Faculty Bibliography

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.

Protein microarrays have been used to explore whether a humoral response to pancreatic cancer-specific tumor antigens has utility as a biomarker of pancreatic cancer. To determine if such arrays can be used to identify novel autoantibodies in the sera from pancreatic cancer patients, proteins from a pancreatic adenocarcinoma cell line (MIAPACA) were resolved by 2-D liquid-based separations, and then arrayed on nitrocellulose slides. The slides were probed with serum from a set of patients diagnosed with pancreatic cancer and compared with age- and sex-matched normal subjects. To account for patient-to-patient variability, we used a rank-based non-parametric statistical testing approach in which proteins eliciting significant differences in the humoral response in cancer compared with control samples were identified. The prediction analysis for microarrays classification algorithm was used to explore the classification power of the proteins found to be differentially expressed in cancer and control sera. The generalization error of the classification analysis was estimated using leave-one-out cross-validation. A serum diagnosis of pancreatic cancer in this set was predicted with 86.7% accuracy, with a sensitivity and specificity of 93.3 and 80%, respectively. Candidate autoantibody biomarkers identified using this approach were studied for their classification power by performing a humoral response experiment on recombinant proteins using an independent sample set of 238 serum samples. Phosphoglycerate kinase-1 and histone H4 were noted to elicit a significant differential humoral response in cancer sera compared with age- and sex-matched sera from normal patients and patients with chronic pancreatitis and diabetes. This work demonstrates the use of natural protein arrays to study the humoral response as a means to search for the potential markers of cancer in serum.

Pancreatic cancer continues to be a malignancy with few therapeutic options. The majority of patients that present for an evaluation have locally advanced or metastatic disease that is incurable by surgical approaches. Chemotherapy and radiotherapy resistance of pancreatic adenocarcinomas limits the efficacy of these therapeutic approaches. Recent evidence supports the existence of human pancreatic cancer stem cells, which appear to drive tumor initiation and progression and are particularly resistant to cell death induced by radiation or chemotherapy. Understanding the mechanisms of pancreatic cancer stem cell self-renewal and resistance to standard therapies may lead to new, more effective therapies to treat this dismal disease.

Activated T cells may express FOXP3. It is thought that FOXP3 is not a specific marker to determine regulatory T cells (Treg) in humans. Here, we examined the functional phenotype and cytokine profile of the in vitro induced FOXP3(+) T cells, primary FOXP3(+) and FOXP3(-) T cells in patients with ulcerative colitis and tumors including colon carcinoma, melanoma, hepatic carcinoma, ovarian carcinoma, pancreatic cancer, and renal cell carcinoma. We observed similar levels of suppressive capacity of primary FOXP3(+) T cells in blood, tumors, and colitic tissues. Compared with primary FOXP3(-) T cells in the same microenvironment, these primary FOXP3(+) T cells expressed minimal levels of effector cytokines, negligible amount of cytotoxic molecule granzyme B, and levels of suppressive molecules interleukin-10 and PD-1. Although the in vitro activated T cells expressed FOXP3, these induced FOXP3(+) T cells expressed high levels of multiple effector cytokines and were not functionally suppressive. The data reinforce the fact that FOXP3 remains an accurate marker to define primary Tregs in patients with cancer and autoimmune disease. We suggest that the combination of FOXP3 and cytokine profile is useful for further functionally distinguishing primary Tregs from activated conventional T cells.