Quantifying the incremental value of deep learning: Application to lung nodule detection.

We present a case study for implementing a machine learning algorithm with an incremental value framework in the domain of lung cancer research. Machine learning methods have often been shown to be competitive with prediction models in some domains; however, implementation of these methods is in early development. Often these methods are only directly compared to existing methods; here we present a framework for assessing the value of a machine learning model by assessing the incremental value. We developed a machine learning model to identify and classify lung nodules and assessed the incremental value added to existing risk prediction models. Multiple external datasets were used for validation. We found that our image model, trained on a dataset from The Cancer Imaging Archive (TCIA), improves upon existing models that are restricted to patient characteristics, but it was inconclusive about whether it improves on models that consider nodule features. Another interesting finding is the variable performance on different datasets, suggesting population generalization with machine learning models may be more challenging than is often considered.

Clinical Utility of Chromosomal Aneusomy in Individuals at High Risk of Lung Cancer.

INTRODUCTION: Low-dose computed tomography screening for lung cancer has a high false-positive rate with frequent discovery of indeterminate pulmonary nodules. Noninvasive biomarkers are needed to reduce false positives and improve risk stratification. A retrospective longitudinal evaluation was performed to assess chromosomal aneusomy in sputum by fluorescence in situ hybridization (CA-FISH) in four nested case-control studies. METHODS: Receiver operating characteristic analysis resulted in two grouped cohorts: a high-risk cohort (Colorado High-Risk Cohort and Colorado Nodule Cohort [68 case patients and 69 controls]) and a screening cohort (American College of Radiology Imaging Network/National Lung Screening Trial and Pittsburgh Lung Screening Study [97 case patients and 185 controls]). The CA-FISH assay was a four-target DNA panel encompassing the EGFR and v-myc avian myelocytomatosis viral oncogene homolog (MYC) genes, and the 5p15 and centromere 6 regions or the fibroblast growth factor 1 gene (FGFR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA). A four-category scale (normal, probably normal, probably abnormal, and abnormal) was applied. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) (with 95% confidence intervals [CIs]) were estimated for each cohort. RESULTS: Sensitivity and specificity were, respectively, 0.67 (95% CI: 0.55-0.78) and 0.94 (95% CI: 0.85-0.98) for high-risk participants and 0.20 (95% CI: 0.13-0.30) and 0.84 (95% CI: 0.78-0.89) for screening participants. The positive and negative LRs were, respectively, 11.66 (95% CI: 4.44-30.63) and 0.34 (95% CI: 0.24-0.48) for high-risk participants and 1.36 (95% CI: 0.81-2.28) and 0.93 (95% CI: 0.83-1.05) for screening participants. CONCLUSION: The high positive LR of sputum CA-FISH indicates that it could be a useful adjunct to low-dose computed tomography for lung cancer in high-risk settings. For screening, however, its low positive LR limits clinical utility. Prospective assessment of CA-FISH in the incidentally identified indeterminate nodule setting is ongoing in the Colorado Pulmonary Nodule Biomarker Trial.

Drivers Motivating Community Health Improvement Plan Completion by Local Public Health Agencies and Community Partners in the Rocky Mountain Region and Western Plains.

CONTEXT: There are numerous drivers that motivate completion of community health improvement plans (CHIPs). Some are more obvious and include voluntary public health accreditation, state requirements, federal and state funding, and nonprofit hospital requirements through IRS regulations. Less is known about other drivers, including involvement of diverse partners and belief in best practices, that may motivate CHIP completion. OBJECTIVE: This research investigated the drivers that motivated CHIP completion based on experiences of 51 local public health agencies (LPHAs). DESIGN: An explanatory mixed-methods design, including closed- and open-ended survey questions and key informant interviews, was used to understand the drivers that motivated CHIP completion. Analysis of survey data involved descriptive statistics. Classical content analysis was used for qualitative data to clarify survey findings. SETTING: The surveys and key informant interviews were conducted in the Rocky Mountain Region and Western Plains among 51 medium and large LPHAs in Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah, and Wyoming. PARTICIPANTS: More than 50% of respondents were public health directors; the balance of the respondents were division/program directors, accreditation coordinators, and public health planners. MAIN OUTCOME MEASURES: CHIP completion. RESULTS: Most LPHAs in the Rocky Mountains and Western Plains have embraced developing and publishing a CHIP, with 80% having completed their plan and another 13% working on it. CHIP completion is motivated by a belief in best practices, with LPHAs and partners seeing the benefit of quality improvement activities linked to the CHIP and the investment of nonprofit hospitals in the process. Completing a CHIP is strengthened through engagement of diverse partners and a well-functioning partnership. CONCLUSION: The future of CHIP creation depends on LPHAs and partners investing in the CHIP as a best practice, dedicating personnel to CHIP activities, and enhancing leadership skills to contribute to a synergistic partnership by effectively working and communicating with diverse partners and developing and achieving common goals.

Colon cancer screening for Colorado's underserved: a community clinic/academic partnership.

BACKGROUND: Colorectal cancer (CRC) is largely preventable by finding and removing adenomas, but many people have not been screened, especially the uninsured with low income. PURPOSE: To establish a statewide infrastructure to ensure that low-income Coloradans receive colonoscopy for CRC screening and diagnostic evaluation. DESIGN: In 2006, a statewide program to provide free colonoscopy to uninsured Coloradans was developed as a partnership between the University of Colorado Cancer Center and Colorado safety-net clinics. Funded by excise tax revenues, the Colorado Colorectal Screening Program (CCSP) successfully embedded screening into primary care, providing patient navigation support and reimbursement that allowed primary care providers to refer patients for colonoscopy. SETTING/PARTICIPANTS: More than 50 safety-net clinics joined the CCSP to provide colonoscopies to uninsured Coloradans with low income, aged ≥50 years or <50 years at elevated risk, lawfully present and needing CRC screening by American Cancer Society consensus guidelines. MAIN OUTCOME MEASURES: Process and clinical outcomes included people screened, show rates, patient satisfaction, and quality measures, such as adenoma detection rate, bowel cleansing quality, and timeliness of care. Program costs and benefits were estimated. The 2013 analysis was completed using 2006-2012 data on 13,252 of 13,774 people receiving colonoscopy. RESULTS: In 2006-2012, the CCSP screened 13,774 people, with 38% minorities and 39% men. Patient navigators ensured >90% of those referred attended their colonoscopy. Adenomas were removed from 27% of patients and 1% had cancers diagnosed. Total direct medical services cost was $998/person receiving colonoscopy. About 325 fewer future incident CRCs were predicted due to adenoma removal, projecting substantial future cost savings. CONCLUSIONS: The CCSP, a successful community clinic/academic partnership provides cost-effective CRC screening and prevention services to low-income uninsured Coloradans and establishes the infrastructure to support screening low-income Coloradans as Affordable Care Act reforms provide payer coverage for them.

Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

OBJECTIVES: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe. DESIGN: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis. SETTING AND PARTICIPANTS: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998. OUTCOME MEASURES: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models. RESULTS: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours. CONCLUSIONS: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

Breast cancer survival in the US and Europe: a CONCORD high-resolution study.

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.

Defining a gene promoter methylation signature in sputum for lung cancer risk assessment.

PURPOSE: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic patients with stage I lung cancer from New Mexico. EXPERIMENTAL DESIGN: Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. RESULTS: Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2-4.2) seen for the PAX5α, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. CONCLUSIONS: These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomographic screening for early detection of lung cancer.

Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.

Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.

The detection of chromosomal aneusomy by fluorescence in situ hybridization in sputum predicts lung cancer incidence.

Lung cancer usually is disseminated (advanced) and has a poor prognosis at diagnosis. Current and former smokers are at a high risk for lung cancer and are candidates for prevention and early detection strategies. Sputum is a potential source of biomarkers that might determine either lung cancer risk or the presence of early lung cancer, but no current sputum test is sufficiently sensitive and specific for effective screening. We used fluorescence in situ hybridization (FISH) to measure chromosomal aneusomy (CA) in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls (matched on age, gender, and date of collection) nested within an ongoing high-risk cohort. The CA-FISH assay was aimed at four DNA targets: epidermal growth factor receptor, MYC, 5p15, and CEP 6. The sensitivity of a positive CA-FISH assay (abnormal for two or more of the four markers) for lung cancer was substantially higher for samples collected within 18 months (76% sensitivity) than for samples collected more than 18 months (31%) before lung cancer diagnosis. Sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). CA-FISH specificity based on samples collected within 18 months before diagnosis was 88%. The adjusted odds ratio (OR) of lung cancer for specimens collected within 18 months before a cancer diagnosis was higher for the CA-FISH assay [OR, 29.9; 95% confidence interval (95% CI), 9.5-94.1] than for previously studied ORs of cytologic atypia (OR, 1.8; 95% CI, 1.3-2.6) and gene promoter methylation (OR, 6.5; 95% CI, 1.2-35.5). Whether CA-FISH is an indicator of extreme risk for incident lung cancer or detects exfoliated cancer cells is unknown. The apparent promise of CA-FISH in sputum for assessing lung cancer risk and/or for lung cancer early detection now needs to be validated in a clinical screening trial.

Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer.

Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3) and 6 (CEP6), may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer). Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS). Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular) and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30-50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p<0.05) and adjusted for histology grade (odds ratio = 17, p<0.05). The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.

The impact of socioeconomic status on survival after cancer in the United States : findings from the National Program of Cancer Registries Patterns of Care Study.

BACKGROUND: Understanding the ways in which socioeconomic status (SES) affects mortality is important for defining strategies to eliminate the unequal burden of cancer by race and ethnicity in the United States. METHODS: Disease stage, treatment, and 5-year mortality rates were ascertained by reviewing medical records, and SES was determined by analyzing income and education at the census tract level for 4844 women with breast cancer, 4332 men with prostate cancer, and 4422 men and women with colorectal cancer who were diagnosed in 7 U.S. states in 1997. RESULTS: Low SES was associated with more advanced disease stage and with less aggressive treatment for all 3 cancers. The hazard ratio (HR) for 5-year all-cause mortality associated with low SES was elevated after a diagnosis of breast cancer when the analysis was adjusted for age (HR, 1.59; 95% confidence interval [CI], 1.35-1.87). Adjustment for mediating factors of race/ethnicity, comorbid conditions, cancer stage, and treatment reduced the association. The age-adjusted mortality risk associated with low SES was elevated after a diagnosis of prostate cancer (HR, 1.33; 95% CI, 1.13-1.57), and multivariate adjustments for mediating factors also reduced that association. There was less association between SES and mortality after a diagnosis of colorectal cancer. For all 3 cancer sites, low SES was a much stronger predictor of mortality among individuals aged <65 years and among individuals from racial/ethnic minority groups. CONCLUSIONS: The current results indicated that low SES is a risk factor for all-cause mortality after a diagnosis of cancer, largely because of a later stage at diagnosis and less aggressive treatment. These findings support the need to focus on SES as an underlying factor in cancer disparities by race and ethnicity.

Survival difference between non-Hispanic black and non-Hispanic white women with localized breast cancer: the impact of guideline-concordant therapy.

OBJECTIVES: This study examined the impact of guideline-concordant therapy on the survival difference between non-Hispanic black (NHB) and non-Hispanic white (NHW) women with localized breast cancer. METHODS: Data analyzed were from the CDC's NPCR Patterns of Care study in which seven population-based state cancer registries participated. We randomly selected 2,362 women who were diagnosed with a first primary localized breast cancer in 1997. Data were abstracted from hospital records, supplemented by information from physician offices and by linkages with state vital records and the National Death Index database. RESULTS: NHB women were more likely than NHW women to receive breast conserving surgery without radiation therapy. In addition, the percentage of NHB women with hormone receptor-positive tumors who received hormonal therapy was lower than that of NHW women. Among those with a tumor size > 3 cm, NHB women were more likely than NHW women to receive multiagent chemotherapy. After controlling for age, the risk of dying from all causes of death was 2.35 times as high for NHB women compared to NHW women. Controlling for treatment further reduced black-white difference in survival with adjustment for sociodemographic and clinical variables. CONCLUSION: NHB women were less likely than NHW women to receive guideline-concordant radiation therapy after breast conserving therapy and hormonal therapy but were more likely to receive chemotherapy. Racial differences in treatment contribute significantly to the worse survival of NHB women compared with NHW women.

Sputum cytologic atypia predicts incident lung cancer: defining latency and histologic specificity.

BACKGROUND: There is a need for early detection methods for lung cancer. Radiologic imaging may be more sensitive for peripheral cancers than for cancers arising in the central airways, from which bronchial epithelial cells are exfoliated into the sputum. METHODS: Sputum samples were collected at baseline and periodically thereafter in a cohort of smokers and former smokers with chronic obstructive lung disease. The association between cytologic atypia and incident lung cancer was assessed by hazard ratios (HR; 95% confidence intervals) using Cox regression and by odds ratios (95% confidence intervals) using logistic regression, adjusting for potential confounding factors. RESULTS: We observed 174 incident lung cancers in a cohort of 2,521 people over 9,869 person-years of observation. Risk for incident lung cancer was increased among those with cytologic atypia graded as moderate or worse (adjusted HR, 2.37; 1.68-3.34). The association between sputum atypia and lung cancer incidence was greatest for those sputum samples collected 5 months or less before the diagnosis of lung cancer (odds ratio, 10.32; 5.34-19.97). The association was substantially stronger for squamous cell lung cancers (HR, 5.13; 2.89-9.10) than for adenocarcinomas (HR, 1.85; 0.94-3.65). CONCLUSION: Cytologic atypia is a marker for increased lung cancer risk. These cytologic changes seem to arise from late events that are most apparent for cancers arising in the central respiratory airways. Whether cytologic atypia might complement radiologic imaging in a combined approach to lung cancer, early detection requires additional evaluation of those two methods used together.

Chromosomal aneusomy in bronchial high-grade lesions is associated with invasive lung cancer.

RATIONALE: The development of lung cancer (LC) is accompanied by field changes in the airway mucosa that may have prognostic importance. OBJECTIVES: To compare patients with prevalent LC to control subjects regarding their histologic dysplasia scores and chromosomal aneusomy as measured by fluorescence in situ hybridization (FISH). METHODS: The most advanced bronchial histology lesion was assessed from each of 44 LC cases and 90 cancer-free control subjects using a four-color FISH probe set encompassing the chromosome 6 centromere, 5p15.2, 7p12 (epidermal growth factor receptor), and 8q24 v-myc myelocytomatosis viral oncogene homolog (MYC) sequences. Histology grades were coded as dysplasia (moderate or severe) or carcinoma in situ (CIS). MEASUREMENTS AND MAIN RESULTS: CIS was the highest histologic grade for 32 subjects, and dysplasia was the highest grade for 102 subjects (54 moderate, 48 severe). Chromosomal aneusomy was seen in 64% of the LC cases, but in only 31% of the control subjects (odds ratio [OR], 4.68; 95% confidence interval [CI]. 1.97-11.04). Among those with any level of dysplasia, the OR for positive FISH and LC was 2.28 (95% CI, 0.75-6.86). Among those with CIS, the OR for positive FISH and LC was 5.84 (95% CI, 1.31-26.01). CONCLUSIONS: Chromosomal aneusomy is associated with LC. Prospective examination of aneusomy as a precursor lesion that predicts LC is needed.

Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort.

A sensitive screening approach for lung cancer could markedly reduce the high mortality rate for this disease. Previous studies have shown that methylation of gene promoters is present in exfoliated cells within sputum prior to lung cancer diagnosis. The purpose of the current study is to conduct a nested case-control study of incident lung cancer cases from an extremely high-risk cohort for evaluating promoter methylation of 14 genes in sputum. Controls (n = 92) were cohort members matched to cases (n = 98) by gender, age, and month of enrollment. The comparison of proximal sputum collected within 18 months to >18 months prior to diagnosis showed that the prevalence for methylation of gene promoters increased as the time to lung cancer diagnosis decreased. Six of 14 genes were associated with a >50% increased lung cancer risk. The concomitant methylation of three or more of these six genes was associated with a 6.5-fold increased risk and a sensitivity and specificity of 64%. This is the first study to prospectively examine a large panel of genes for their ability to predict lung cancer and shows the promise of gene promoter hypermethylation in sputum as a molecular marker for identifying people at high risk for cancer incidence.

Lack of association between sputum atypia and chronic obstructive pulmonary disease mortality.

HYPOTHESIS: Chronic obstructive pulmonary disease (COPD) and lung cancer are thought to share common elements in pathogenesis. The authors hypothesized that sputum atypia would reflect the processes leading to progressive airflow obstruction and might be a novel biomarker of more rapidly progressive COPD. METHODS: The authors analyzed the association between COPD death and sputum cytologic atypia in an ongoing cohort of 2013 smokers with varying degrees of airflow obstruction during the period between January 1, 1993, and July 1, 2001. RESULTS: There were 326 deaths attributed to COPD over 4495 person-years, giving a COPD death rate of 7.25 deaths per 100 person-years, which is highly elevated compared with fewer than 0.2 COPD deaths per 100 person-years for the United States population aged between 65 and 74 years. Sputum atypia was not associated with either the degree of airflow obstruction or death from COPD. COPD death was associated with age and degree of airflow obstruction, as expected. CONCLUSION: Sputum cytologic atypia is not predictive of death from COPD. As sputum cytologic grades of moderate or worse atypia are associated with a significant increase in the risk for lung cancer and do not denote a group with increased competing death rates from COPD, patients with sputum atypia are a good high risk group in whom chemoprevention and early detection studies can be conducted.

Multi-target interphase fluorescence in situ hybridization assay increases sensitivity of sputum cytology as a predictor of lung cancer.

Survival rates for lung cancer are low because patients have disseminated disease at diagnosis; therefore tests for early diagnosis are highly desirable. This pilot study investigated occurrence of chromosomal aneusomy in sputum from a 33 case-control cohort matched on age, gender, and date of sample collection. Subjects had chronic obstructive pulmonary disease and > or = 30 pack-years of tobacco use, and aneusomy was tested using a multi-target DNA FISH assay (LAVysion, Abbott/Vysis). In specimens collected within 12 months of lung cancer diagnosis, abnormality was more frequent among the 18 cases (41%) than the 17 controls (6%; P = 0.04). Aneusomy had no significant association with cytologic atypia, which might indicate that molecular and morphological changes could be independent markers of tumorigenesis. Combining both tests, abnormality was found in 83% of the cases and 20% of the controls (P = 0.0004) suggesting that FISH may improve the sensitivity of cytologic atypia as a predictor of lung cancer.

Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction.

Individuals with cytological atypia in sputum may be at increased risk for lung cancer. We conducted a longitudinal analysis of the association between lung cancer incidence and cytological atypia in sputum samples collected prospectively from an ongoing cohort of adults at high risk for lung cancer. Cohort members had a smoking history of > or = 30 pack-years and chronic obstructive pulmonary disease documented by pulmonary airflow testing. Sputum samples collected at baseline and periodically thereafter were examined by standard cytological methods. From the cohort of 2,006 people, there were 83 incident lung cancers over 4,469 person-years of observation. At baseline, the association between personal and behavioral characteristics, and sputum cytological atypia was assessed by multiple logistic regression. The association between sputum cytological atypia and incident lung cancer was then assessed by hazard ratios using proportional hazards regression analysis, adjusting for potential confounding factors. Cytological atypia graded as moderate or worse was associated with continuing cigarette smoking (adjusted odds ratio, 2.5; 95% confidence interval, 1.5-4.1), and with lower levels of intake of fruits and vegetables (P for trend = 0.04). Atypia was not associated with several other factors, including the degree of airflow obstruction, the use of vitamin supplements, nonsteroidal anti-inflammatory drugs, or metered-dose steroid inhalers. Incident lung cancer was increased among those with moderate or worse cytological atypia (adjusted hazards ratio, 2.8; 95% confidence interval, 1.4-5.5). This association was not confounded by other risk factors. We conclude that in this high-risk cohort, cytological atypia is associated with continuing smoking and low intake of fruits and vegetables, but that independent of these and other factors, the risk of incident lung cancer is increased among those with moderate or worse grades of cytological atypia in their sputum.