Faculty Bibliography

BACKGROUND: A combination of biomarkers in a multivariate model may predict disease with greater accuracy than a single biomarker employed alone. We developed a non-linear method of multivariate analysis, weighted digital analysis (WDA), and evaluated its ability to predict lung cancer employing volatile biomarkers in the breath. METHODS: WDA generates a discriminant function to predict membership in disease vs no disease groups by determining weight, a cutoff value, and a sign for each predictor variable employed in the model. The weight of each predictor variable was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve minus a fixed offset of 0.55, where the AUC was obtained by employing that predictor variable alone, as the sole marker of disease. The sign (+/-) was used to invert the predictor variable if a lower value indicated a higher probability of disease. When employed to predict the presence of a disease in a particular patient, the discriminant function was determined as the sum of the weights of all predictor variables that exceeded their cutoff values. The algorithm that generates the discriminant function is deterministic because parameters are calculated from each individual predictor variable without any optimization or adjustment. We employed WDA to re-evaluate data from a recent study of breath biomarkers of lung cancer, comprising the volatile organic compounds (VOCs) in the alveolar breath of 193 subjects with primary lung cancer and 211 controls with a negative chest CT. RESULTS: The WDA discriminant function accurately identified patients with lung cancer in a model employing 30 breath VOCs (ROC curve AUC=0.90; sensitivity=84.5%, specificity=81.0%). These results were superior to multilinear regression analysis of the same data set (AUC=0.74, sensitivity=68.4, specificity=73.5%). WDA test accuracy did not vary appreciably with TNM (tumor, node, metastasis) stage of disease, and results were not affected by tobacco smoking (ROC curve AUC=0.92 in current smokers, 0.90 in former smokers). WDA was a robust predictor of lung cancer: random removal of 1/3 of the VOCs did not reduce the AUC of the ROC curve by >10% (99.7% CI). CONCLUSIONS: A test employing WDA of breath VOCs predicted lung cancer with accuracy similar to chest computed tomography. The algorithm identified dependencies that were not apparent with traditional linear methods. WDA appears to provide a useful new technique for non-linear multivariate analysis of data

PURPOSE OF REVIEW: Mesothelioma is an aggressive malignancy of the pleura with poor survival. There will be approximately 3000 cases of mesothelioma in the United States annually. Multimodality treatment including neoadjuvant chemotherapy in selected individuals followed by extrapleural pneumonectomy and radiation has been studied in recent trials for its effects on disease free and overall survival This review provides a general overview of malignant mesothelioma with a summary of the most significant articles from within the past year as well as from the past. RECENT FINDINGS: Areas of recent interest include the evaluation of osteopontin and mesothelin as new tumor markers for mesothelioma. New phase III trials have been performed to evaluate the use of combined chemotherapy regimens. SUMMARY: Malignant mesothelioma is a very difficult malignancy to treat. Patients with the disease usually have an occupational asbestos exposure, and in some, viral exposure with SV40. There have been many historical treatments including combinations of local control with surgery and radiation as well as attempts to prevent systemic failure with chemotherapy. Novel therapies including intrapleural chemotherapy, photodynamic therapy and hyperthermic perfusion have also been used with some success. Finally there are several attempts at immunomodulating and targeted treatments, which are in phase I/II trials

PURPOSE OF REVIEW: Simian virus 40 is present in some human malignant mesotheliomas. The evidence in favor and against a pathogenic role of simian virus 40 in malignant mesothelioma is discussed in this review. RECENT FINDINGS: When simian virus 40 is injected intracardially into hamsters, 60% develop and die of malignant mesothelioma. Moreover, some human malignant mesotheliomas contain and express simian virus 40 DNA and proteins. To date, over 50 laboratories have detected simian virus 40 in malignant mesotheliomas and in other tumors; however, the variability of the percentage of positivity led to a controversy about the role and significance of simian virus 40 in malignant mesotheliomas. Compared with other cell types, human mesothelial cells are unusually susceptible to simian virus 40-induced malignant transformation. The presence of simian virus 40 in malignant mesothelioma has been associated with the activation of specific oncogene pathways. Cocarcinogenesis between simian virus 40 and asbestos in causing malignant mesotheliomas has been demonstrated in three separate research laboratories using different experimental approaches. Epidemiological data possibly linking simian virus 40 and malignant mesothelioma is lacking owing to unattainable identification of infected from noninfected cohorts. SUMMARY: Available evidence appears sufficient to link simian virus 40 either alone or in conjunction with asbestos in causing malignant mesotheliomas; however, it is still insufficient to speculate about the contribution of simian virus 40 to the overall incidence of malignant mesotheliomas

Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase exerts antiproliferative and cytotoxic effects in vitro and in vivo and has been shown to act synergistically with different cancer therapeutic agents. The cytotoxic and cytostatic effects of ranpirnase are the consequence of tRNA degradation that results in the disruption of protein translation and the induction of programmed cell death (apoptosis). Ranpirnase has been shown to target malignant cells both in human cancer cell lines and in animal models, and has demonstrated efficacy in the treatment of several human cancers in clinical studies. Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs

BACKGROUND: Recent advances in genomics, proteomics, and the increasing demands for biomarker validation studies have catalyzed changes in the landscape of cancer research, fueling the development of tissue banks for translational research. A result of this transformation is the need for sufficient quantities of clinically annotated and well-characterized biospecimens to support the growing needs of the cancer research community. Clinical annotation allows samples to be better matched to the research question at hand and ensures that experimental results are better understood and can be verified. To facilitate and standardize such annotation in bio-repositories, we have combined three accepted and complementary sets of data standards: the College of American Pathologists (CAP) Cancer Checklists, the protocols recommended by the Association of Directors of Anatomic and Surgical Pathology (ADASP) for pathology data, and the North American Association of Central Cancer Registry (NAACCR) elements for epidemiology, therapy and follow-up data. Combining these approaches creates a set of International Standards Organization (ISO) - compliant Common Data Elements (CDEs) for the mesothelioma tissue banking initiative supported by the National Institute for Occupational Safety and Health (NIOSH) of the Center for Disease Control and Prevention (CDC). METHODS: The purpose of the project is to develop a core set of data elements for annotating mesothelioma specimens, following standards established by the CAP checklist, ADASP cancer protocols, and the NAACCR elements. We have associated these elements with modeling architecture to enhance both syntactic and semantic interoperability. The system has a Java-based multi-tiered architecture based on Unified Modeling Language (UML). RESULTS: Common Data Elements were developed using controlled vocabulary, ontology and semantic modeling methodology. The CDEs for each case are of different types: demographic, epidemiologic data, clinical history, pathology data including block level annotation, and follow-up data including treatment, recurrence and vital status. The end result of such an effort would eventually provide an increased sample set to the researchers, and makes the system interoperable between institutions. CONCLUSION: The CAP, ADASP and the NAACCR elements represent widely established data elements that are utilized in many cancer centers. Herein, we have shown these representations can be combined and formalized to create a core set of annotations for banked mesothelioma specimens. Because these data elements are collected as part of the normal workflow of a medical center, data sets developed on the basis of these elements can be easily implemented and maintained

OBJECTIVE: The optimal procedure for resection of malignant pleural mesothelioma is controversial, partly because previous analyses include small numbers of patients. We performed a multi-institutional study to increase statistical power to detect significant differences in outcome between extrapleural pneumonectomy and pleurectomy/decortication. METHODS: Patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at 3 institutions were identified. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis. RESULTS: From 1990 to 2006, 663 consecutive patients (538 men and 125 women) underwent resection. The median age was 63 years (range, 26-93 years). The operative mortality was 7% for extrapleural pneumonectomy (n = 27/385) and 4% for pleurectomy/decortication (n = 13/278). Significant survival differences were seen for American Joint Committee on Cancer stages 1 to 4 (P < .001), epithelioid versus non-epithelioid histology (P < .001), extrapleural pneumonectomy versus pleurectomy/decortication (P < .001), multimodality therapy versus surgery alone (P < .001), and gender (P < .001). Multivariate analysis demonstrated a hazard rate of 1.4 for extrapleural pneumonectomy (P < .001) controlling for stage, histology, gender, and multimodality therapy. CONCLUSION: Patients who underwent pleurectomy/decortication had a better survival than those who underwent extrapleural pneumonectomy; however, the reasons are multifactorial and subject to selection bias. At present, the choice of resection should be tailored to the extent of disease, patient comorbidities, and type of multimodality therapy planned

Malignant pleural mesothelioma (MPM) is a rare but lethal cancer associated with asbestos exposure. Worldwide, the incidence of MPM is expected to increase over the next 20 years. The molecular and genetic profiling of MPM tumors and patients, and improved understanding of the pathogenesis of MPM may lead to novel diagnostic, preventative and therapeutic strategies. Treatment options for MPM remain limited and no consensus exists at this time. Multimodality therapy that combines surgery, chemotherapy and radiation offers the best chance for long-term survival in select patients

The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In three of seven human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY290042. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1, whereas overexpression of Fra-1 blocked the expression of mitogen/extracellular signal-regulated kinase kinases (MEK)5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors

BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a potential marker for malignant pleural mesothelioma (MPM), which may be useful for screening high-risk asbestos-exposed individuals. METHODS: We evaluated SMRP in serum from MPM patients (n = 90), lung cancer patients (n = 170), age and tobacco-matched asbestos-exposed individuals (n = 66), and in MPM pleural effusions (n = 45), benign effusions (n = 30), and non-MPM effusions (n = 20) using the MesoMark enzyme-linked immunosorbent assay kit (Fujirebio Diagnostics, Malvern, PA). Receiver operating characteristic (ROC) curves were used to define true and false positive rates at various cutoffs. RESULTS: Mean serum SMRP levels were higher in MPM compared with lung cancer (5.67 +/- 0.82 nM [mean +/- standard error of the mean vs 1.99 +/- 0.43 nM, p < 0.001), and stage I MPM SMRP levels (n = 12; 2.09 +/- 0.41 nM) were significantly higher than those in asbestos-exposed individuals (0.99 +/- 0.09 nM, p = 0.02, respectively). Stage 2 to 4 SMRP serum levels were significantly higher than those for stage 1 MPM. The area under the ROC curve for serum SMRP was 0.81 for differentiating MPM and asbestos-exposed individuals; cutoff = 1.9 nM (sensitivity = 60%, specificity = 89%). The MPM pleural effusion SMRP was significantly higher than benign or other non-MPM pleural effusions (65.57 +/- 11.33 nM vs 27.46 +/- 11.25 nM [p = 0.003] and 18.99 +/- 7.48 nM [p = 0.044], respectively). CONCLUSIONS: These data support SMRP as a promising marker for MPM in both serum and pleural effusion fluid, and justify prospective screening studies of SMRP in combination with other markers for screening of asbestos-exposed cohorts