Faculty Bibliography

INTRODUCTION: Surgery is the treatment of choice for early-stage lung cancer (LC). Although lobectomy (L) is the historic standard treatment, the issue of whether long-term outcomes of sublobar resection (SL) are comparable is still under debate. The objective of this study was to perform a review of the literature on 5-year survival rates after SL compared to L for patients with early-stage LC. METHODS: A priori inclusion criteria were as follows: (1) observational studies, (2) L compared to SL for early-stage LC, (3) radiographic staging by computed tomography scan, and (4) 5-year survival reported. A Medline search through January 2015 resulted in 31 studies representing 23 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study. RESULTS: L was performed in 4564 patients and SL in 2287 patients. Of 19 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities or impaired cardiopulmonary function. Four studies showed no difference in 5-year survival, 13 favored L, and six favored SL. One propensity score study favored L and the other favored SL. Of 20 studies reporting recurrence rate, 11 favored L and nine favored SL. CONCLUSIONS: Studies comparing 5-year survival rates of SL to L are sufficiently heterogeneous to prevent carrying out traditional meta-analysis. SL survival is often similar to L when adjustments are made for age, comorbidities, or impaired cardiopulmonary function. New approaches are needed for the comparison of L to SL.

BACKGROUND: While low dose computed tomography (LDCT) screening for lung cancer is recommended for high-risk smokers, ages 55-74 years, information about asbestos exposure may not be routinely elicited. Asbestos exposure is associated with declining respiratory function over time; however, the effect of a history of asbestos exposure in LDCT screening cohorts is limited. We report the relationship between asbestos exposure and pulmonary function in a cohort of heavy smokers with a history of occupational asbestos exposure, hypothesizing that these subjects will have additional decreased pulmonary function. We also examined relationships between spirometric measurements and the presence of isolated pleural plaques. METHODS: A cross-sectional study was performed using data from the NYU Lung Cancer Biomarker Center cohort to compare study subjects with a history asbestos exposure primarily in the period since 1970 when tighter federal standards were in place (n = 359) to those without asbestos exposure (n = 1038) with respect to pulmonary function, LDCT lung imaging findings, and clinical symptoms. We further classified individuals with asbestos exposure by length of exposure time to examine the effect of duration of exposure on pulmonary function. Lastly, for asbestos-exposed participants, we examined the association of spirometric measurements with the presence of absence of isolated pleural plaques. RESULTS: Individuals with asbestos exposure had decreased FVC % predicted compared to those with no asbestos exposure (76% vs. 85% predicted, P < 0.01) and FEV1 % predicted (64% vs. 67% predicted, P < 0.01). Since there was no change in FEV1 /FVC ratio, the findings are consistent with restrictive impairment. Those with >/=20 years of exposure had a lower mean FVC % predicted compared to those with less than 20 years of exposure (74% vs. 78% predicted, P = 0.017). Individuals with asbestos exposure were more likely to have pleural plaques (P < 0.001) on CT. Those with isolated pleural plaques had lower mean % predicted FEV1 (P = 0.005) and FVC (P = 0.001) compared to those without pleural plaques. CONCLUSIONS: Occupational asbestos exposure in a cohort of heavy smokers was associated with a significant restrictive decline in pulmonary function, with longer duration of exposure associated with greater decline. The presence of isolated pleural plaques was also associated with reduced lung function. Am. J. Ind. Med. 9999:1-8, 2016. (c) 2016 Wiley Periodicals, Inc.

INTRODUCTION: The reduction in lung cancer mortality associated with computed tomography (CT) screening has led to its increased use and a concomitant increase in the detection of benign pulmonary nodules. Many individuals found to have benign nodules undergo unnecessary, costly, and invasive procedures. Therefore, there is a need for companion diagnostics that stratify individuals with pulmonary nodules into high-risk or low-risk groups. Lung cancers can trigger host immune responses and elicit antibodies against tumor antigens. The identification of these autoantibodies (AAbs) and their corresponding antigens may expand our knowledge of cancer immunity, leading to early diagnosis or even benefiting immunotherapy. Previous studies were performed mostly in the context of comparing cancers and healthy (smoker) controls. We have performed one of the first studies to understand humoral immune response in patients with cancer, patients with benign nodules, and healthy smokers. METHODS: We first profiled seroreactivity to 10,000 full-length human proteins in 40 patients with early-stage lung cancer and 40 smoker controls by using nucleic acid programmable protein arrays to identify candidate cancer-specific AAbs. Enzyme-linked immunosorbent assays of promising candidates were performed on 137 patients with lung cancer and 127 smoker controls, as well as on 170 subjects with benign pulmonary nodules. RESULTS: From protein microarray screening experiments using a discovery set of 40 patients and 40 smoker controls, 17 antigens showing higher reactivity in lung cancer cases relative to the controls were subsequently selected for evaluation in a large sample set (n = 264) by using enzyme-linked immunosorbent assay. A five-AAb classifier (tetratricopeptide repeat domain 14 [TTC14], B-Raf proto-oncogene, serine/threonine kinase [BRAF], actin like 6B [ACTL6B], MORC family CW-type zinc finger 2 [MORC2], and cancer/testis antigen 1B [CTAG1B]) that can differentiate lung cancers from smoker controls with a sensitivity of 30% at 89% specificity was developed. We further tested AAb responses in subjects with CT-positive benign nodules (n = 170), and developed a five-AAb panel (keratin 8, type II, TTC14, Kruppel-like factor 8, BRAF, and tousled like kinase 1) with a sensitivity of 30% at 88% specificity. Interestingly, messenger RNA levels of six AAb targets (TTC14, BRAF, MORC family CW-type zinc finger 2, cancer/testis antigen 1B, keratin 8, type II, and tousled like kinase 1) were also found to increase in lung adenocarcinoma tissues based on The Cancer Genome Atlas data set. CONCLUSION: We discovered AAbs associated with lung adenocaricnoma that have the potential to differentiate cancer from CT-positive benign diseases. We believe that these antibodies warrant future validation using a larger sample set and/or longitudinal samples individually or as a panel. They could potentially be part of companion molecular diagnostic modalities that will benefit subjects undergoing CT screening for lung cancer.

Isolated lung perfusion (ILP) is a surgical technique developed to treat pulmonary metastases. During ILP, high-dose chemotherapy is delivered into the pulmonary vasculature, minimizing systemic exposure and delivering the chemotherapeutic agent directly to the lung. ILP has been studied extensively in a variety of animal models and in humans in phase I trials. The most frequently studied chemotherapeutic agents used in ILP are doxorubicin, 5-flurodeoxyuridine, tumor necrosis factor-alpha, paclitaxel, melphalan, gemcitabine, and cisplatin. Phase I clinical trials with ILP have shown that ILP can be safely performed in humans but with mixed clinical results and poor long-term survival.

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. There is an urgent need to identify new therapies for treating MPM patients. The notion of "addicted" receptor tyrosine kinase (RTK) signalling networks, and RTK inhibitors are emerging as areas of considerable importance in cancer therapy. We and others have identified c-MET, RON, Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate targets. Several agents have been developed which target these. BMS-777607/ASLAN002 or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, RON, Axl and Tyro3 at nanomolar concentrations while LCRF0004 specifically targets RON. These drugs may therefore have applicability in the treatment/management of MPM. Methods: A panel of MPM cell lines and encompassing normal pleural cell lines were screened for expression of Tyro3, c-MET, RON and Axl by RT-PCR, and subsequently examined in a cohort of patient samples comprising benign, epithelial, biphasic, and sarcomatoid histologies. The effects of small molecule inhibitors LCRF0004 and BMS-777607/ASLAN002 on MPM cellular health were assessed both in vitro and in vivo. The effects of BMS-777607/ASLAN002 conjugated to a novel nanodiamond delivery system have also been examined on cell lines. Results: Expression of various RON isoforms, c-MET, Tyro3 and Axl were observed in all cell lines. Significantly higher expression of all genes were found in the malignant tumour material versus benign pleura. Both LCRF0004 and BMS-777607/ASLAN002 show significant anti-tumour efficacy both in vitro and in vivo. Nanodiamond conjugates of BMS-777607/ASLAN002 have greater anti-proliferative efficacy over BMS-777607/ASLAN002 alone. Conclusion: Our results suggest that targeting the RON/MET/TAM signalling pathway may be an effective therapeutic strategy for the treatment of MPM

BACKGROUND: Inflammatory cytokines are at the intersection of tumor cell biology and host immune response. Peripheral cytokine expression levels may reflect the microscopic tumor milieu, and specific cytokines play an integral role in tumor initiation, growth, and metastasis. High-throughput cytokine analysis may identify panels for early-stage non-small cell lung cancer (NSCLC) diagnosis and identify individuals at high-risk for lung cancer with indeterminate lung nodules 8-20 mm in size. METHODS: Thirteen serum cytokines from the NYU Lung Cancer Biomarker Center cohort with early-stage NSCLC were analyzed using bead-based immunoassay technology. RESULTS: In the NYU cohort, a one unit increase in interferon-gamma increased risk of lung cancer by 3% (OR = 1.03, 95% CI, 1.02-1.05) and a one unit increase in TNF-alpha decreased the risk of lung cancer by 53% (OR = 0.47, 95% Cl, 0.31-0.71) when both cytokines were included in a logistic regression model with adjustments for age and pack-years of smoking. The resulting AUC for the Receiver Operating Characteristic (ROC) curve was 0.88; the sensitivity and specificity at the optimal cutpoint were 78.9% and 90.3%, respectively. CONCLUSIONS: Cytokines have limited value in the early diagnosis of early-stage NSCLC. Our review of the literature suggests that although inflammation is important for the development of NSCLC, that cytokines are increased in more advanced lung cancer than when the diagnosis occurs at presentation.

BACKGROUND: Lung cancer is the leading cause of cancer mortality in the United States. Non-small cell lung cancer accounts for 85% of all lung cancers for which adenocarcinoma is the most common histological type. Management of lung cancer is hindered by high false-positive rates due to difficulty resolving between benign and malignant tumors. Better molecular analysis comparing malignant and non-malignant tissues will provide important evidence of the underlying biology contributing to tumorigenesis. METHODS: We utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the adenocarcinoma proteome. Identified proteins were subsequently assessed against clinicopathological variables. RESULTS: Top cancer-associated protein alterations were characterized by: (1) elevations in APEX1, HYOU1 and PDIA4, indicative of increased DNA repair machinery and heightened anti-oxidant defense mechanisms; (2) increased LRPPRC, STOML2, COPG1 and EPRS, suggesting altered tumor metabolism and inflammation; (3) reductions in SPTB, SPTA1 and ANK1 implying dysregulation of membrane integrity; and (4) decreased SLCA41 suggesting altered pH regulation. Increased protein levels of HYOU1, EPRS and LASP1 in NSCLC adenocarcinoma was independently validated by tissue microarray immunohistochemistry. Immunohistochemistry for HYOU1 and EPRS indicated AUCs of 0.952 and 0.841, respectively, for classifying tissue as malignant. Increased LASP1 correlated with poor overall survival (HR 3.66 per unit increase; CI 1.37-9.78; p = 0.01). CONCLUSION: These results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets.