BACKGROUND The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop. METHODS We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCOM2012) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk. RESULTS The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCOM2012 criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P = 0.01), without loss of specificity (62.9% and. 62.7%, respectively; P = 0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCOM2012 risk (P = 0.61 for interaction). CONCLUSIONS The use of the PLCOM2012 model was more sensitive than the NLST criteria for lung-cancer detection.

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The PLCO lung cancer risk models demonstrate high discrimination and calibration.

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clinicaltrials.gov Identifier: NCT00002540.

While severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor (TNF)-α] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein (CRP), sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. Odds ratios (OR) and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR 1.7, 95% CI 1.1–2.8; Ptrend=0.02) and sCD27 (OR 5.3, 95% CI 2.9–9.4; Ptrend<0.0001). These associations remained in analyses of cases diagnosed 6+ years following blood collection (sTNF-R1: OR 2.1, 95% CI 1.0–4.0, Ptrend=0.01; sCD27: OR 4.1, 95% CI 1.9–8.5, Ptrend=0.0001). Elevated levels of IL-10, TNF-α and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis, and were null for cases diagnosed 6+ years post-collection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis.

In the baseline screen, nearly half the cancers were stage I. Whether this experience results in a reduction in lung cancer mortality is yet to be seen.

IntroductionCD30 is a member of the tumor necrosis factor receptor superfamily. Originally described as a marker on Reed-Sternberg cells in Hodgkin lymphoma (HL), CD30 is expressed widely in HL and anaplastic large-cell lymphoma (ALCL), a rare subtype of nonHodgkin lymphoma (NHL), and infrequently expressed among other types of NHL. 1,2 Among normal lymphocytes, CD30 is expressed only by activated B cells and T cells. In the case of T cells, CD30 is preferentially expressed by activated cells predisposed to producing T helper 2 (Th2)-type B-cell-stimulatory cytokines. 3,4 The interaction of CD30 with its ligand (CD30L) appears to promote secondary humoral responses in normal B cells. 5 The effects of CD30 activation on tumor cells appear to be complex: they appear to induce cell proliferation in HL cells of T-cell origin and to promote apoptosis in ALCL cells. 6,7 The extracellular portion of CD30 is proteolytically cleaved from CD30 ϩ cells, possibly on activation by CD30L, to produce a soluble form of the molecule (sCD30) detectable in serum. 5 Elevated serum sCD30 is observed for several viral infections, autoimmune diseases, and atopic conditions, 1,5 and has been proposed as a marker for a Th2-oriented immune response. 4,8,9 Increased circulating sCD30 is also present among CD30 ϩ lymphoid malignancies such as HL and ALCL. 1,5 The physiologic effects, if any, of sCD30 are unknown. 5,6 Sustained B-cell proliferation is suspected to be an important mechanism contributing to the accumulation of genetic errors that can lead to lymphomagenesis. 10,11 Breen et al recently hypothesized that elevated circulating sCD30 levels reflect an immunologic milieu conducive to B-cell NHL, 12 which includes more than 90% of all diagnosed NHL. 13 In a small nested case-control investigation conducted within the Multicenter AIDS Cohort Study, they observed significantly higher baseline serum sCD30 levels among persons who subsequently developed AIDS-related NHL compared with cancer-free controls. 12 To determine whether circulating sCD30 levels are associated with NHL risk among immunocompetent persons, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. MethodsDetailed descriptions of the PLCO Cancer Screening Trial have been previously reported. In brief, between 1993 and 2001, approximately 155 000 subjects in 10 cities (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St Louis, MO; and Washington, DC) 55 to 74 years of age were recruited from the general population and randomized to the screening or nonscreening arm of the study. All screening-arm subjects provided nonfasting baseline blood samples that were processed and frozen within 2 hours of collection and stored at Ϫ70°C. Persons were followed up for all cancer diagnoses by annual mailed questionnaire, in addition to the PLCO Cancer Screening Trial disease outcomes by annual screening examinations during the first 6 years of ...