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Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions. We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40-69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking. These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.

Background: Early changes in alpha-fetoprotein (AFP) are a promising surrogate endpoint for systemic treatment outcomes in hepatocellular carcinoma (HCC). Objectives: We sought to investigate the utility of AFP response across first-line sorafenib (1L SOR) and later-line checkpoint inhibitor (CPI) therapies. Design: We conducted a multicenter, retrospective cohort study of patients with advanced HCC who received 1L SOR and any subsequent CPI. Methods: The primary outcomes were overall survival (OS) and time on treatment (TOT). Pre-treatment AFP and the lowest AFP within 3 months of treatment initiation were used to calculate the percent change in AFP for each treatment. AFP response was defined as an AFP reduction by ⩾20% within 3 months, and AFP progression was defined as an increase in AFP by ⩾20% within 3 months. Patients with baseline AFP < 20 ng/mL were considered not evaluable for AFP change. Results: Of 176 study patients, 46 (28%) received CPI after SOR, and 125 (71%) had a baseline AFP ⩾ 20. Patients who experienced AFP response on SOR had significantly longer OS and TOT than those who did not and those who were not evaluable (OS: median 689 vs 320 vs 452 days, log-rank p < 0.001; TOT: median log of days 5.2 vs 4.5 vs 4.9, p < 0.001). Patients with AFP progression following SOR had significantly shorter OS than those who did not and those who were not evaluable (median 304 vs 557 vs 452, log-rank p = 0.008). Similarly, patients with AFP response following CPI therapy had a significantly reduced risk of death compared with those who did not have an AFP response (hazard ratio 0.13, 95% confidence interval 0.03–0.60, p = 0.009). Conclusion: Early AFP response with 1L SOR and any subsequent CPI was associated with longer OS and TOT, and early AFP progression was associated with shorter OS and TOT. These data support utilizing longitudinal AFP changes as a surrogate endpoint in HCC systemic therapy.

Abstract Background KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). Materials and Methods We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. Results One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. Conclusions Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA. This retrospective analysis of patients with metastatic and locally advanced pancreatic ductal adenocarcinoma characterizes prognostic or predictive genomic markers for this patient population, with a focus on KRAS mutational variants and their interaction with concurrent molecular alterations.

Objectives Most previous studies of the association between psychosocial stress and musculoskeletal illness among computer users have been cross-sectional and have yielded inconsistent results. The association between a measure of psychosocial stress, \"job strain\", and incident neck-shoulder and arm-hand musculoskeletal symptoms was investigated among recently hired computer users. Methods The participants worked for one of several large employers and were followed prospectively for 6 months. The \"job demands\" and \"decision latitude\" subscales of the Job Content Questionnaire were used to estimate the job-strain quadrants and a ratio measure of job strain which was subsequently categorized. Incident musculoskeletal symptoms were obtained with weekly diaries. Proportional hazards models were used to estimate associations between job strain and incident musculoskeletal symptoms. Results Those in the high-strain quadrant were at increased risk of neck-shoulder symptoms [hazard ratio (HR) 1.65, 95% confidence interval (95% CI) 0.91-2.99] when compared with those in the low-strain quadrant. Those in the highest strain-ratio category were also at increased risk of neck-shoulder symptoms when compared with those in the lowest strain-ratio category (HR 1.52,95% CI 0.88-2.62). Modification by previous years of computer use was observed, with an elevated risk observed for those in the highest job-strain ratio category who also had low previous computer use (HR 3.16, 95% CI 1.25-8.00). There did not appear to be an association between either measure of job strain and incident arm-hand symptoms. Conclusions In this cohort, workers who reported high job strain were more likely to develop neck-shoulder symptoms.

Objective: Previous studies suggest that smoking may be inversely associated with risk of melanoma. We attempted to replicate this finding using data from the Cancer Prevention Study II (CPS-II) and CPS-II Nutrition cohort, two large prospective cohort studies of cancer mortality and incidence, respectively, with long-term follow-up. Methods: Cox proportional hazards regression analysis was used to examine the association between smoking status and risk of melanoma mortality and incidence among Caucasians in these cohorts. Analyses were adjusted by age, occupation, latitude and educational status. Results: The incidence rate of melanoma was lower in current than never smokers in both men [hazard ratio (HR): 0.70, 95% confidence interval (CI): (0.48-1.02)] and women [0.50 (0.30-0.83)]; incidence was not lower in former than in never smokers for either sex. The death rate from melanoma was lower in male current than never smokers [0.77 (0.62-0.94)], and in male and female former smokers [0.86 (0.73-1.01)] and [0.83 (0.65-1.06)], respectively. No trends in incidence or mortality were observed in male or female current smokers with years of smoking or cigarettes per day. Conclusions: This study provides limited support for the hypothesis that smoking reduces melanoma risk. The inconsistent results by smoking status and lack of clear dose-response relationships weaken the evidence for causality.

Objective Growing evidence that ultrafine particles in ambient air can cause brain lesions in animals led us to investigate whether particulate components of air pollution may be associated with brain cancer risk in humans. Air pollution has been associated with respiratory disorders and cardiovascular morbidity and mortality, but associations between air pollutants and brain cancer have not been investigated in adults. Methods The analyses included 1,284 deaths due to brain cancer from the Cancer Prevention Study-II, an ongoing prospective mortality study of adults in the United States and Puerto Rico conducted by the American Cancer Society. Air pollution data from national databases for metropolitan areas were combined with residential history and vital status data to estimate exposure to particulate and gaseous air pollution. Results We found no elevated risk for estimated measures of air pollutants, an unanticipated reduction in risk was found between gaseous air pollutants and brain cancer mortality. Conclusion The findings do not provide evidence of increased risk of brain cancer mortality due to air pollutants.