A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma.

Prediagnostic serum concentration of soluble CD30 (sCD30), a marker for chronic B-cell stimulation, has been associated with increased risk of developing AIDS-related non-Hodgkin lymphoma (NHL) in a recent study of HIV(+) patients. To investigate among healthy persons whether serum sCD30 is associated with NHL risk, we carried out a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. There was a strong dose-response relationship between prediagnostic sCD30 concentration and NHL risk among 234 cases and 234 individually matched controls (odds ratio [95% confidence interval] for second, third, and fourth quartiles vs first quartile: 1.4 [0.8-2.6], 2.2 [1.2-4.1], 4.1 [2.2-7.8]; P(trend) < .001), which persisted among cases diagnosed 6 to 10 years after providing a blood sample. Given that a similar relationship has been observed among HIV(+) patients, our findings suggest that chronic B-cell stimulation may be an important mechanism involved in B-cell lymphomagenesis among severely immunocompromised and healthy populations alike.

Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial.

CONTEXT: The effect on mortality of screening for lung cancer with modern chest radiographs is unknown. OBJECTIVE: To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed. INTERVENTION: Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009. MAIN OUTCOME MEASURES: Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality. RESULTS: Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10). CONCLUSION: Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00002540.

Associations between anthropometry, cigarette smoking, alcohol consumption, and non-Hodgkin lymphoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Prospective studies of lifestyle and non-Hodgkin lymphoma (NHL) are conflicting, and some are inconsistent with case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was used to evaluate risk of NHL and its subtypes in association with anthropometric factors, smoking, and alcohol consumption in a prospective cohort study. Lifestyle was assessed via questionnaire among 142,982 male and female participants aged 55-74 years enrolled in the PLCO Trial during 1993-2001. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards regression. During 1,201,074 person-years of follow-up through 2006, 1,264 histologically confirmed NHL cases were identified. Higher body mass index (BMI; weight (kg)/height (m)(2)) at ages 20 and 50 years and at baseline was associated with increased NHL risk (P(trend) < 0.01 for all; e.g., for baseline BMI > or =30 vs. 18.5-24.9, hazard ratio = 1.32, 95% confidence interval: 1.13, 1.54). Smoking was not associated with NHL overall but was inversely associated with follicular lymphoma (ever smoking vs. never: hazard ratio = 0.62, 95% confidence interval: 0.45, 0.85). Alcohol consumption was unrelated to NHL (drinks/week: P(trend) = 0.187). These data support previous studies suggesting that BMI is positively associated with NHL, show an inverse association between smoking and follicular lymphoma (perhaps due to residual confounding), and do not support a causal association between alcohol and NHL.

Appraisal of immunoglobulin free light chain as a marker of response.

The immunoglobulin free light chain (FLC) assay is an invaluable tool for following patients with oligosecretory plasma cell dyscrasia. Baseline values have also been shown to be prognostic in all plasma cell disorders tested. A looming question, however, is the role it should play in following myeloma patients with disease that is measurable using serum and urine electrophoresis. We used the data and stored samples from a mature Eastern Cooperative Oncology Group clinical trial (E9486) to assess serum levels of FLC at baseline and after 2 months of alkylator-based therapy. For serial determinations, the absolute level of involved serum FLC or the difference of the involved and uninvolved FLC is preferred over the ratio of involved to uninvolved FLC. FLC response after 2 months of therapy was superior to early M-protein measurement to predict overall response. The ideal cut-point for FLC change appears to be between 40% and 50% reduction. The correlation between serial measurements of serum FLC and urine M-protein is inadequate to abolish the serial 24-hour urine protein. Although baseline values of FLC are prognostic in newly diagnosed myeloma patients, serial measurements do not appear to have added value in patients who have M-proteins measurable by electrophoresis.

Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival.

BACKGROUND: We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma. We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials. RESULTS: Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes. CONCLUSION: A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.

Factors associated with human small aggressive non small cell lung cancer.

BACKGROUND: Some non-small cell lung cancers (NSCLC) progress to distant lymph nodes or metastasize while relatively small. Such small aggressive NSCLCs (SA-NSCLC) are no longer resectable with curative intent, carry a grave prognosis, and may involve unique biological pathways. This is a study of factors associated with SA-NSCLC. METHODS: A nested case-case study was embedded in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. SA-NSCLC cases had stage T1, N3, and/or M1 NSCLC (n = 48) and non-SA-NSCLC cases had T2 to T3, N0 to N2, and M0 NSCLC (n = 329). Associations were assessed by multiple logistic regression. RESULTS: SA-NSCLCs were associated with younger age at diagnosis [odds ratio (OR)(>or=65 versus <65), 0.44; 95% confidence interval (95% CI), 0.22-0.88], female gender, family history of lung cancer, and the interaction gender*family history of lung cancer and were inversely associated with ibuprofen use (OR(yes versus no), 0.29; 95% CI, 0.11-0.76). The ORs for associating gender (women versus men) with SA-NSCLC in those with and without a family history of lung cancer were 11.76 (95% CI, 2.00-69.22) and 1.86 (95% CI, 0.88-3.96), respectively. These associations held adjusted for histology and time from screening to diagnosis and when alternative controls were assessed. CONCLUSION: SA-NSCLC was associated with female gender, especially in those with a family history of lung cancer. If these exploratory findings, which are subject to bias, are validated as causal, elucidation of the genetic and female factors involved may improve understanding of cancer progression and lead to preventions and therapies. Ibuprofen may inhibit lung cancer progression.

Abnormalities on chest radiograph reported in subjects in a cancer screening trial.

BACKGROUND: Chest radiographs (CXRs) are commonly performed for diagnostic and other purposes. There is little literature either on the prevalence in the general population of various abnormalities seen on CXRs or on the risks associated with these abnormalities. METHODS: We followed up > 70,000 men and women who were enrolled in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Subjects received four annual posteroanterior CXRs for the early detection of lung cancer. Radiologists noted the presence of non-cancer-related abnormalities as well as nodules/masses that were suspicious for lung cancer. Subjects were followed up for mortality and cancer incidence. RESULTS: Abnormalities that were not suspicious for lung cancer were observed on 35% of examinations, compared to 8% of examinations with findings that were suspicious for cancer. The most commonly reported noncancer abnormalities were granuloma (10.7% of examinations), scarring/pulmonary fibrosis (8.2% of examinations), bone/soft tissue lesions (5.5% of examinations), cardiac abnormalities (4.4% of examinations), pleural fibrosis (3.6% of examinations), and COPD/emphysema (2.5% of examinations). Most noncancer abnormalities were more prevalent in men, older subjects, and smokers. Controlling for age, smoking, and other factors, scarring/pulmonary fibrosis was significantly associated with an increased risk of lung cancer with a hazard ratio (HR) of 2.0, while cardiac abnormalities (HR, 2.1), scarring/pulmonary fibrosis (HR, 1.4), COPD (HR, 1.7), and pleural fluid (HR, 2.3) were significantly associated with increased overall (ie, non-lung cancer) mortality. CONCLUSION: Abnormalities that are not suspicious for lung cancer are common in a population undergoing screening. Some of these abnormalities are associated with an increased risk for lung cancer incidence and/or overall mortality.

Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study.

Chromosome 13 abnormalities (Delta13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of Delta13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for Delta13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with Delta13 were more likely to have a serum monoclonal protein at a concentration < or =1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), gamma light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and Delta13 correlated (P = 0.03). Patients with Delta13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and had a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of Delta13 and survival remained an independent prognostic variable in a regression model. Among patients with Delta13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features.

Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation.

These consensus guidelines have been compiled with input from the Scientific Advisors of the International Myeloma Foundation. Their production involved several steps including: A 3-day Scientific Advisors meeting, during which each specific area was presented and discussed (May 2002). Review of key literature, especially randomized study results, but also Medline, Internet, Cochrane database searches, and prior guidelines (Br J Haematol 115: 522-540, 2001). Feedback from patients participating in the International Myeloma Foundation, patient programs. These guidelines encompass both the published literature and expert opinions. Recommendations based upon expert opinions are identified as such. The intent is for the guidelines to be international in scope, plus provide recommendations for both clinical practice and research approaches. 'Consensus' reflects general, although not necessarily unanimous, agreement. Details are discussed as appropriate. For convenience, the recommendations are divided into: 1. Diagnostic criteria. 2. Staging and prognostic factors. 3. Frontline therapy. 4. High-dose therapy and transplant. 5. Maintenance therapy. 6. Supportive care and management of specific complications. 7. Novel therapies and new technologies.

Pentostatin, chlorambucil and prednisone therapy for B-chronic lymphocytic leukemia: a phase I/II study by the Eastern Cooperative Oncology Group study E1488.

Pentostatin is a purine nucleoside analog with demonstrated activity in low-grade lymphoid malignancies. The purpose of this study was to determine the dose of pentostatin (dCF) that could be combined with chlorambucil and prednisone to treat chronic lymphocytic leukemia (CLL), evaluate the toxicity of the resulting regimen and to estimate its efficacy. This was a multi-institutional Eastern Cooperative Oncology Group (ECOG) phase I-II study. Individuals with active B-CLL were eligible if they had no prior treatment or were in sensitive first relapse, provided they had normal renal and hepatic function. Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m2 and prednisone 80 mg/day, 1-5 of each 14-day cycle. The pentostatin dose was 2 mg/m2 IV, day 1 for the first 6 patients; 3 mg/m2 IV, day 1 for the next 6 patients; and 4 mg/m2 IV, day 1 for the last set of 6 patients. Fifty-five patients were entered. Because of increasing toxicity with no apparent improvement in clinical efficacy on escalation of the pentostatin dose, 2 mg/m2 was chosen as the phase II dose, and 43 patients were treated at this level. Thirty-nine of these patients were eligible, of which 38 were evaluable for response, 36 of these 38 had no prior treatment. Complete response (CR) manifested by normal bone marrow morphology, peripheral blood counts and resolution of any lymphadenopathy or hepatosplenomegaly occurred in 17 patients (45%). The overall objective response rate was 87%. The median response duration was 33 months and the median survival 5 years. The median time to treatment failure is 32 months. Severe (Grade 3+) infections were seen in 31% of patients and included bacterial pneumonia (n = 4), Pneumocystis pneumonia (n = 1), fungal pneumonia (n = 2), urinary tract infection with sepsis (n = 1) and Herpes Zoster (n = 5). Overall, 11 patients had H. Zoster while on study. Due to toxicity, 33% of patients stopped therapy. Pentostatin, chlorambucil and prednisone is a highly active regimen in CLL but cannot be recommended in present form because of an unacceptable incidence of opportunistic infections. These findings add to other recent reports which suggest combination therapy with pentostatin and alkylators are active in B-CLL. However, these combination chemotherapies will need to be combined with appropriate addition of anti-bacterial and anti-viral prophylaxis to reduce infection risk for B-CLL patients.

A randomized trial of induction therapy (daunorubicin, vincristine, prednisone versus daunorubicin, vincristine, prednisone, cytarabine and 6-thioguanine) in adult acute lymphoblastic leukemia with long-term follow-up: an Eastern Cooperative Oncology Group Study (E3486).

In this study of previously untreated adult acute lymphocytic leukemia (ALL) performed by the Eastern Cooperative Oncology Group, patients were randomized to induction therapy with either DVP (daunorubicin 45 mg/m2 daily, days 1, 2 and 3; prednisone 60 mg/m2 daily orally days 1-35; and vincristine 2 mg intravenously on days 1, 8, 15 and 22) or DATVP (daunorubicin 60 mg/m2 daily, days 1, 2 and 3; cytarabine 25 mg/m2 intravenous bolus followed by 200 mg/m2 daily as a continuous infusion on days 1-5; 6-thioguanine 100 mg/m2 orally every 12 h on days 1-5; vincristine 2 mg intravenously on days 1 and 8; and prednisone 60 mg/m2/day orally, days 1-7. Complete responders to both regimens received the same post-remission therapy, which consisted of a single course of cytarabine 3 gm/m2 infused over 1 h every 12 h for 12 doses. One month later those patients still in remission received six cycles of consolidation therapy with MACHO (cyclophosphamide 650 mg/m2, doxorubicin 40 mg/m2 vincristine 2mg all intravenously on day 1 with prednisone 100 mg/m2 orally daily on days 1-5. Methotrexate 200 mg/m2 intravenously and L-asparaginase 6000 U/m2 were given on day 22 and each course was given every 5 weeks. A single dose of intrathecal methotrexate was also given with each MACHO course. There were 276 evaluable patients randomized in this study. Complete response rates were 71% for DVP and 58% for DATVP. Median durations of complete response were 5.5 and 6.8 months, respectively. Median survival of all randomized patients was 14.4 months in each group. DATVP was more toxic than DVP. Intensification of treatment for adults with ALL may not improve outcome. Progress in the treatment of adults with ALL will require the identification of new agents for this neoplasm.

Interval lung cancers not detected on screening chest X-rays: How are they different?

BACKGROUND: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial provides us an opportunity to describe interval lung cancers not detected by screening chest X-ray (CXR) compared to screen-detected cancers. METHODS: Participants were screened for lung cancer with CXR at baseline and annually for two (never smokers) or three (ever smokers) more years. Screen-detected cancers were those with a positive CXR and diagnosed within 12 months. Putative interval cancers were those with a negative CXR screen but with a diagnosis of lung cancer within 12 months. Potential interval cancers were re-reviewed to determine whether lung cancer was missed and probably present during the initial interpretation or whether the lesion was a "true interval" cancer. RESULTS: 77,445 participants were randomized to the intervention arm with 70,633 screened. Of 5227 positive screens from any screening round, 299 resulted in screen-detected lung cancers; 151 had potential interval cancers with 127 CXR available for re-review. Cancer was probably present in 45/127 (35.4%) at time of screening; 82 (64.6%) were "true interval" cancers. Compared to screen-detected cancers, true interval cancers were more common among males, persons with <12 years education and those with a history of smoking. True interval lung cancers were more often small cell, 28.1% vs. 7.4%, and less often adenocarcinoma, 25.6% vs. 56.2% (p<0.001), more advanced stage IV (30.5% vs. 16.6%, p<0.02), and less likely to be in the right upper lobe, 17.1% vs. 36.1% (p<0.02). CONCLUSION: True interval lung cancers differ from CXR-screen-detected cancers with regard to demographic variables, stage, cell type and location. ClinicalTrials.gov number: NCT00002540.

Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial.

Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55-74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy.

Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation.

INTRODUCTION: Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. METHODS: Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. RESULTS: During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. CONCLUSION: The PLCO lung cancer risk models demonstrate high discrimination and calibration.

Dietary factors and risk of chronic lymphocytic leukemia and small lymphocytic lymphoma: a pooled analysis of two prospective studies.

BACKGROUND: Other than male sex, family history, advanced age, and race, risk factors for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are unknown. Very few studies have investigated diet in relation to these leukemias, and no consistent associations are known. METHODS: Using two large prospective population-based studies, we evaluated the relationship between diet and CLL/SLL risk. Among 525,982 men and women free of cancer at enrollment, we identified 1,129 incident CLL/SLL cases during 11.2 years of follow-up. RESULTS: We found no associations between total fat, saturated fat, fiber, red meat, processed meat, fruit, or vegetable intake and risk of CLL/SLL. We noted a suggestive positive association between body mass index and CLL/SLL (hazard ratio, 1.30; 95% confidence interval, 0.99-1.36). CONCLUSION: We did not find any associations between food or nutrient intake and CLL/SLL. IMPACT: Our large prospective study indicates that diet may not play a role in CLL/SLL development.

Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung cancer risk.

A previously published case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found a significant relationship of serum levels of total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides) to prospective lung cancer risk. The present paper examines this relationship in the context of single-nucleotide polymorphisms (SNPs) in genes important in the metabolism of tobacco smoke carcinogens. DNA was extracted from the subjects' lymphocytes and analyzed for SNPs in 11 locations on four genes related to tobacco carcinogen metabolism. Logistic regressions on case-control status were used to estimate main effects of SNPs and biomarkers and their interactions adjusting for potential confounders. Of the 11 SNPs, only one, in CYP1B1, significantly interacted with total NNAL affecting risk for lung cancer. At low NNAL levels, the variant appeared protective. However, for those with the minor variant, the risk for lung cancer increased with increasing NNAL five times as rapidly compared to those without it, so that at high NNAL levels, this SNP's protection disappears. Analyzing only adenocarcinomas, the effect of the variant was even stronger, with the risk of cancer increasing six times as fast. A common polymorphism of CYP1B1 may play a role in the risk of NNK, a powerful lung carcinogen, in the development of lung cancer in smokers.

Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

BACKGROUND: The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers. METHODS: A total of 77 464 participants, aged 55-74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided. RESULTS: Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%-7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (P(trend) < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non-small cell lung cancers. Among non-small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I-II) stage. CONCLUSIONS: The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.