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Inflammatory cytokines and non-small cell lung cancer in a CT-scan screening cohort: Background review of the literature

DeCotiis, Christopher; Hu, Yingjie; Greenberg, Alissa K; Huie, Maryann; Tsay, Jun-Chieh J; Pass, Harvey; Goldberg, Judith D; Rom, William N
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.
PMID: 26756613
ISSN: 1875-8592
CID: 1912582

Molecular characterization of the peripheral airway field of cancerization in lung adenocarcinoma

Tsay, Jun-Chieh J; Li, Zhiguo; Yie, Ting-An; Wu, Feng; Segal, Leopoldo; Greenberg, Alissa K; Leibert, Eric; Weiden, Michael D; Pass, Harvey; Munger, John; Statnikov, Alexander; Tchou-Wong, Kam-Meng; Rom, William N
Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets.
PMCID:4338284
PMID: 25705890
ISSN: 1932-6203
CID: 1473472

CT Findings Affects Smoking Behavior In Lung Cancer Screening Cohort [Meeting Abstract]

Tsay, J. J.; Eylers, E.; Greenberg, A. K.; Sherman, S. E.; Rom, W. N.
ISI:000209838200069
ISSN: 1073-449x
CID: 2960152

HYPONATREMIA IN HOSPITALIZED PATIENTS WITH CIRRHOSIS: INTERIM DATA FROM AN OBSERVATIONAL, PROSPECTIVE, MULTI-CENTER, GLOBAL HYPONATREMIA REGISTRY [Meeting Abstract]

Sigal, S.; Amin, A.; Chiong, J.; Dasta, J.; Greenberg, A.; Verbalis, J.; Chiodo, J.; Friend, K.
ISI:000322983000243
ISSN: 0168-8278
CID: 2972172

Aryl hydrocarbon receptor and lung cancer

Tsay, Junchieh J; Tchou-Wong, Kam-Meng; Greenberg, Alissa K; Pass, Harvey; Rom, William N
The leading cause of lung cancer is exposure to cigarette smoke and other environmental pollutants, which include formaldehyde, acrolein, benzene, dioxin, and polycyclic aromatic hydrocarbons (PAHs). PAHs and dioxins are exogenous ligands that directly bind to the aryl hydrocarbon receptor (AhR), a transcription factor that activates xenobiotic metabolism, histone modification (an important step in DNA methylation) and, ultimately, tumorigenesis. In this review article we summarize the current understanding of AhR and its role in the development of lung cancer, including its influence on cell proliferation, angiogenesis, inflammation, and apoptosis.
PMCID:3771678
PMID: 23564762
ISSN: 0250-7005
CID: 287292

Cigarette smoke induces methylation of the tumor suppressor gene NISCH

Ostrow, Kimberly; Michailidi, Christina; Guerrero-Preston, Rafael; Greenberg, Alissa; Rom, William; Sidransky, David; Hoque, Mohammad
We have previously identified a putative tumor suppressor gene, NISCH, whose promoter is methylated in lung tumor tissue as well as in plasma obtained from lung cancer patients. NISCH was observed to be more frequently methylated in smoker lung cancer patients than in non-smoker lung cancer patients. Here, we investigated the effect of tobacco smoke exposure on methylation of the NISCH gene. We tested methylation of NISCH after oral keratinocytes were exposed to mainstream and side stream cigarette smoke extract in culture. Methylation of the promoter region of the NISCH gene was also evaluated in plasma obtained from lifetime non-smokers and light smokers (< 20 pack/year), with and without lung tumors, and heavy smokers (20+ pack/year) without disease. Promoter methylation of NISCH was tested by quantitative fluorogenic real-time PCR in all samples. Promoter methylation of NISCH occurred after exposure to mainstream tobacco smoke as well as to side stream tobacco smoke in normal oral keratinocyte cell lines. NISCH methylation was also detected in 68% of high-risk, heavy smokers without detectable tumors. Interestingly, in light smokers, NISCH methylation was present in 69% of patients with lung cancer and absent in those without disease. Our pilot study indicates that tobacco smoke induces methylation changes in the NISCH gene promoter before any detectable cancer. Methylation of the NISCH gene was also found in lung cancer patients' plasma samples. After confirming these findings in longitudinally collected plasma samples from high-risk populations (such as heavy smokers), examining patients for hypermethylation of the NISCH gene may aid in identifying those who should undergo additional screening for lung cancer.
PMCID:3674047
PMID: 23503203
ISSN: 1559-2294
CID: 302852

Chemoprevention of lung cancer: prospects and disappointments in human clinical trials

Greenberg, Alissa K; Tsay, Jun-Chieh; Tchou-Wong, Kam-Meng; Jorgensen, Anna; Rom, William N
Decreasing the risk of lung cancer, or preventing its development in high-risk individuals, would have a huge impact on public health. The most effective means to decrease lung cancer incidence is to eliminate exposure to carcinogens. However, with recent advances in the understanding of pulmonary carcinogenesis and the identification of intermediate biomarkers, the prospects for the field of chemoprevention research have improved dramatically. Here we review the most recent research in lung cancer chemoprevention-focusing on those agents that have been investigated in human clinical trials. These agents fall into three major categories. First, oxidative stress plays an important role in pulmonary carcinogenesis; and therefore, antioxidants (including vitamins, selenium, green tea extracts, and isothiocyanates) may be particularly effective in preventing the development of lung cancer. Second, inflammation is increasingly accepted as a crucial factor in carcinogenesis, and many investigators have focused on anti-inflammatory agents, such as glucocorticoids, NSAIDs, statins, and PPARgamma agonists. Finally, the PI3K/AKT/mTOR pathway is recognized to play a central role in tobacco-induced carcinogenesis, and inhibitors of this pathway, including myoinositol and metformin, are promising agents for lung cancer prevention. Successful chemoprevention will likely require targeting of multiple pathways to carcinogenesis-both to minimize toxicity and maximize efficacy.
PMCID:3730305
PMID: 24216701
ISSN: 2072-6694
CID: 626982

Current readings: blood-based biomarkers for lung cancer

Tsay, Jun-Chieh J; Decotiis, Christopher; Greenberg, Alissa K; Rom, William N
Lung cancer is the leading cause of cancer deaths worldwide largely owing to diagnosis of the disease at an advanced stage. Recent advances in blood-based biomarker research have the potential to reduce mortality by providing a means for detecting lung cancer at an earlier stage. Since the publication of the National Lung Cancer Screening Trial demonstrating reduction in mortality with computed tomography (CT) scan screening, the U.S. Preventive Services Task Force has released a draft statement recommending annual low-dose CT scan screening for high-risk patients. However, CT screening has a high false-positive rate leading to the need for additional imaging and invasive procedures. In this article, we review recent literature on blood-based lung cancer biomarkers that we believe will have a significant role in enhancing screening efficacy in the near future.
PMCID:3969813
PMID: 24673963
ISSN: 1043-0679
CID: 865632

Bronchial brushings' microRNA and field cancerization in lung adenocarcinoma [Meeting Abstract]

Tsay, J J; Tchou-Wong, K; Yie, T; Leibert, E; Segal, L N; Greenberg, A; Pass, H; Rom, W N
Rationale: Cigarette smoke causes a field of injury and molecular changes in the airways even in histologically normal areas termed "field cancerization" which describes the site(s) of neoplasia and adjacent normal tissue with molecular abnormalities in common. MicroRNAs ( miRNAs) are small, non-coding RNAs that act as post-transcriptional regulators of gene expression by recognizing target sites in the 3' untranslated regions (3'UTRs) via incomplete base-pairing and induce mRNA degradation or translational repression. Deregulation of miRNAs has been linked to cancer initiation and progression, and miRNAs may act as tumor suppressor genes or oncogenes. We hypothesized that miRNA expression in the peripheral airways of smokers with lung cancer is distinct from that of smokers without lung cancer and therefore, miRNAs can be used as biomarkers for the early detection of lung cancer. Methods: We collected human peripheral airway epithelial cells by bronchoscopic brushing from the unaffected lung of thirteen smokers with lung adenocarcinoma and twelve control smokers. Total RNA was extracted from the peripheral airway epithelial cells by miRNAeasy and miRNA profiling was performed using the TaqMan Quantitative qRT-PCR miRNA Assay. Results: Comparison of miRNA levels in peripheral airway epithelial cells from smokers with or without lung cancer demonstrated 53 miRNAs that were significantly different (p<0.05) between the two groups. The majority of miRNAs were up-regulated (41 miRNAs) in lung cancer patients, including miR-21, miR-26a, miR-31, miR-34c, and miR-205. Down-regulated miRNAs included let-7b, let-7e, and miR-126. Several of the miRNAs with increased expression are of interest: miR-21 inhibits tumor suppressor protein PTEN, miR-26a suppresses PTEN and increases AKT phosphorylation and nuclear factor kappaB (NFkappaB) activation, miR-31 represses tumor suppressor genes LATS2 and PPP2R2A, miR-205 is associated with cancer relapses, and miR-34c, a p53 target induced by DNA damage, suggests the involvement of p53 pathway in field carcinogenesis. Down-regulated let-7b leads to higher expression of CYP2J2 and decreased miR-126 enhances adhesion, migration and invasion through increased Crk protein. Further gene expression and pathway analyses will corroborate the relationship between miRNAs and predicted pathways in real time. Conclusion: We discovered a profile of miRNAs in the contralateral lung of patients with lung cancer as biomarkers of field cancerization in smokers with lung adenocarcinoma. Further knowledge of field cancerization may lead to better understanding of tumorigenesis and development of biomarkers for early lung cancer detection
EMBASE:71984243
ISSN: 1073-449x
CID: 1769082

Pulmonary Nodules: growth rate assessment in patients by using serial CT and three-dimensional volumetry

Ko, Jane P; Berman, Erika J; Kaur, Manmeen; Babb, James S; Bomsztyk, Elan; Greenberg, Alissa K; Naidich, David P; Rusinek, Henry
PURPOSE: To determine the precision of a three-dimensional (3D) method for measuring the growth rate of solid and subsolid nodules and its ability to detect abnormal growth rates. MATERIALS AND METHODS: This study was approved by the Institutional Research Board and was HIPAA compliant. Informed consent was waived. The growth rates of 123 lung nodules in 59 patients who had undergone lung cancer screening computed tomography (CT) were measured by using a 3D semiautomated computer-assisted volume method. Clinical stability was established with long-term CT follow-up (mean, 6.4 years+/-1.9 [standard deviation]; range, 2.0-8.5 years). A mean of 4.1 CT examinations per patient+/-1.2 (range, two to seven CT examinations per patient) was analyzed during 2.4 years+/-0.5 after baseline CT. Nodule morphology, attenuation, and location were characterized. The analysis of standard deviation of growth rate in relation to time between scans yielded a normative model for detecting abnormal growth. RESULTS: Growth rate precision increased with greater time between scans. Overall estimate for standard deviation of growth rate, on the basis of 939 growth rate determinations in clinically stable nodules, was 36.5% per year. Peripheral location (P=.01; 37.1% per year vs 25.6% per year) and adjacency to pleural surface (P=.05; 38.9% per year vs 34.0% per year) significantly increased standard deviation of growth rate. All eight malignant nodules had an abnormally high growth rate detected. By using 3D volumetry, growth rate-based diagnosis of malignancy was made at a mean of 183 days+/-158, compared with radiologic or clinical diagnosis at 344 days+/-284. CONCLUSION: A normative model derived from the variability of growth rates of nodules that were stable for an average of 6.4 years may enable identification of lung cancer.
PMCID:3267080
PMID: 22156993
ISSN: 0033-8419
CID: 159309