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Peroxisomes play a role in lipid metabolism and regulation of reactive oxygen species, but its role in development and progression of non-small cell lung cancer (NSCLC) is not well understood. Here, we investigated the associations between 9708 single-nucleotide polymorphisms (SNPs) in 113 genes in the peroxisome-related pathways and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the Harvard Lung Cancer Susceptibility (HLCS) study. In 1185 NSCLC patients from the PLCO trial, we found that 213 SNPs were significantly associated with NSCLC overall survival (OS) (p ≤ 0.05, Bayesian false discovery probability [BFDP] ≤ 0.80), of which eight SNPs were validated in the HLCS data set. In a multivariate Cox proportional hazards regression model, two independent SNPs (rs9384742 DDO and rs9825224 PEX5L) were significantly associated with NSCLC survival (hazards ratios [HR] of 1.17 with 95% CI [confidence interval] of 1.06-1.28 and 0.86 with 95% CI of 0.77-0.96, respectively). Patients with one or two protective genotypes had a significantly higher OS (HR: 0.787 [95% CI: 0.620-0.998] and 0.691 [95% CI: 0.543-0.879], respectively). Further expression quantitative trait loci analysis using whole blood and lung tissue showed that the minor allele of rs9384742 DDO was significantly associated with decreased messenger RNA (mRNA) expression levels and that DDO expression was also decreased in NSCLC tumor tissue. Additionally, high PEX5L expression levels were significantly associated with lower survival of NSCLC. Our data suggest that variants in these peroxisome-related genes may influence gene regulation and are potential predictors of NSCLC OS, once validated by additional studies., (© 2022 Wiley Periodicals LLC.)

Background: Biomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis., Objectives: The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence., Methods: Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level., Results: In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray's test, P= 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P= 0.4670)., Conclusions: The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence.

The mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10 -4 ), 1.26 (1.12-1.42, 1.10 × 10 -4 ) and 0.73 (0.63-0.86, 1.63 × 10 -4 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (P trend  < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC., (© 2021 UICC.)

Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in nonsmall cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (p < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295 G > T, AMD1 rs1279590 G > A and MSRA rs73534533 C > A) were replicated in the validation dataset, and their meta-analysis showed an adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and p meta  = 2.86 × 10 -6 , 0.81 (0.73-0.91) and p meta  = 4.63 × 10 -4 , and 0.77 (0.68-0.89) and p meta  = 2.07 × 10 -4 , respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (p trend  < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (p < 0.0001 and < 0.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients., (© 2019 UICC.)

The complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody-based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two-phase analysis of two independently published genome-wide association studies (GWASs) for associations between genetic variants in a complement-related immunity gene-set and overall survival of non-small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false-positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single-nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single-locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07-1.40, P = 0.002] and 1.16 (1.07-1.27, 6.45 × 10 -4 ), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival-associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement-related immunity genes might be predictors of NSCLC survival, particularly for the short-term survival, possibly by modulating the expression of genes involved in the host immunity., (© 2018 UICC.)

Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. We report the spectrum of sequential CT findings in patients with advanced stage lung cancer who received nivolumab in an effort to better inform appropriate imaging strategies., Materials and Methods: We identified all patients at our institution with advanced NSCLC who received nivolumab. Pre- and posttreatment CT scans were reviewed and categorized based on radiographic response to therapy. Demographic data as well as survival data were recorded., Results: There were 34 patients with advanced NSCLC who received nivolumab with sufficient follow-up data. Nineteen patients were classified as responders to treatment; 6 (32%) of 19 showed improvement on their initial follow-up CT and had an average survival of 11.2 months, whereas 13 (68%) of 19 responders initially had stable or progressive disease on CT with an average survival of 11.6 months. Fifteen patients were classified as nonresponders to treatment with an average survival of 3.4 months., Conclusion: Novel immunotherapies such as nivolumab mechanistically differ from conventional chemotherapy. Some patients have improved survival despite initial radiographic progression of disease. Our findings underscore the heterogeneous radiographic appearance at follow-up CT in patients with lung cancer who ultimately respond to nivolumab., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Most pulmonary nodules found on imaging studies are indeterminate, but because of the concern for lung cancer, all patients require further evaluation with resultant radiation risk, significant cost, and delays in diagnosis. We hypothesized that a diagnostic blood test based on detection of autoantibodies against cancer antigens would be able to distinguish a benign nodule from lung cancer., Methods: We identified a panel of 25 serum autoantibodies associated with NSCLC and constructed a protein microarray containing the autoantigens. We tested the microarray with human sera (from 125 patients with NSCLC and 125 matched controls with a benign nodule) and attempted to develop a classification algorithm that would separate the two groups., Results: In the training data set the logistic regression c-index statistic was 0.691; in the validation data set, the model predicting the score generated from the training set model had a c-index of 0.490. The relationship between the score and outcome (final diagnosis) was not statistically significant (p = 0.460)., Conclusions: When the current panel of antigens and assay format was used, classification algorithms based on levels of autoantibodies to cancer antigens did not prove to have statistically significant value for predicting the presence of cancer. We suggest that there are inherent biological limitations to this approach., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma., (Copyright ©ERS 2015.)

Introduction: Patients with stage I non-small-cell lung cancer (NSCLC) have a wide variation in outcomes, most likely because there are undetected metastases at presentation. We retrospectively reviewed patients with early stage lung cancer to determine if FDG uptake of the primary tumor as measured on positron emission tomography (PET) at the time of diagnosis was associated with overall survival (OS) or time to recurrence (TTR)., Methods: We reviewed the Tumor Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5-year period who underwent an FDG-PET/computed tomography within 90 days before surgery. Kaplan-Meier curves were used to describe the survival and TTR experience within subgroups defined by PET maximum standardized uptake value (SUVmax). Cox proportional hazards model was used to assess the impact of PET SUVmax as a continuous variable on OS and TTR. Logistic regression was used to analyze the effect of SUVmax on dichotomized outcomes., Results: Three hundred thirty-six consecutive patients (176 women and 160 men) with stage I NSCLC were retrospectively reviewed. Mean SUVmax was 9.2 ± 6.9 (range 0.6-30.3). The hazard or risk of dying and recurrence increased significantly as SUVmax increased (p = 0.0008 and 0.024, respectively)., Conclusions: Preoperative FDG uptake in the primary tumor in patients with stage I disease is associated with OS and TTR. This may be useful in identifying early stage patients who may benefit from more aggressive therapy after surgical resection.

Introduction: Treatment patterns and cost implications of increased positron emission tomography imaging use since Medicare approval in 1998 are not well understood. We examined rates of surgery, radiotherapy, and chemotherapy and inpatient and total health care costs between 1998 and 2005 among Medicare beneficiaries with non-small-cell lung cancer., Methods: Patients in this retrospective cohort study were 51,374 Medicare beneficiaries diagnosed with non-small-cell lung cancer between 1996 and 2005. The main outcome measures were receipt of surgical resection, radiotherapy, and chemotherapy and inpatient and total health care costs within 1 year of diagnosis., Results: Between 1996-1997 and 2004-2005, the proportion of patients undergoing surgical resection decreased from 29% to 25%, the proportion receiving radiation therapy decreased from 49% to 43%, and inpatient costs decreased from $28,900 to $26,900. The proportion of patients receiving chemotherapy increased from 25% to 40% and total costs increased from $47,300 to $52,200 (p < 0.001 for all comparisons). Changes in use and costs remained after adjustment for shifting demographic characteristics during the study period., Conclusions: Adoption of positron emission tomography between 1998 and 2005 was accompanied by decreases in rates of surgery and radiotherapy and in short-term inpatient costs among Medicare beneficiaries with non-small-cell lung cancer, although there was an increase in chemotherapy and overall costs.

Importance: Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment., Objective: To estimate overdiagnosis in the National Lung Screening Trial (NLST)., Design, Setting, and Participants: We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm., Main Outcomes and Measures: We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (PS), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer., Results: During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38., Conclusions and Relevance: More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.

Purpose: To explore demographic and regional factors associated with the use of positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) and to determine whether their associations with PET use has changed over time., Materials and Methods: The Office of Human Research Ethics at the University of North Carolina and the institutional review board of the Duke University Health System approved (with waiver of informed consent) this retrospective analysis of Surveillance Epidemiology and End Results Medicare data for Medicare beneficiaries given a diagnosis of NSCLC between 1998 and 2007. The primary outcome was change in the number of PET examinations 2 months before to 4 months after diagnosis, examined according to year and sociodemographic subgroup. PET use was compared between demographic and geographic subgroups and between early (1998-2000) and late (2005-2007) cohorts by using χ(2) tests. Factors associated with use of PET during the study period were further examined by using logit and linear probability multivariable regression analyses., Results: The final cohort included 46 544 patients with 46 935 cases of NSCLC. By 2005, more than half of patients underwent one or more PET examinations, regardless of demographic subgroup. In multivariable logistic regression analysis, patients who underwent PET were more likely to be married, nonblack, and younger than 80 years and to live in census tracts with higher education levels or in the Northeast (P < .001 for all). Living within 40 miles of a PET facility was initially associated with undergoing PET (P < .001), but this association disappeared by 2007. Imaging rates increased more rapidly in patients who were nonblack (P ≤ .01), patients who were younger than 81 years (P < .001), and patients who lived in the Northeast and South (P < .001)., Conclusion: PET imaging among Medicare beneficiaries with NSCLC was initially concentrated among nonblack patients younger than 81 years. Despite widespread adoption among all subgroups, differences within demographic subgroups remained.

Purpose: Previous studies have linked the use of positron emission tomography (PET) with improved outcomes among patients with non-small-cell lung cancer (NSCLC). However, this association may be confounded by PET-induced stage migration and selection bias. We examined the association between PET use and overall survival among Medicare beneficiaries with NSCLC., Patients and Methods: Retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) -Medicare data was used to characterize changes in overall survival, stage-specific survival, and stage distribution among Medicare beneficiaries with NSCLC between 1998 and 2003., Results: A total of 97,007 patients with NSCLC diagnosed between 1998 and 2003 met the study criteria. Two-year and 4-year survival remained unchanged, despite widespread adoption of PET. The proportion of patients staged with advanced disease increased from 44% to 50%. Upstaging of disease was accompanied by stage-specific improved survival, with 2-year survival of stage IV disease increasing from 8% to 11% between 1998 and 2003. PET was more likely to be administered to patients with less advanced disease (stages I through IIIA) and greater overall survival., Conclusion: Overall survival among Medicare beneficiaries with NSCLC was unchanged between 1998 and 2003, despite widespread adoption of PET. The association between PET use and increased survival likely reflects an artifact of selection bias and consequent stage migration.

Introduction: Lung cancers can display immune cell infiltration although the role of an adaptive immune response in disease pathogenesis is unknown. To investigate the possibility of a functional humoral response to the tumor, we surveyed histologic sections from non-small cell lung cancer (NSCLC) tumors for germinal centers (GCs) and assessed whether there was an association between the presence of GCs and tumor stage., Methods: Tumor sections from 91 patients with all stages of NSCLC were examined by a pathologist blinded to clinical data. GCs were identified by hematoxylin and eosin staining patterns and confirmed by immunohistochemical staining for B-cell markers, BCL-6 and CD21. The distribution of GCs within the tumor or the tumor margin was recorded. Statistical analysis was performed to evaluate the association between stage and presence of GCs., Results: Thirty-five percent of all tumors evaluated contained GCs, and sections evaluated by immunohistochemistry showed positive staining for both B-cell markers. GCs were seen both within the tumor and the tumor margin, consistent with an immune response to antigen stimulation. Patients with stage I NSCLC had a higher prevalence of intratumoral GCs than patients with stages II to IV (Cochran-Armitage Trend Test p = 0.02011). There was no association of stage with GCs in the tumor margin., Conclusions: Intratumoral GCs are associated with early-stage NSCLC. Further characterization of intratumoral GCs may lead to new diagnostic and therapeutic strategies based on manipulation of the adaptive immune response.

Background: The aim of the current study was to determine whether the [18F]-2-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) standardized uptake value (SUV) in patients with a new diagnosis of stage I lung cancer correlates with a specific cellular component in the primary tumor., Methods: This study was Health Insurance Portability and Accountability Act compliant and approved by our Institutional Review Board with a waiver of informed consent. Forty patients with stage I nonsmall cell lung cancer (NSCLC) who underwent FDG-PET imaging at the time of diagnosis followed by surgical resection were retrospectively identified. Histologic sections of the primary tumor were reviewed by a pathologist without any clinical data and scored according to the percentage of each cellular component (tumor cells, normal stroma, inflammatory cells, necrosis, fibrosis, and other). Each component was compared with maximal (SUV(max)) and mean (SUV(mean)) SUVs using Pearson correlation coefficient analysis., Results: The mean SUV(max) and SUV(mean) values for 40 stage I NSCLC tumors were 8.8 and 5.4, respectively. The mean histologic composition of tumor specimens in order of frequency was as follows: tumor cells (38.9%), fibrosis (30.8%), inflammatory cells (14.8%), normal stroma (5.2%), necrosis (5.8%), and other components (4.5%); however, there was considerable variation noted among individual tumors. There was no statistically significant correlation between SUV(max) (r = .19; P = .24) or SUV(mean) (r = .017; P = .29) and the proportion of tumor cells in the tumor mass or any other cellular components., Conclusions: The cellular composition of stage I NSCLC appears to be highly variable, with no correlation noted between a specific tumor cellular component and FDG activity., (Cancer 2010. (c) 2010 American Cancer Society.)

Purpose: To discover diagnostic biomarkers associated with early-stage non-small cell lung cancer (NSCLC), we searched for autoantibodies preferentially present in stage I patients compared with patients with advanced-stage disease. Here we describe an autoantibody against complement factor H (CFH) and this autoantibody's association with early-stage NSCLC., Experimental Design: Immunoblots were used to detect autoantibodies in the sera of stage I NSCLC patients. An autoantibody recognizing a 150 kDa protein was discovered, and the protein was identified by mass spectrometry. The association of the autoantibody with early-stage disease was suggested by the results of immunoblot analysis with sera from 28 stage I patients and 28 stage III/IV patients. This association was confirmed by protein microarray of sera from 125 NSCLC patients of all stages as well as 125 controls matched by age, gender, and smoking history., Results: The immunoreactive protein was identified as CFH. By immunoblot analysis, anti-CFH autoantibody was found in 50% of stage I NSCLC patients and 11% of late-stage NSCLC patients (P = 0.003). By protein microarray analysis, patients with stage I NSCLC had a significantly higher incidence of anti-CFH antibody than those with late-stage NSCLC (P = 0.0051). The percentage of sera with a positive level of CFH autoantibody was 30.4% in stage I, 21.1% in stage II, 12.5% in stage III, 7.4% in stage IV, and 8.0% in the control group., Conclusions: These findings suggest that in patients with NSCLC, CFH autoantibody is a molecular marker associated with early-stage disease., ((c) 2010 AACR.)

Background: In clinical trials, change in tumor size is used to stratify patients into response categories. The objective of the current study was to: 1) determine whether early change in the tumor size were correlated with survival in patients with advanced nonsmall cell lung cancer (NSCLC) using modified response categories from the Response Evaluation Criteria in Solid Tumors (RECIST), and 2) to determine whether there was an optimal percentage change in tumor size that could be used to define a partial response that also correlated with survival., Methods: A total of 99 consecutive patients presenting for the treatment of advanced NSCLC during the year 2003 who had computed tomography (CT) scans before and after treatment available for review were included in the study. The largest target thoracic lesion was measured on CT before treatment, and again 2 months to 3 months after the initiation of treatment. Percent change in tumor size was calculated. The relation between tumor response and patient survival was investigated., Results: There was no definite relation noted between early tumor response and patient survival (P = .754). Patients who had any initial reduction in tumor size were not found to have a significantly different survival compared with patients with initial disease progression (P = .580). In addition, there was no particular percent reduction in tumor size that was found to optimally correlate with survival., Conclusions: There is no evidence of a relation between early changes in tumor size and survival among patients with advanced stage NSCLC. To predict survival in patients with advanced NSCLC, response criteria other than change in lesion size are needed., ((c) 2008 American Cancer Society.)

Purpose: To determine whether the amount of fluorine-18 fluorodeoxyglucose (FDG) uptake in the primary lung cancer on positron emission tomography (PET) imaging at the time of presentation has prognostic significance in patients with advanced-stage non-small-cell lung cancer (NSCLC)., Patients and Methods: A retrospective review identified 214 patients with advanced-stage NSCLC (stage IIIA, IIIB, and IV) who underwent FDG PET study at the time of diagnosis. Extensive clinical data, including tumor histologic cell type, pathologic stage at presentation, and treatment, were recorded. The maximum standardized uptake value (SUV(max)) in the primary tumor on FDG PET on survival was examined using Cox proportional hazards regression., Results: One hundred fifty-eight (74%) of the 214 patients died and 56 patients were reported alive at 27 months (range, 3 to 140 months) after the diagnosis of NSCLC. Using the median SUV(max) of 11.1, the patient population was subdivided. The median survival of the 106 patients with the primary tumor having an SUV(max) less than 11.1 was 16 months (95% CI, 12 to 21 months), whereas the median survival of the 108 patients with the primary tumor having an SUV(max) > or = 11.1 was 12 months (95% CI, 10 to 15 months). Univariate and multivariate analysis did not provide evidence that survival for patient subgroups defined by the median SUV(max) were significantly different (univariate P = .11; multivariate P = .45)., Conclusion: FDG uptake of the primary lesions in patients with a new diagnosis of advanced-stage NSCLC does not have a significant relationship with survival.

Hypothesis: The 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography is an imaging tool for assessing clinical tumor, node, metastasis in non-small cell lung cancer (NSCLC). Primary tumor standardized uptake value (SUV) has been studied as a potential prognostic factor for survival. However, the sample sizes are limited leading to conduct a meta-analysis to improve the precision in estimating its effect., Methods: We performed a systematic literature search. For each publication, we extracted an estimate of the hazard ratio (HR) for comparing patients with a low and a high SUV and we aggregated the individual HRs into a combined HR, using a random-effects model., Results: We found 13 eligible studies dedicated to NSCLC. Most of them included patients with stages I to III/IV and used a SUV assessment corrected for body weight. Number of patients ranged from 38 to 315 (total: 1474); 11 studies identified a high SUV as a poor prognostic factor for survival although two studies found no significant correlation between SUV and survival. SUV measurement and SUV threshold for defining high SUV were study dependent, eight studies looked for a so-called best cutoff (maximizing the logrank test statistic) without adjusting the p value for multiplicity. Overall, the combined HR for the 13 reports was 2.27 (95% confidence interval [CI]: 1.70-3.02); excluding the studies proposing a "best" cutoff, it was 2.08 (95% CI: 1.431-3.04)., Conclusion: Our meta-analysis suggests that the primary tumor SUV measurement has a prognostic value in NSCLC; these results should be confirmed in a meta-analysis on individual patients' data.

Purpose: Currently, a blood test for lung cancer does not exist. Serum biomarkers that could aid clinicians in making case management decisions would be enormously valuable. We used two proteomic platforms and a literature search to select candidate serum markers for the diagnosis of lung cancer., Methods: We initially assayed six serum proteins, four discovered by proteomics and two previously known to be cancer associated, on a training set of sera from 100 patients (50 with a new diagnosis of lung cancer and 50 age- and sex-matched controls). Classification and Regression Tree (CART) analysis selected a panel of four markers that most efficiently predicted which patients had lung cancer. An independent, blinded validation set of sera from 97 patients (49 lung cancer patients and 48 matched controls) determined the accuracy of the four markers to predict which patients had lung cancer., Results: Four serum proteins-carcinoembryonic antigen, retinol binding protein, alpha1-antitrypsin, and squamous cell carcinoma antigen-were collectively found to correctly classify the majority of lung cancer and control patients in the training set (sensitivity, 89.3%; specificity, 84.7%). These markers also accurately classified patients in the independent validation set (sensitivity, 77.8%; specificity, 75.4%). Remarkably, 90% of patients who fell into any one of three groupings in the CART analysis had lung cancer., Conclusion: This panel of four serum proteins is valuable in suggesting the diagnosis of lung cancer. These data may be useful for treating patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer.

Background: The purpose was to evaluate the clinical utility of serum haptoglobin (Hp) and posttranslational glycan modifications of Hp for the diagnosis of nonsmall cell lung cancer (NSCLC)., Methods: Serum proteins from patients with a new diagnosis of NSCLC and age- and sex-matched controls without cancer were compared using 2-dimensional difference gel electrophoresis (2D-DIGE). Four of the differentially expressed gel spots were identified as the beta chain of Hp. Immunoblots confirmed sialyl and fucosyl group posttranslational modifications (PTMs) of Hp. Serum enzyme-linked immunosorbent assays (ELISAs) for total Hp, sialylated Hp (SAHp), and fucosylated Hp (FHp) were designed, and levels of each were measured in an independent sample set of 74 patients. Receiver operating characteristic (ROC) analysis assessed the clinical diagnostic utility of each marker., Results: Statistically significant differences between lung cancer patients and matched controls were found by ELISA for Hp (P < .002), SAHp (P < .001), and FHp (P < .04). ROC analysis determined an area under the curve (AUC) of 0.754 for Hp, 0.740 for SAHp, and 0.794 for FHp. In addition, serum concentrations correlated with stage; Hp (r = 0.388; P = .018), SAHp (r = 0.300; P = .072), and FHp (r = 0.363; P = .027)., Conclusions: Hp and 2 of its glycoforms, SAHp and FHp, are potentially useful in the clinical diagnosis of NSCLC. The markers increase with stage, suggesting they may also be useful in stratifying patients at presentation and in following patients after treatment., ((c) 2007 American Cancer Society.)

Introduction: Positron emission tomography (PET) has improved the accuracy of staging non-small cell lung cancer (NSCLC), although some early-stage patients will still relapse. The purpose of this study was to determine the sites and time to recurrence in patients with clinical stage I NSCLC whose initial staging evaluation included conventional imaging and fluorodeoxyglucose-PET., Methods: This study was approved by our institutional review board and complies with the Health Insurance Portability and Accountability Act. We retrospectively searched our PET database and identified 231 patients (125 women, 106 men; ages 36-93 years) with primary NSCLC and clinical stage I disease. The sites and time to recurrence were recorded. The average follow-up time was 33 months., Results: Of the 231 patients with clinical stage I tumors, 196 patients (85%) had pathological stage I disease. Two patients developed a second primary lung cancer, and 40 patients (20%) developed local or distant recurrence. Ninety-three percent of all patients remained disease free at 1 year, and 27% (11/40) of those who recur do so in the first year. The most common site of first recurrence was the thorax, followed by the brain, bone, and adrenal glands., Conclusions: Twenty percent of stage I NSCLC patients staged with conventional imaging and PET will develop recurrent NSCLC. The sites of recurrence with the addition of PET are similar to those reported with staging by conventional imaging alone. Additional studies are needed to determine the optimal time for follow-up imaging if intervention for recurrent disease is shown to improve survival.

Background: Early stage lung cancer has a variable prognosis, and there are currently no markers that predict which patients will recur. This study examined the relation between tumor-regulatory T (Treg) cells and total tumor-infiltrating T-cell lymphocytes (TIL) to determine whether they correlated with recurrence., Methods: The authors reviewed all patients in our tissue databank from 1996 to 2001 and identified 64 consecutive pathologic stage I non-small cell lung cancer (NSCLC) patients who had surgical resection and at least a 2.5 years disease-free follow-up or documented recurrence within 2 years. Immunohistochemical analyses were performed on paraffin-embedded lung cancer tissue and the relation between Treg cells, TIL, and disease-specific survival was determined. A risk index was devised deductively for various possible combinations of Treg cells and TIL., Results: Treg cells and TIL were detected in 33 of 64 (51%) and 53 of 64 (83%) patients, respectively. When data were analyzed by using a Treg/TIL Combination Risk Index, patients with high-risk and intermediate-risk indices had hazard ratios of 8.2 (P = .007) and 3.3 (P = .109), respectively., Conclusions: Patients with stage I NSCLC who have a higher proportion of tumor Treg cells relative to TIL had a significantly higher risk of recurrence. These data may be useful, particularly if combined with a panel of tumor markers, to suggest at the time of diagnosis which patients with seemingly early-stage NSCLC will relapse., (Copyright 2006 American Cancer Society.)

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of adenocarcinoma with unique epidemiology, pathology, radiographic presentation, clinical features, and natural history compared with other non-small cell lung cancer (NSCLC) subtypes. Classically, BAC demonstrates a relatively slow growth pattern and indolent clinical course. However, in a subset of patients, rapid growth and death from bilateral diffuse consolidative disease occurs within months of diagnosis or recurrence. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. The initial radiographic presentation of BAC varies considerably, from single ground glass opacities (GGOs) or nodules of mixed ground glass and solid attenuation to diffuse consolidative or bilateral multinodular disease. The rising incidence of BAC is also reflected in recent lung cancer screening studies employing helical computed tomography (CT), where the differential diagnosis of GGOs includes not only BAC and overt adenocarcinoma, but inflammatory disease, focal fibrosis, and atypical adenomatous hyperplasia. Because advanced-stage BAC presents as measurable mass lesions in fewer than 50% of cases, determination of radiographic response to therapy by standard criteria is often difficult. Here, we review current data regarding the radiographic imaging of BAC: its radiographic presentations in asymptomatic early-stage and in advanced-stage disease, the functional imaging characteristics of BAC, and challenges of response assessment, including evolving opportunities for computer-assisted image analysis.

Cyclophilin A (CypA) was recently reported to be overexpressed in non-small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer.

Biomarkers have the potential to significantly change diagnostic strategies and influence therapeutic management. We developed a MALDI-TOF protein expression profiling platform for biomarker discovery and a proof-of-principle study identified two proteins, cyclophilin A (CyPA) and macrophage migration inhibitory factor (MIF), that were overexpressed in non-small cell lung cancer (NSCLC). The current study focused on evaluating the potential of CyPA and MIF as prognostic markers in patients with a new diagnosis of lung cancer for rapid translation into clinical practice. Two hundred and thirty-four primary NSCLC specimens reflecting a broad range of histologies and stages were examined for CyPA and MIF reactivity by tissue microarray immunohistochemistry (TMA-IHC). The percent tumor cell reactivity, staining intensity and a composite staining score were compared with overall patient survival by Kaplan-Meier curves, log rank test and Cox model statistics. Although both proteins were overexpressed in most NSCLC tumors, neither CypA nor MIF showed a correlation with outcome. This pilot project approach can expedite integration of newly discovered biomarkers into clinical practice, with the goal of improving stratification of patients into appropriate treatment regimens. While both proteins considered in this study were overexpressed in the vast majority of NSCLCs, they were not found to be of prognostic significance.

Background: Early lung carcinoma detection strategies involving imaging studies have yet to demonstrate a reduction in mortality. Identification of serum biomarkers that could complement radiologic studies and facilitate earlier diagnosis of lung carcinoma would be of significant benefit to patients. In the current pilot study, the authors evaluated two overexpressed proteins in lung carcinoma, serum amyloid A (SAA) and macrophage migration inhibitory factor (MIF), as potential diagnostic serum biomarkers for this malignancy., Methods: Serum levels of SAA and MIF were measured in 50 patients using enzyme-linked immunosorbent assays. The sensitivity, specificity, and accuracy of the markers in detecting lung carcinoma were determined., Results: SAA levels in patients with lung carcinoma were greater than in the control patients (P = 0.07). Serum SAA levels did not exhibit a correlation with tumor size or clinical stage and were higher in patients with squamous cell carcinoma than in patients with other histologic disease types. MIF was unable to differentiate patients with lung carcinoma from patients with other diseases., Conclusions: SAA possesses potential utility as a serum biomarker for lung carcinoma, probably in conjunction with other serum markers that improve its diagnostic accuracy. Before a larger study is performed, the discovery of additional biomarkers to enhance the specificity of SAA in the diagnosis of lung carcinoma is recommended., (Copyright 2004 American Cancer Society.)

The purpose of this study was to compare the accuracy and agreement of whole-body positron-emission tomography (PET) scan to bone scintigraphy for the detection of bony metastases in staging patients with newly diagnosed lung cancer. The tumor registry and nuclear medicine database at our institution were queried and identified all patients between July 1998 and August 2002 with a new diagnosis of lung cancer, a whole-body 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET scan, and a bone scan prior to therapy. All of these patients' radiologic reports were then retrospectively reviewed, and confirmation of bone metastases was determined by consideration of all available clinical information. The sensitivity, specificity, and accuracy for each study were then calculated. Two hundred and fifty-seven patients fulfilled the entrance criteria. One hundred and four patients (40%) presented with stage IV disease, and bone metastases were confirmed in 57 (22%) patients. The accuracies of PET and bone scan were 94 and 85% (P < 0.05), sensitivity values were 91 and 75%, and specificity values were 96 and 95%, respectively. The weighted-kappa statistic suggested moderate agreement between the two modalities KW = 0.510, 95% CI, 0.402-0.618). The use of both whole-body PET and bone scintigraphy as initial staging studies in lung cancer patients provides redundant information about the presence of bony metastases. The improvement in accuracy and sensitivity with PET suggests bone scan can be eliminated from the staging evaluation at presentation. Due to its retrospective nature, the results of this study are subject to several forms of bias including selection bias, verification bias, test review bias, and incorporation bias. A prospective trial with appropriate verification of bony metastases is suggested to confirm the results.

Current diagnostic and therapeutic strategies for lung cancer have had no significant impact on lung cancer mortality over the last several decades. This study used a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) discovery platform to generate protein expression profiles in search of overexpressed proteins in lung tumors as potentially novel molecular targets. Two differentially expressed protein peaks at m/z 12338 and 17882 in the MALDI-TOF spectra were identified in lung tumor specimens as macrophage migration inhibitory factor and cyclophilin A, respectively. Overexpression of both proteins was confirmed by Western blotting, and cyclophilin A was localized to the tumor cells by immunohistochemistry. These data demonstrate the feasibility of using a MALDI-TOF platform to generate protein expression profiles and identify potential molecular targets for cancer diagnostics and therapeutics.

Background: Recently, there has been increased interest in the use of computed tomography (CT) for lung carcinoma screening. For this technique to be effective, small tumors must be detected at an earlier stage than large lesions. However, to the authors's knowledge, the relationship between the size of small primary (< or = 3 cm) neoplasms and disease stage at presentation has never been established clearly. The current study was performed to determine whether smaller lesions indeed have an earlier stage distribution compared with larger tumors., Methods: The Duke University Medical Center Tumor Registry identified 620 patients (261 women and 359 men, with a mean age of 67 years) who presented with pathologically proven primary nonsmall cell lung carcinomas measuring < or = 3 cm between 1980-1999. Surgical, pathologic, and imaging information was reviewed retrospectively to confirm the size of the lesion and the disease stage at the time of presentation. The distribution of tumor size within each stage and the distribution of disease stage according to tumor size were determined., Results: Tumors occurring in patients with TNM Stage IIIB disease were slightly larger than those found in patients with either more advanced or less advanced disease. However, there was no apparent statistically significant relation between the stage distribution and the size of the primary lesion., Conclusions: The current study data did not find a statistically significant relation between the size of small primary lung tumors and the distribution of disease stage at the time of presentation. This finding suggests that the detection of small tumors using screening CT may not result in a shift to an earlier disease stage distribution. A reduction in mortality needs to be demonstrated by appropriate clinical trials prior to the initiation of mass CT screening programs., (Copyright 2001 American Cancer Society.)

Purpose: To correlate FDG activity on PET with the expression of glucose transporter proteins Glut-1 and Glut-3 in patients with early stage non-small cell lung cancer (NSCLC)., Methods: Over a 5 year period, all patients with a PET scan and clinical stage I NSCLC underwent an immunohistochemical analysis of their tumor for Glut-1 and Glut-3 expression. The amount of FDG uptake in the primary lesion was measured by a standardized uptake ratio (SUR) and correlated with immunohistochemical results., Results: Seventy-three patients with a mean age of 66 years had clinical stage I disease. The final pathologic stage showed 64 patients with stage IA/B disease, eight with stage IIA disease, and one patient with pathologic stage IIIA (T1N2) disease. Glut-1 transporter expression was significantly higher than Glut-3 (P<0.0001), and although there was some association between the SUR and Glut-1 (P=0.085) and SUR and Glut-3 (P=0.074) expression, this did not reach statistical significance., Conclusions: Glut-1 and Glut-3 transporter expression did not demonstrate a statistically significant correlation with FDG uptake in potentially resectable lung cancer. It appears that these transporters alone do not affect the variation in FDG activity in early stage NSCLC.

Purpose: To determine the accuracy of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the evaluation of regional lymph nodes in patients with stage I non-small cell lung cancer (NSCLC)., Materials and Methods: Imaging and clinical findings obtained during 5 years in 84 patients (mean age, 66 years) were reviewed. Patients had thoracic computed tomographic findings of stage I NSCLC, an FDG PET study, and histopathologic proof of lung cancer. At the time of diagnosis, disease stage was assigned on the basis of FDG PET results and was compared with the histopathologic stage to determine the accuracy of PET., Results: When PET stage was compared with histopathologic stage, the disease in 72 (86%) patients was accurately staged with PET, understaged in two (2%), and overstaged in 10 (12%). The overall sensitivity, specificity, and positive and negative predictive values for PET of regional lymph nodal metastases were 82%, 86%, 47%, and 97%, respectively., Conclusion: FDG PET enables accurate staging of regional lymph node disease in patients with stage I NSCLC. A negative PET scan in these patients suggests that mediastinoscopy is unnecessary and that these patients can proceed directly to thoracotomy.

Objective: The purpose of this study was to determine the relationship between tumor size and survival in patients with stage IA non-small cell lung cancer (non-small cell lung cancer; ie, lesions < 3 cm)., Method: Five hundred ten patients with pathologic stage IA (T1N0M0) non-small cell lung cancer were identified from our tumor registry over an 18-year period (from 1981 to 1999). There were 285 men and 225 women, with a mean age of 63 years (range, 31 to 90 years). The Cox proportional model was used to examine the effect on survival. Tumor size was incorporated into the model as a linear effect and as categorical variables. The Kaplan-Meier product limit estimator was used to graphically display the relationship between the tumor size and survival., Results: The Cox proportional hazards model did not show a statistically significant relationship between tumor size and survival (p = 0.701) as a linear effect. Tumor size was then categorized into quartiles, and again there was no statistically significant difference in survival between groups (p = 0.597). Tumor size was also categorized into deciles, and there was no statistical relationship between tumor size and survival (p = 0.674)., Conclusions: This study confirms stratifying patients with stage IA non-small cell lung cancer in the same TNM classification, given no apparent difference in survival. Unfortunately, these data caution that improved small nodule detection with screening CT may not significantly improve lung cancer mortality. The appropriate prospective randomized trial appears warranted.

Objective: We determined the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for patients with treated lung cancer., Materials and Methods: We examined patients who underwent FDG PET after first-line treatment for non-small cell lung cancer. FDG PET results were correlated with survival rates to determine whether FDG PET findings were predictive of outcomes., Results: After initial therapy, 113 patients with non-small cell lung cancer underwent FDG PET. One hundred patients had positive FDG PET results and a median survival of 12 months (95% confidence interval, 9.2-15.4). Thirteen patients had negative FDG PET results, and 11 (85%) of these patients are still living at a median follow-up of 34 months. The difference in survival for patients with positive and negative FDG PET results was statistically significant (p = 0.002)., Conclusion: FDG PET has prognostic value and strongly correlates with survival rates of patients with treated lung cancer. Patients with positive FDG PET results have a significantly worse prognosis than patients with negative results. Additionally, FDG PET may be helpful in guiding therapeutic treatments.

Positron emission tomography is a clinically useful imaging modality that complements conventional radiologic studies in the evaluation of focal pulmonary opacities, lung cancer staging, tumor recurrence, treatment response, and prognosis.

Imaging plays an essential role in diagnosing, staging, and following patients with lung cancer. Most tumors are found on chest radiographs, although further evaluation with thoracic computed tomography is performed to stage local disease. Additional radiologic studies, including radionuclide bone scan, brain computed tomography, or magnetic resonance imaging are typically used in select patients in the search for extrathoracic metastases. More recently, whole body positron emission tomography imaging has become an extremely useful tool in evaluating the primary tumor, regional lymph nodes, and distant sites of disease in lung cancer patients. With continued improvements in diagnostic imaging modalities, definition of risk groups, discovery of molecular markers, and development of new therapeutic strategies, improved survival rates should result in the future. This review focuses on the current imaging techniques used to evaluate patients with lung cancer.

Background: A fundamental property of malignant tumors is increased glucose metabolism, which can be estimated by imaging the glucose analog fluorodeoxyglucose (FDG). The aim of this study was to determine whether FDG uptake in lung carcinoma, as measured on positron emission tomography (PET) imaging in patients with newly diagnosed bronchogenic carcinoma, has prognostic significance., Methods: A retrospective review of all patients with a new diagnosis of nonsmall cell lung carcinoma and FDG-PET imaging was performed. Stage at presentation, cell type, tumor size, and survival data were recorded. For each patient, a standardized uptake ratio (SUR) was calculated for the primary lesion on PET and was correlated with clinical information to determine prognostic significance., Results: One hundred fifty-five patients, with a mean age of 56 years, were enrolled. One hundred eighteen patients (76%) had lesions with SUR values <10 and had a median survival of 24.6 months (95% confidence interval [CI]: 20.9-41.1). Thirty-seven patients (24%) had tumor lesions with SUR values >10 and had a median survival of 11.4 months (95% CI: 9.3-19.4). An SUR >10 correlated with poorer survival (P = 0.0049). Patients with primary lesions >3 cm and an SUR > 10 had the worst prognosis, with a median survival of 5.7 months (95% CI: 4.0-13.1). Multivariate analysis demonstrated than an SUR > 10 provided prognostic information independent of the clinical stage and lesion size., Conclusions: On PET studies of patients with lung carcinoma, FDG uptake within the primary lesion correlates with survival.

A variety of neuropeptide receptors have been detected in human lung cancer. They are thought to play a role in autocrine/paracrine regulation of cell growth, and may be clinically useful as diagnostic, prognostic or therapeutic targets. The current study characterizes the molecular structure of the delta opioid receptor and its gene expression level in lung cancer cell lines relative to normal human lung using a sensitive RT-PCR approach. The goals of this investigation were a) to define the correlation between receptor binding and gene expression in lung cancer cell lines, and b) to determine the cDNA sequence integrity of this receptor in comparison to the receptor recently found in human brain. Five small cell lung cancer (SCLC) cell lines revealed size-matched RT-PCR products which strongly hybridized to the human brain delta opioid receptor probe. One of three non-small cell lung cancer (NSCLC) cell lines (NCI-H23), known to be negative by binding analysis, demonstrated low level expression. No gene expression was found in normal human lung. RT-PCR products from two SCLC cell lines (SCLC-22H and 16HC) as well as the low level expressing NSCLC cell line (NCI-23) were subjected to bidirectional DNA sequence analysis and the receptor ends were resolved using a 3'-end RACE and 5'-end gene-specific approach. The isolated cDNA sequences proved to be identical to the published human brain delta opioid receptor sequence. These data show that lung cancers with neuroendocrine features express human brain delta opioid receptors in contrast to normal lung, and that the delta opioid receptor mRNA in lung cancer is not mutated. This unique feature of lung cancer may be exploitable for diagnostic, prognostic, and therapeutic strategies.