Faculty Bibliography

BACKGROUND: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. RESULTS: We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1beta, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. CONCLUSIONS: These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.

Background: The Radiation Therapy Oncology Group (RTOG) protocol 0618 was a phase II trial utilizing SBRT to treat early stage non-small cell lung cancer in operable patients (pts). Methods: All pts were deemed operable by a thoracic surgeon utilizing specific criteria. Pts with biopsy proven peripheral T1-T3, N0, M0 tumors were eligible. The prescription dose was 18 Gy X 3 fractions delivered in 1-2 weeks. The primary endpoint was 2-year primary tumor control (PTC, avoidance of in-field (INF) and marginal failure (MF)) with overall and progression free survival (OS, PFS), adverse events (AE), local (LF), regional (RF), and distant failure (DF) as secondary endpoints. Early surgical salvage was directed as part of protocol design in the event of LF after SBRT. Results: The study opened December 2007 and closed May 2010 after accruing a total of 33 pts. Of 26 evaluable pts, 23 had T1, and 3 had T2 tumors. Median age was 72 years. Median FEV1, DLCO at enrollment were 72%, 68% predicted, respectively. 4 pts (16%) had SBRT related grade 3 AEs while 0 had grade 4-5 AEs. Median follow-up was 25 months. 2 pts have been scored with INF (11.7 and 12.4 months post SBRT) and 1 with MF (32.5 months post SBRT) giving an estimated 2-year primary tumor failure rate of 7.7% (95% CI: 0.0%, 18.1%). 2-year estimates of LF (primary tumor plus involved lobe failure), RF, and DF are 19.2% (95% CI: 3.7%, 34.7%), 11.7% (95% CI: 0.0%, 24.5%), and 15.4% (95% CI: 1.2%, 29.6%), respectively. Only one patient was eligible for attempted surgical salvage and underwent lobectomy 1.2 years post SBRT complicated by a grade 4 cardiac arrhythmia. 2-year estimates of PFS and OS are 65.4% (95% CI: 44.0%, 80.3%) and 84.4% (95% CI: 63.7%, 93.9%), respectively. Conclusions: SBRT given appears to be associated with a high rate of PTC, moderate treatment related morbidity, and infrequent need for surgical salvage in operable early stage lung cancer pts with peripheral lesions. These results support ongoing enrollment into the ACOSOG Z40!

Background: Cytoreductive surgery for malignant pleural mesothelioma (MPM) should be reserved for patients with favorable tumor biology. Osteopontin (OPN) and the ratio of absolute neutrophil to absolute lymphocyte counts (NLR) have been reported as possible prognostic biomarkers. These were studied with other clinical/ laboratory variables in a mixed surgical/non-surgical MPM population to define independent predictors of survival (OS) and progression (TTP). Methods: Forty-four MPM patients (12 F, 32M; 26 cytoreduction, 18 no cytoreduction; 31 epithelial, 13 non-epithelial; 15 Stage I/II, 29 Stage III/IV) were examined with regard to pretreatment plasma OPN (ELISA, R&D, Minneapolis, MN), NLR age, gender, therapy, histology, stage, platelet count and WBC count. Cut points for age, OPN, NLR, platelets, and WBC were determined by X-tile Software (Yale, New Haven, CT) and univariate/multivariate Cox analyses performed. Results: Median OS were 11 m, 21m, and 8m for all 44 MPMs, cytoreduced and non-cytoreduced MPMs, respectively. Of platelet count, WBC, NLR, and OPN, only OPN was statistically significant between Stage I/II and Stage III/IV (80.3 ng/ml vs 148 ng/ml, p<0.018). The only independent covariate predictive of OS was plasma OPN. For TTP in cytoreduced patients, only age, stage, platelet count, and OPN were significant in univariate analysis, and multivariate modeling retained stage (p=0.04, HR=2.75, 95% CI=1.0517 to 7.1879) and OPN (p=0.0008, HR=17.471, 95% CI=3.3054 to 92.3461). Conclusions: Plasma OPN is promising for the stratification of tumors into good or bad risk categories and to help select potential candidates for cytoreduction and further postoperative therapy. (Table Presented)

OBJECTIVES: Integrin-linked kinase (ILK) is an intracellular protein implicated in chronic inflammation and neoplastic transformation. In a recently accomplished pilot study, we showed that ILK can be detected in the serum of patients with benign and malignant chest diseases, including malignant pleural mesothelioma (MPM). Interestingly, average serum ILK concentrations were 10 times higher in MPM patients when compared with the rest of the study population, and a diagnostic test solely based on serum ILK concentration could discriminate between MPM and non-MPM with considerable accuracy. This study aimed to investigate whether serum ILK concentration could also be used to discriminate between MPM and asbestos exposure only. METHODS: Using a self-developed sandwich enzyme-linked immunosorbent assay, we measured serum ILK concentrations in 101 MPM patients, and 96 asbestos-exposed, but healthy insulation workers. Seventy-three MPM patients had an epitheloid subtype (72.3%), and 42 had a Stage I or II disease (41.6%). RESULTS: When compared with asbestos-exposed individuals, MPM patients of all clinical stages had significantly higher (mean +/- standard deviation, median) serum ILK concentrations (10.7 +/- 13.6, median 7 ng/ml vs 3.1 +/- 4.6, median 1.4 ng/ml; P < 0.001). Among MPM patients, the serum ILK concentration was significantly higher at advanced disease stages III + IV than at early stages I + II (13.7 +/- 15.9, median 8.5 ng/ml vs 6.7 +/- 7.8, median 3.5 ng/ml; P = 0.02). Using serum ILK to discriminate between MPM patients and asbestos-exposed individuals yielded an area under the curve of 0.69 (95% confidence interval 0.63-0.76). The corresponding sensitivity and specificity for a cut-off of 4.49 ng/ml ILK are 61.4 and 80.2%, respectively. CONCLUSIONS: These data show significant differences between MPM patients and asbestos-exposed but healthy individuals concerning their serum ILK concentration. Furthermore, since ILK levels are increased in advanced MPM stages in comparison with early MPM stages, we suggest evaluating its potential use as a marker of disease progression in MPM.

The search for biomarkers in the management of lung cancer involves the use of multiple platforms to examine changes in gene, protein, and microRNA expression. Multiple studies have been published in an attempt to describe early detection, diagnostic, prognostic, and predictive biomarkers using chiefly tissues and blood elements. Studies are characterized by a lack of commonality of specific biomarkers, and a lack of validated, clinically useful markers. The future of biomarker discovery as a means of tailoring therapy for patients with lung cancer will involve next-generation sequencing along with collaborative efforts to integrate and validate candidate markers.

Treatment for locally advanced non-small cell lung cancer is complex. It may best be described as chemotherapy-based multimodality therapy, but there is little consensus on the optimal approach for local therapy. With the integration of the 7th edition of the staging system, the role for surgery in stage IIIB is limited to only biopsies and staging procedures. Surgery plays a more important role in stage IIIA disease, when the extent of mediastinal lymph node involvement is the principal factor dictating the benefit that can be derived from resection. In N2-negative, stage IIIA patients (T4N0, T3N1, T4N1), surgery is the primary therapy. These tend to be large and complex resections that include removal of neighboring involved structures. In the larger cohort of N2-positive, stage IIIA patients, surgery is reserved for those with occult or resectable N2 involvement and not used for bulky mediastinal disease. Significant controversy exists regarding which patients with potentially resectable N2 should receive surgery and how to best integrate a resection with chemotherapy and radiation.

Objective: Glycomics is an emerging area for understanding carcinogenesis; studies in glycobiology have documented that aberrant glycosylation accompanies malignant transformation. We have used glycomic profiling of serum using nano-liquid chromatography-mass spectrometry and using biostatistics we report glycomics patterns distinguishing between non-small cell lung cancer cases (NSCLC) versus healthy controls. Methods: First, we obtained pre-operative sera of non-small lung cancer cases (Stages I-II) and healthy controls from the NYU biorepository. The serum sample set consisted of 50 lung cancer (adenocarcinoma) patients, 50 healthy controls and 28 COPD patients, matched on gender, smoking status, pack/year for smokers, and as best as possible for age. The samples are analyzed by extracting the N-glycans in sera and measuring the relative concentrations using nano-liquid chromatography-mass spectrometry (nano-LC-MS). Bioinformatic analysis was performed to identify glycans that are differentially present in patients with cancer compared to COPD and healthy controls using feature selection and classification algorithms. We further investigated whether a combination of multiple glycans (i.e. multiplex classifier) could improve predictive performance over individual glycans. Results: Of 330 glycans detected in the NYU serum set, twenty glycans were significantly differentiating (either over- or under-expressed) between cancer, COPD and controls at a false discovery rate < 0.05. Of these glycan features, 11 were different between cancer samples and control samples, while 14 glycans differed significantly between cancer samples and COPD samples. COPD samples differed significantly from Control samples for only one glycan in concentration, indicating large similarity in the glycosylation pattern between COPD and controls. Based on the glycomic profiles, cancer cases were well separated from both control and COPD samples, while COPD and control samples were not discriminated well from each other. Th!