to interpret differences in the experimentally measured reflectance and fluorescence spectra of freshly excised human pancreatic tissues: normal, adenocarcinoma, and pancreatitis (inflammation). The model provided the first quantitative links between spectroscopic measurements and histological characteristics in the human pancreas. The reflectance model enabled the first (to our knowledge) extraction of wavelength resolved absorption and reduced scattering coefficients for normal and diseased human pancreatic tissues. The fluorescence model employed reflectance information to extract attenuation free "intrinsic" endogenous fluorescence spectra from normal pancreatic tissue, pancreatic adenocarcinoma, and pancreatitis. The method developed is simple, intuitive, and potentially useful for a range of applications in optical tissue diagnostics. This approach is potentially applicable to in vivo studies, because it can account for the absorptive effects of blood in tissues.

BACKGROUND & AIMS/OBJECTIVE:Cigarette smoking is an established risk factor for pancreatic cancer, but there is conflicting evidence regarding the effects of alcohol consumption. The effects of cigarettes and alcohol on age of sporadic pancreatic cancer diagnosis have not been examined; we evaluated the independent and synergistic effects of lifetime cigarette smoking and alcohol consumption on age at pancreatic cancer diagnosis in the United States. METHODS:We analyzed data on cigarette smoking and alcohol consumption from the IMPAC Services, Inc Cancer Information Resource File (CIRF), collected from June 1, 1993, to December 31, 2003, for 29,239 reported, histologically confirmed cases of pancreatic adenocarcinoma. We also analyzed data on cigarette smoking and alcohol consumption for 820 histologically confirmed cases of pancreatic adenocarcinoma from the University of Michigan Pancreatic Cancer Registry (UMPCR), collected from January 2004 to October 2007. RESULTS:Current cigarette smokers were diagnosed at significantly younger ages than never smokers, according to data from the CIRF and UMPCR (8.3 and 6.3 y, respectively); the UMPCR data indicated dose effects. Past and current alcohol consumption were associated with younger age at diagnosis in both databases. Current smokers who were current drinkers were diagnosed significantly earlier (CIRF, 10.2 y; UMPCR, 8.6 y) than abstainers. Past cigarette smoking was associated modestly with younger diagnosis age. CONCLUSIONS:Cigarette smoking and alcohol consumption were associated with younger age at pancreatic cancer presentation and have a combined effect on diagnosis age. Past cigarette smoking is less influential. Smoking cessation programs could help prevent pancreatic cancer.

Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1beta (IL-1beta), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.