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mp3 file (49.6MB). Patients with recurrent metastatic non-small cell lung cancer have a morbid prognosis, but a new epigenetic therapy may have potential for this population. Cancer Discovery Editors-in-Chief Jose Baselga, M.D., Ph.D. and Lewis C. Cantley, Ph.D. moderated a press conference about this research on Wednesday, Nov. 9, 2011.

CCR Translation for This Article from Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer

PDF file - 2177KB, Scatter Plots of Gene Re-expression with Decitabine or Trichostatin-A in Eight Non-Small Cell Lung Cancer Cell Lines.

PDF file - 287KB, DNA Methylation of CDO1, HOXA9, and TAC1 is Highly Sensitive for Stage I NSCLC in the Cancer Genome Atlas.

Supplementary Tables S1-S4 from Promoter Hypermethylation of Hallmark Cancer Genes in Atypical Adenomatous Hyperplasia of the Lung

Purpose: Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis.Experimental Design: Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival.Results: CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan–Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR.Conclusions: Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development. Clin Cancer Res; 18(17); 4743–52. ©2012 AACR.

PDF file - 399KB, Kaplan-Meier Survival Curves for Non-Small Cell Lung Cancer for p16 methylation in combination with APC, RASSF1, or CDH13.

Purpose: Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer.Experimental Design: Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples.Results: We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort.Conclusion: This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC. Clin Cancer Res; 20(7); 1856–64. ©2014 AACR.

PDF file, 545K, Kaplan-Meier survival estimates of time-to-recurrence in 99 patients with duodenal adenocarcinomas by (A) age, (B) stage, (C) differentiation, and (D) chemotherapy and/or radiotherapy.

Purpose: According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis.Experimental Design: We evaluated AAHs, adjacent normal lung tissue, and synchronous lung adenocarcinomas for promoter hypermethylation of genes implicated in lung tumorigenesis (p16, TIMP3, DAPK, MGMT, RARβ, RASSF1A, and hTERT).Results: For individual genes and the number of genes methylated, we observed a significant increase in the frequency of promoter hypermethylation in the histologic progression from normal to AAH, with low-grade or high-grade atypia, and finally to adenocarcinoma (Ptrend ≤ 0.01). Multifocal AAHs from individual patients had distinct patterns of promoter hypermethylation, suggesting divergent epigenetic field defects. There were statistically significant positive associations for the presence of promoter hypermethylation of individual and multiple genes with advanced histology, with odds ratios between 4.3 and 58.5. p16 conveyed the strongest individual association for promoter hypermethylation when comparing tumor or high-grade AAH to low-grade AAH or normal tissue, with an odds ratio of 45.5 (95% confidence interval, 5.8-360.5).Conclusion: This study shows epigenetic progression in the earliest stages of glandular neoplasia of the lung and has implications for early lung cancer detection.

PDF file - 100KB, DNA Methylation of CDO1, HOXA9, and TAC1 is Highly Sensitive for Stage I NSCLC in the Cancer Genome Atlas.

PDF file, 113K, Supplementary Figure Legend; Supplementary Table S1. List of primers used for methylation-specific PCR; S 2. List of KRAS mutations in patients with duodenal Adenocarcinomas; S3. Five year and 10 year cumulative proportion of overall survival and time-to-recurrence for different molecular groups; S4. Univariate and multivariate Cox proportional hazard analysis of overall survival and time-to-recurrence for CIMP, MLH1 methylation or MSI status.

Purpose: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.Experimental Design: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model.Results: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37–4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07–5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16–34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04–4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00–5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05–1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03–16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109).Conclusions: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer. Clin Cancer Res; 17(6); 1535–45. ©2011 AACR.

PDF file, 428K, Kaplan-Meier survival estimates of overall survival in 99 patients with duodenal adenocarcinomas by (A) age, (B) stage, and (C) MSI status.

PDF file, 342K, Distributions of MSI, CIMP and MLH1 methylation in 99 patients with duodenal adenocarcinomas.

XLSX file - 25KB, List of Infinium 450K Methylation Probes from Figure 1.

PDF file, 382K, Summary of promoter hypermethylation frequency in CIMP− and CIMP+ duodenal adenocarcinomas as detected by methylation-specific PCR. Black and gray boxes indicate the presence or absence of hypermethylation, respectively.

Supplementary Figures S1-S3; Supplementary Tables S1-S6.

PDF file - 108KB

Supplementary Table 1 from Hypermethylation of ASC/TMS1 Is a Sputum Marker for Late-Stage Lung Cancer

DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancer-free smokers, 15% (3 of 18) of patients with stage I non–small-cell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancer-free individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease. (Cancer Res 2006; 66(12): 6210-8)

Background National costs of lung cancer care exceed $12 billion. We investigate the resource-savings benefit of a single-day thoracic oncology multidisciplinary clinic (MDC) in the diagnostic period prior to non–small-cell lung cancer (NSCLC) treatment. Materials and Methods From July 2007 to January 2015, patients with NSCLC treated with multimodality therapy at a tertiary hospital-based cancer center in Maryland were identified. Patient and treatment details were collected. Health care resources utilized in the 90 days prior to receipt of first oncologic treatment were identified using billed activity codes. Associated total charges, including professional fees and hospital-based technical fees, were identified and inflated to 2014 dollars using the Consumer Price Index. Codes were categorized into provider visits, procedures, pathology/laboratory, radiology, and other tests. χ2, Student t, and Wilcoxon rank-sum tests compared charges of patients seen in and out of the MDC. Results Two-hundred ninety-seven (non-MDC = 161, 54%; MDC = 136, 46%) of 308 patients identified had total charges available. Patients seen through MDC had on average a 23% decrease in total charges per patient incurred ($5839 savings; range, $5213-$6464) compared with patients seen through non-MDC settings. Evaluation through MDC reduced the average number of provider visits per patient (non-MDC, 6.8 vs. MDC, 4.8; P Conclusions Evaluation of patients with NSCLC through a coordinated single-day MDC reduced hospital charges per patient by 23% during the diagnostic period prior to treatment when compared with evaluation through traditional referral-based thoracic oncology clinics.

OBJECTIVES: The tendency for patients with primary focal hyperhidrosis (PFH), characterized by excessive sweating, to experience psycho-social deficits is well documented. In addition, although endoscopic thoracic sympathectomy (ETS) effectively corrects PFH, its role in the psycho-social management of these patients remains unclear. Here, we examined changes in psychiatric symptomatology and psychotropic medication usage in PFH patients following ETS. METHODS: In total, 106 PFH patients underwent ETS and were compared against 213 matched controls. Information on psychiatric diagnosis and prescription was obtained through a retrospective chart review. Prospectively, PFH patients completed Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales to evaluate pre- and postoperative quality-of-life and psycho-social impairment. RESULTS: A significantly greater proportion of PFH patients had been prescribed psychotropic medication (37.7%) compared to controls (14.1%) despite no differences in the proportion of psychiatric diagnoses. Following ETS, 52.5% of the PFH patients who were using psychotropic medications reduced their prescription regimen, compared to only 10% of control patients (P

Background Obesity has increased dramatically in the American population during the past 2 decades. Approximately 35% of adults are obese. Although obesity represents a major health issue, the association between obesity and operative outcomes has been a subject of controversy. We queried the National Surgical Quality Improvement Program (NSQIP) database to determine whether an increased body mass index (BMI) affects the outcomes of pulmonary resection for lung cancer. Methods We identified 6,567 patients with a diagnosis of lung cancer who underwent pulmonary resection from 2005 to 2012 in the NSQIP database. We stratified this population into 6 BMI groups according to the World Health Organization classification. The primary outcome measured was 30-day mortality; secondary outcomes included length of stay (LOS), operative time, and NSQIP-measured postoperative complications. We performed both unadjusted analysis and adjusted multivariable analysis, controlling for statistically significant variables. Results Adjusted multivariable logistic regression showed no increase in 30-day mortality, overall morbidity, and serious morbidity among obese patients. Adjusted Poisson regression revealed greater operative times for both obese and underweight patients compared with normal weight patients. Overall, obese patients were younger and had a greater percentage of preoperative comorbidities, including diabetes, hypertension, dyspnea, renal disease, and history of previous cardiac surgery. The prevalence of active smokers was greater among patients with low and normal BMI. Underweight patients had a greater risk-adjusted LOS relative to normal weight patients, whereas overweight and mildly obese patients had lesser risk-adjusted LOS. Conclusion The results of our analysis suggest that obesity does not confer greater mortality and morbidity after lung resection.

Robot-assisted surgical techniques have been introduced in recent years as an alternative minimally invasive approach for lung surgery. While the advantage of video-assisted thoracoscopic surgery (VATS) over thoracotomy for anatomical lung resection has been extensively reported, the results of robotic video-assisted thoracoscopic surgery (RVATS) compared to VATS are still under investigation.We performed a retrospective review of lung cancer patients, undergoing minimally invasive segmentectomy or lobectomy between December 2007 and May 2014. A robotic program was introduced in 2011. Relevant early surgical outcomes were compared between VATS and RVATS, including mortality, morbidity, conversion to thoracotomy, length of stay (LOS), and reoperation.Eighty (60.2%) patients underwent VATS resection, while 53 (39.8%) had a RVATS procedure. The two groups presented no meaningful differences at baseline, in terms of age, race, body mass index, and preoperative comorbidities. Adenocarcinoma was the most common histology in both groups. Patients in the RVATS group had significantly more segmentectomies (11.3% versus 1.2%, P = .016). There were no postoperative deaths. RVATS appeared to be associated with fewer conversions to open (13.2% versus 26.2%, P = .025) and more lymph nodes retrieved (9 versus 7, P = .049). We found no significant differences in terms of other individual complications, including tracheostomy, reintubation, pneumonia, pulmonary embolism, and cerebrovascular events.According to our results, the introduction of a robotic program did not negatively affect the early surgical outcomes of a well-established oncologic minimally invasive thoracic program. Potential advantages of RVATS still need to be explored in terms of long-term outcomes.

Purpose: Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Experimental Design: Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival. Results: CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan–Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR. Conclusions: Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development. Clin Cancer Res; 18(17); 4743–52. ©2012 AACR.

Background The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. Methods A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. Results Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p = 0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm 3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm 3 or greater (8 versus 40 months; p = 0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group ( p = 0.001 and p p = 0.061). Conclusions The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.

Background The flank is commonly used for primary xenografts in mice, but it is rare for these tumors to metastasize. Tail vein injection creates a pattern of metastases, but is artificial. We hypothesized that the liver is a convenient alternative xenograft site and that metastases would gradually proceed spontaneously. Materials and Methods Using 15 NOD.CB17-Prkdcscid/NcrCrl (NOD/SCID) mice, 10,000 A549 cells were xenografted into the liver while a second group of five mice were xenografted in the flank with 100,000 A549 cells as a control. Mice were euthanized and grossly dissected at 7 wk. A third group of seven mice received liver xenografts with A549 and a mouse each week was euthanized for 7 wk and evaluated. The liver, lung, and spleen were examined histologically. Results At 7 wk, 15/15 liver xenografted mice had gross primary tumor in the liver. Histologic review confirmed multiple microscopic foci of metastatic disease in all mice (15/15) throughout the lungs, mediastinal nodes, and spleen. The control group had primary tumor in the flank (4/5), but none had histologic evidence of metastases. Serially euthanized liver xenografted mice revealed evidence of a gradual spontaneous metastatic model system with the first histologic findings of micrometastases appearing in the lungs by wk 5, which became wide spread by wk 7. Splenic and mediastinal lymph node metastases developed in wk 6 and 7. Conclusions Liver xenografting of A549 cells into NOD/SCID mice is a reliable way of developing widespread micrometastases. This model allows the study of a gradually developing solid tumor with subsequent metastatic spread.

Purpose: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis. Experimental Design: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model. Results: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37–4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07–5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 8.61, 95% CI: 2.16–34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR = 2.06, 95% CI: 1.04–4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00–5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05–1.89, P = 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03–16.83, P = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109). Conclusions: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer. Clin Cancer Res; 17(6); 1535–45. ©2011 AACR.

Methylation of tumor suppression genes (TSGs) is common in myeloid malignancies. However, application of this as a molecular marker for risk stratification in patients with AML is limited.To elucidate the impact of patterns of TSG methylation on outcome in cytogenetically normal patients, 106 samples from patients with having normal cytogenetic AML were evaluated for methylation of 12 genes by MSP. For sake of comparison, samples from patients with AML and abnormal cytogenetics (n = 63) were also evaluated.Methylation frequencies in the whole group (n = 169) were similar to previous reports for CDH1 (31%), ER (31%), FHIT (9%), p15 (INK4b) (44%), p73 (25%), and SOCS1 (75%). Methylation of CTNNA1 was observed in 10%, CEBP-α in16%, CEBP-δ in 2%, MLH1 in 24%, MGMT in 11% and DAPK in 2% of AML samples. We find that DNA methylation was more prevalent in patients with normal compared to karyotypically abnormal AML for most genes; CEBPα (20% vs 9%), CTNNA1 (14% vs 4%), and ER (41% vs 19%) (p0.05 for all comparisons). In contrast, p73 was more frequently methylated in patients with karyotypic abnormalities (17% vs 38%; p0.05), perhaps due to specific silencing of the pro-apoptotic promoter shifting p73 gene expression to the anti-apoptotic transcript. In AML patients with normal cytogenetics, TSG methylation was not associated with event free or overall survival in a multivariate analysis.In patients with AML, TSG methylation is more frequent in patients with normal karyotype than those with karyotypic abnormalities but does not confer independent prognostic information for patients with normal cytogenetics.

Background Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. Methods This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. Results Never smokers were significantly more likely than current smokers to be women (P Conclusions Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal.

Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.

Objective We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. Methods Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. Results Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). Conclusions Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (≥RAEB2), but not in low-risk MDS (

Purpose: According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis. Experimental Design: We evaluated AAHs, adjacent normal lung tissue, and synchronous lung adenocarcinomas for promoter hypermethylation of genes implicated in lung tumorigenesis (p16, TIMP3, DAPK, MGMT, RARβ, RASSF1A, and hTERT). Results: For individual genes and the number of genes methylated, we observed a significant increase in the frequency of promoter hypermethylation in the histologic progression from normal to AAH, with low-grade or high-grade atypia, and finally to adenocarcinoma (Ptrend ≤ 0.01). Multifocal AAHs from individual patients had distinct patterns of promoter hypermethylation, suggesting divergent epigenetic field defects. There were statistically significant positive associations for the presence of promoter hypermethylation of individual and multiple genes with advanced histology, with odds ratios between 4.3 and 58.5. p16 conveyed the strongest individual association for promoter hypermethylation when comparing tumor or high-grade AAH to low-grade AAH or normal tissue, with an odds ratio of 45.5 (95% confidence interval, 5.8-360.5). Conclusion: This study shows epigenetic progression in the earliest stages of glandular neoplasia of the lung and has implications for early lung cancer detection.

Background: Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor. Methods: Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence. Results: In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC. Conclusions: Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence. Copyright © 2008 Massachusetts Medical Society.

Purpose The present investigation prospectively examined active cigarette smoking and household passive smoke exposure and the risk of developing rectal cancer. Methods Cigarette smoking data were collected on all household members during two private censuses in Washington County, Maryland. These two cohorts were followed up, one cohort from 1963–1978 and the other from 1975–1994 for first-time diagnoses of rectal cancer. We identified 148 and 169 rectal cancer cases in the 1963 and 1975 cohorts, respectively. Relative risks were estimated by means of Poisson regression models. Results In men, the adjusted relative risks (aRR) and 95% confidence intervals (CI) for the association between current smoking and rectal cancer were 3.1 (1.2–7.8) in the 1963 cohort and 1.8 (0.9–3.7) in the 1975 cohort; the corresponding aRRs in women were 0.9 (0.5–1.8) and 1.6 (0.9–3.8) in the 1963 and 1975 cohorts, respectively. In nonsmokers, household passive smoke exposure was strongly associated with rectal cancer among men in the 1963 cohort (aRR = 5.8; 1.8–18.4) but not the 1975 cohort (aRR = 1.1; 0.2–5.0). In women, household passive exposure was not strongly associated with rectal cancer in either cohort. Conclusions The results of our study suggest that active cigarette smoking may contribute to rectal cancer risk, but inconsistencies in the findings preclude drawing strong, clear-cut inferences.

Complex esophageal reconstruction (CER) is defined as restoring esophageal continuity in a previously operated field, using a nongastric conduit, or after esophageal diversion. This study compares the outcomes of CER with non-CER (NCER), which uses an undisturbed stomach for reconstruction.This single-institution retrospective cohort study compares 75 CERs with 75 NCERs from 1995 to 2014 that were matched for cancer versus benign disease. Distributions of demographic characteristics, comorbidities, and complications were compared between CER and NCER. Odds of mortality at 30 and 90 days were calculated with logistic regression. Overall survival was illustrated with Kaplan-Meier method and Cox proportional hazards regression.Although patients were similar in age, sex, and preoperative comorbidities, more non-white patients underwent CER (p = 0.04). Most NCER patients had adenocarcinoma (44%) or Barrett's high-grade dysplasia (39%); most CER patients had other benign disease (44%) or squamous cell carcinoma (24%, p0.01). CER had statistically significantly higher rates of reoperation, pneumonia, infection, and gastrointestinal complications, and longer median length of stay than NCER. Odds of mortality for CER and NCER at 30 days (odds ratio [OR] 1.0, 95% CI: 0.1 to 16.3), 90 days (OR 2.6, 95% CI: 0.5 to 13.9) and overall (adjusted hazard ratio 1.56, 95% CI: 0.9 to 2.7) were not statistically significantly different.Compared with NCER, CER patients had higher rates of return to the operating room, more postoperative infections and gastrointestinal complications, and longer length of stay. However, 30-day, 90-day, and overall survival were similar. CER should be offered to patients with acceptable risks and anticipated long-term survival.

Made available in DSpace on 2022-04-28T19:01:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-01-01 National Institutes of Health Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylation-mediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies. Department of Biology University of São Paulo State Department of Surgery Johns Hopkins University Department of Oncology Johns Hopkins University Laboratory of Cancer Epigenetics Université Libre de Bruxelles Department of Pathology Johns Hopkins University Department of Urology Johns Hopkins University

DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancer-free smokers, 15% (3 of 18) of patients with stage I non–small-cell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancer-free individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease. (Cancer Res 2006; 66(12): 6210-8)

Purpose People with HIV infection in the United States frequently smoke tobacco. We sought to characterize lung cancer incidence among HIV-infected individuals, examine whether cancer risk was related to HIV-induced immunosuppression, and assess whether the high prevalence of smoking explained elevated risk. Methods We conducted a retrospective cohort study at an HIV specialty clinic in Baltimore, MD (1989-2003). Incident lung cancers were identified using hospital records. We used negative binomial regression to compare incidence across subgroups defined by demographics, use of highly active antiretroviral therapy (HAART), and HIV markers. Standardized incidence ratios (SIRs) compared incidence with an urban reference population (Detroit, MI). We adjusted SIRs for the effect of smoking, using smoking prevalences estimated from part of the cohort and the general population. 95% CIs and P values were two sided. Results Thirty-three lung cancers were observed among 5,238 HIV-infected patients (incidence: 170 per 100,000 person-years). Incidence increased with age (P < .0001), but did not differ by sex, race, or CD4 count. Incidence tended to increase with calendar year (P = .09) and HAART use (P = .10), and was inversely related to HIV viral load (P = .03), but these associations were attenuated with age adjustment. The SIR was 4.7 (95% CI, 3.2 to 6.5) versus the general population. Twenty-eight lung cancer patients (85%) and 69% of the cohort were smokers. After smoking adjustment, risk remained elevated (SIR, 2.5; 95% CI, 1.6 to 3.5). Conclusion Lung cancer risk was substantially elevated in HIV-infected individuals. Incidence was unrelated to HIV-induced immunosuppression. Notably, incidence remained high after adjustment for smoking, suggesting the involvement of additional factors.

Purpose: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor. Experimental Design: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who underwent a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARβ was examined using methylation-specific polymerase chain reaction. Results: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5–71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases. Conclusions: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hyper-methylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.

Background This study was performed to test the hypothesis that a history of other primary neoplasms before a lung cancer diagnosis increases the risk of subsequent malignancy. Methods Of 8363 lung cancer patients seen from 1978 to 2002, 881 (11%) had at least 1 previous nonlung primary malignancy. Charts were analyzed for the occurrence of subsequent malignancies. Results Lung cancer diagnosis in 881 patients consisted of 75% non–small cell, 12% small cell, and 13% other histologies. The median age was 66 years, with 56% male, 76% white, and 86% smokers. Of the 881 patients, 92% had no subsequent cancer (group 1), and 8% went on to experience the development of a new primary neoplasm (including lung) after their lung cancer (group 2). After adequate follow-up, the cumulative probability of developing a subsequent cancer did not differ markedly between those with and without a prior non–lung cancer diagnosis at 2 years (12% vs 10%) or 5 years (16% vs 15%). Group 1 patients had a significantly lower 1- and 5-year survival than group 2 patients (59% vs 48% and 29% vs 17%, respectively; P = .008). Although multivariate analysis suggested that stage, history of tobacco-associated neoplasm, and history of definitive surgical resection were important determinants in predicting long-term survival, a prior malignancy was not an independent risk factor in the development of subsequent malignancy. Conclusions The risk of developing a subsequent malignancy is very high in lung cancer patients with prior primary malignancies, but it is not markedly different from the risks experienced by patients with no prior malignancies.

Background The aberrant promoter methylation of the mismatch repair gene, hMLH1, is associated with microsatellite instability (MSI) in cancer cells and often is associated with a favorable prognosis. Methods Pancreatic endocrine neoplasms (PENs) were obtained from 48 patients who underwent surgical resection. Methylation-specific polymerase chain reaction was used to detect methylation in the hMLH1 promoter. Tumor MSI at loci BAT26, BAT25, D2S123, D5S346, and D17S250 was determined with microsatellite polymerase chain reaction. Results Hypermethylation of the hMLH1 promoter was present in 11 of 48 PENs (23%). Five of the 11 hMLH1-methylated PENs were found to be microsatellite unstable, and MSI was restricted to PENs with hMLH1 hypermethylation. Tumor recurrence at 2 years after surgical resection was significantly less common among the hMLH1-methylated PENs (11%), compared with the unmethylated PENs (35%; P = .038). Patients with hMLH1-methylated PENs experienced improved 5-year survival (100%) compared with patients with unmethylated tumors (56%; P = .010). Likewise, MSI-positive PENs were associated with improved survival compared with MSI-negative tumors (100% vs 59%; P = .017) at 5 years. Conclusion As in hereditary nonpolyposis colorectal cancer in which MSI is associated with improved survival, methylation of hMLH1 leads to MSI in PENs and affords a favorable prognosis.

The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-β, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P = 0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P = 0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.

Pancreatic endocrine neoplasms (PENs), commonly referred to as islet cell tumors, are a unique group of malignancies often characterized by a clinical neuroendocrine syndrome attributable to the selective overproduction and humoral circulation of pancreas-specific hormones. Approximately 2000 new cases of PENs are diagnosed each year in the United States; of these cases, 60-70% are associated with a clinical syndrome resulting from the secretion of a single functional hormone.1 The remaining one third of PENs secrete no clinically detectable biologically active hormones and most often present as space occupying lesions causing obstructive jaundice, upper gastrointestinal luminal obstruction, bleeding, or abdominal pain. While many functional PENs follow an indolent course, a substantial proportion of functional and nonfunctional tumors are defined by aggressive biology, resulting in early locoregional invasion of lymph node basins and adjacent organs, as well as metastases to the liver and beyond.2,3 Although histologic characteristics, including tumor size, pleomorphism, neurovascular invasion, and metastases to the regional lymph nodes or liver, have been used for predicting long-term survival, these factors have not proven to be entirely reliable prognostic markers for PENs after surgical resection.3-6 In recent years, several studies have reported a number of genes with important implications in the tumorigenesis of the pancreatic islets. These have included deletional mutations in the MEN1 gene on chromosome 11q, activation of the HER-2/neu proto-oncogene, overexpression of cyclin D1, point mutations in the DPC4/Smad4 gene, and deletion of a putative tumor suppressor gene on chromosome 3p.7-11 In addition to the genetic mutations of MEN1, molecular alterations of the cell cycle control gene, INK4a/p16, appear to be particularly important contributors to the pathogenesis of PENs.12-15 While homozygous deletions of INK4a/p16 have been found to variable degrees in PENs, the presence of epigenetic alterations, namely aberrant hypermethylation involving the promoter region of this locus, has been reported in PENs regardless of functional status.12-14 The combination of genetic and epigenetic alterations involving tumor suppressor genes contributes to the biology of several solid human tumors. Of the several epigenetic mechanisms that play a role in tumorigenesis (including chromosomal histone deacetylation and loss of genomic imprinting), DNA methylation of tumor suppressor gene promoter sites has been studied most extensively for its potential to predict tumor behavior.16-18 Silencing of tumor suppressor gene expression by promoter hypermethylation at CpG-rich islands is common among several human malignancies.19 Several reports have validated that the hypermethylation of promoter regions for such genes as INK4a/p16, E-cadherin, and hMLH1 correlates directly with the loss of transcription of these tumor suppressor genes in a variety of tumors.19-22 The purpose of this investigation was to determine the methylation status of several tumor suppressor genes to gain insight into the heterogeneous biology affiliated with nonfunctional PENs. The unique methylation pattern associated with each PEN in our study was analyzed for its ability to predict clinical outcomes after surgical resection.

Background: Epidemiological evidence suggests that HIV-infected individuals are at increased risk of lung cancer, but no data exist because large computed tomography (CT) screening trials routinely exclude HIV-infected participants. Methods: From 2006 to 2013, we conducted the world's first lung cancer screening trial of 224 HIV-infected current/former smokers to assess the CT detection rates of lung cancer. We also used 130 HIV-infected patients with known lung cancer to determine radiographic markers of lung cancer risk using multivariate analysis. Results: Median age was 48 years with 34 pack-years smoked. During 678 person-years, one lung cancer was found on incident screening. Besides this lung cancer case, 18 deaths (8%) occurred, but none were cancer related. There were no interim diagnoses of lung or extrapulmonary cancers. None of the pulmonary nodules detected in 48 participants at baseline were diagnosed as cancer by study end. The heterogeneity of emphysema across the entire lung as measured by CT densitometry was significantly higher in HIV-infected subjects with lung cancer compared with the heterogeneity of emphysema in those without HIV ( p ⩽ 0.01). On multivariate regression analysis, increased age, higher smoking pack-years, low CD4 nadir, and increased heterogeneity of emphysema on quantitative CT imaging were all significantly associated with lung cancer. Conclusions: Despite a high rate of active smoking among HIV-infected participants, only one lung cancer was detected in 678 patient-years. This was probably because of the young age of participants suggesting that CT screening of high-risk populations should strongly consider advanced age as a critical inclusion criterion. Future screening trials in urban American must also incorporate robust measures to ensure HIV patient compliance, adherence, and smoking cessation.