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Incidence of esophageal and gastric cancer has been linked to low B‐vitamin status. We conducted matched nested case–control studies of incident esophageal squamous cell carcinoma (ESCC; 340 case–control pairs) and gastric cancer (GC; 352 case–control pairs) within the Golestan Cohort Study. The primary exposure was plasma biomarkers: riboflavin and flavin mononucleotide (FMN) (vitamin B2), pyridoxal phosphate (PLP) (B6), cobalamin (B12), para‐aminobenzoylglutamate (pABG) (folate), and total homocysteine (tHcy); and indicators for deficiency: 3‐hydroxykyurenine‐ratio (HK‐r for vitamin B6) and methylmalonic acid (MMA for B12). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression adjusting for matching factors and potential confounders. High proportions of participants had low B‐vitamin and high tHcy levels. None of the measured vitamin B levels was associated with the risk of ESCC and GC, but elevated level of MMA was marginally associated with ESCC (OR = 1.42, 95% CI = 0.99–2.04) and associated with GC (OR = 1.53, 95% CI = 1.05–2.22). Risk of GC was higher for the highest versus lowest quartile of HK‐r (OR = 1.95, 95%CI = 1.19–3.21) and for elevated versus non‐elevated HK‐r level (OR = 1.59, 95% CI = 1.13–2.25). Risk of ESCC (OR = 2.81, 95% CI = 1.54–5.13) and gastric cancer (OR = 2.09, 95%CI = 1.17–3.73) was higher for the highest versus lowest quartile of tHcy. In conclusion, insufficient vitamin B12 was associated with higher risk of ESCC and GC, and insufficient vitamin B6 status was associated with higher risk of GC in this population with prevalent low plasma B‐vitamin status. Higher level of tHcy, a global indicator of OCM function, was associated with higher risk of ESCC and GC. [ABSTRACT FROM AUTHOR]

Objectives: To determine the associations between waterpipe use, duration, and intensity of use with prevalence and incidence of metabolic syndrome and its components (increased waist circumference, triglycerides, fasting glucose, blood pressure and decreased high-density lipoprotein cholesterol). Methods: We conducted cross-sectional and prospective analyses using data from the Pars Cohort Study in southern Iran, encompassing 9,264 participants at the baseline, and 5,002 randomly selected in a repeated follow-up. We used multivariate logistic regression models adjusted for age, sex, education, wealth score, physical activity and cigarette pack-years to report odds ratios (OR) and 95% confidence intervals (CI). Results: Among 9,264 participants, 3,119 (33.7%) had metabolic syndrome, and 3,482 (37.6%) had ever smoked waterpipe, with both more common in women than in men. In adjusted models, former waterpipe use was significantly associated with prevalence (OR = 1.43, 95% CI: 1.23–1.68) and incidence (OR = 1.57, 95% CI: 1.19–2.06) of the metabolic syndrome while current waterpipe use was not. Past use was associated with increased risk in all components of metabolic syndrome; current use was associated with increases in all except high blood glucose and hypertension. Past waterpipe users had higher waterpipe use intensity (before quitting) in comparison with current users (2.3 vs. 2.0 waterpipes per day, p < 0.01) and had started waterpipe smoking at a younger age (27.2 vs. 30.1 years, p < 0.01). Conclusion: Waterpipe use was associated with metabolic syndrome and its components, especially among former users potentially due to higher intensity and earlier initiation of use. [ABSTRACT FROM AUTHOR]

Background Reducing cigarettes per day may lower the risk of lung cancer compared with continuing to smoke at the same intensity. Other changes in smoking behaviors, such as increasing cigarette consumption or quitting for a period and relapsing, may also affect lung cancer risk. Methods We examined changes in smoking status and cigarettes per day among 24 613 Finnish male smokers aged 50-69 years who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Longitudinal data on smoking were collected during study follow-up visits 3 times a year (approximately every 4 months) between 1985 and 1993. Incident lung cancer patients through 2012 were identified by the Finnish Cancer Registry. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Results Compared with smoking 20 cigarettes per day continuously across the intervention period, reducing an average of 5 cigarettes per day per year while smoking was associated with a 20% lower risk of lung cancer (95% CI = 0.71 to 0.90). A substantially lower risk of lung cancer was also observed when participants smoked at 50% (RR = 0.72, 95% CI = 0.57 to 0.90) and 10% (RR = 0.55, 95% CI = 0.36 to 0.83) of study visits, relative to smoked at 100% of study visits. Conclusions Smokers may lower their risk of lung cancer by reducing smoking intensity (cigarettes per day while smoking) and the time they smoke. However, quitting smoking completely is the most effective way for smokers to reduce their risk of lung cancer. [ABSTRACT FROM AUTHOR]

Background In the United States, lung cancer death rates have been declining for decades, primarily as a result of pronounced decreases in cigarette smoking. It is unclear, however, whether there have been similar declines in mortality rates of lung cancer unrelated to smoking. We estimated trends in US lung cancer death rates attributable and not attributable to smoking from 1991 to 2018. Methods The study included 30- to 79-year-olds in the National Health Interview Survey who were linked to the National Death Index, 1991-2014. Adjusted hazard ratios for smoking status and lung cancer death were estimated, and age-specific population attributable fractions were calculated. Annual population attributable fractions were multiplied by annual US national lung cancer mortality, partitioning rates into smoking-attributable and smoking-unrelated lung cancer deaths. All statistical tests were 2-sided. Results During 1991-2018, the proportion of never smokers increased among both men (35.1%-54.6%) and women (54.0%-65.4%). Compared with those who had ever smoked, those who had never smoked had 86% lower risk (hazard ratio = 0.14; 95% confidence interval [CI] = 0.12 to 0.16) of lung cancer death. The fraction of lung cancer deaths attributable to smoking decreased from 81.4% (95% CI = 78.9 to 81.4) to 74.7% (95% CI = 78.1 to 71.4). Smoking-attributable lung cancer death rates declined 2.7% per year (95% CI = ‒2.9% to ‒2.5%) and smoking-unrelated lung cancer death rates declined 1.8% per year (95% CI = ‒2.0% to ‒1.5%); these declines have accelerated in recent years. Conclusions An increasing proportion of lung cancer deaths are unrelated to smoking based on declines in smoking prevalence. Smoking-unrelated lung cancer death rates have declined, however, perhaps because of decreases in secondhand smoke and air pollution exposure as well as treatment improvements. [ABSTRACT FROM AUTHOR]

ConclusionHigher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Despite decades of declining mortality rates, lung cancer remains the leading cause of cancer death in the United States. This article examines lung cancer incidence, stage at diagnosis, survival, and mortality using population‐based data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries. Over the past 5 years, declines in lung cancer mortality became considerably greater than declines in incidence among men (5.0% vs. 2.6% annually) and women (4.3% vs. 1.1% annually), reflecting absolute gains in 2‐year relative survival of 1.4% annually. Improved outcomes likely reflect advances in treatment, increased access to care through the Patient Protection and Affordable Care Act, and earlier stage diagnosis; for example, compared with a 4.6% annual decrease for distant‐stage disease incidence during 2013–2019, the rate for localized‐stage disease rose by 3.6% annually. Localized disease incidence increased more steeply in states with the highest lung cancer screening prevalence (by 3%–5% annually) than in those with the lowest (by 1%–2% annually). Despite progress, disparities remain. For example, Native Americans have the highest incidence and the slowest decline (less than 1% annually among men and stagnant rates among women) of any group. In addition, mortality rates in Mississippi and Kentucky are two to three times higher than in most western states, largely because of elevated historic smoking prevalence that remains. Racial and geographic inequalities highlight longstanding opportunities for more concerted tobacco‐control efforts targeted at high‐risk populations, including improved access to smoking‐cessation treatments and lung cancer screening, as well as state‐of‐the‐art treatment. Recent declines in lung cancer mortality have outpaced those for incidence, reflecting gains in relative survival that are partly due to recent shifts to earlier stage at diagnosis. Persistent racial and geographic disparities reflect longstanding opportunities for public health intervention to reduce smoking and improve health care access. [ABSTRACT FROM AUTHOR]

Background Opioid safety initiatives may secondarily impact opioid prescribing and pain outcomes for cancer care. Methods We reviewed electronic health record data at a tertiary Veterans Affairs system (VA Palo Alto) for all patients from 2015 to 2021. We collected outpatient Schedule II opioid prescriptions data and calculated morphine milligram equivalents (MMEs) using Centers for Disease Control and Prevention conversion formulas. To determine the clinical impact of changes in opioid prescription, we used the highest level of pain reported by each patient on the 0-to-10 Numeric Rating Scale in each year, categorized into mild (0-3), moderate (4-6), and severe (7 and above). Results Among 89 569 patients, 9073 had a cancer diagnosis. Cancer patients were almost twice as likely to have an opioid prescription compared with noncancer patients (69.0% vs 36.7%, respectively). The proportion of patients who received an opioid prescription decreased from 27.1% to 18.1% (trend P  < .01) in cancer patients and from 17.0% to 10.2% in noncancer patients (trend P  < .01). Cancer and noncancer patients had similar declines of MMEs per year between 2015 and 2019, but the decline was more rapid for cancer patients (1462.5 to 946.4, 35.3%) compared with noncancer patients (1315.6 to 927.7, 29.5%) from 2019 to 2021. During the study period, the proportion of noncancer patients who experienced severe pain was almost unchanged, whereas it increased among cancer patients, reaching a significantly higher rate than among noncancer patients in 2021 (31.9% vs 27.4%, P  < .01). Conclusions Our findings suggest potential unintended consequences for cancer care because of efforts to manage opioid-related risks. [ABSTRACT FROM AUTHOR]

Background: Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk‐prediction model (called SPLC‐RAT) was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. The predictive performance of SPLC‐RAT was evaluated in a hospital‐based cohort of lung cancer survivors. Methods: The authors analyzed data from 8448 ever‐smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997–2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC‐RAT and further explored the potential of improving SPLC detection through risk model‐based surveillance using SPLC‐RAT versus existing clinical surveillance guidelines. Results: Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person‐years. The application of SPLC‐RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10‐year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC‐RAT development cohort), the observed SPLC incidence was significantly elevated in the high‐risk versus low‐risk subgroup (13.1% vs. 1.1%, p < 1 × 10–6). The risk‐based surveillance through SPLC‐RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow‐ups needed to detect one SPLC (162 vs. 202). Conclusion: In a large, hospital‐based cohort, the authors validated the predictive performance of SPLC‐RAT in identifying high‐risk survivors of SPLC and showed its potential to improve SPLC detection through risk‐based surveillance. Plain Language Summary: Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC).However, no evidence‐based guidelines for SPLC surveillance are available for lung cancer survivors.Recently, an SPLC risk‐prediction model was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking.Using a large, real‐world cohort of lung cancer survivors, we showed the high predictive accuracy and risk‐stratification ability of the SPLC risk‐prediction model.Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model‐based surveillance strategies compared to the existing consensus‐based clinical guidelines, including the National Comprehensive Cancer Network. Given the rapidly growing number of lung cancer survivors who are now at high risk of developing second primary lung cancer (SPLC), previous studies have identified SPLC risk factors and developed SPLC risk‐prediction models, but they lack insight into real‐world validation to help improve clinical decision‐making in SPLC surveillance for lung cancer survivors. Using a large, hospital‐based real‐world cohort of lung cancer survivors, the authors validated the predictive accuracy of an SPLC risk‐prediction model (area under the curve of 0.81), that can identify high‐risk lung cancer survivors for SPLC and can be incorporated into clinical decision‐making for SPLC surveillance to improve the systematic management of lung cancer survivors. [ABSTRACT FROM AUTHOR]

Rationale: Particulate matter ≤2.5 μm in aerodynamic diameter (PM2.5) is an established cause of lung cancer, but the association with ultrafine particulate matter (UFP; aerodynamic diameter < 0.1 μm) is unclear. Objectives: To investigate the association between UFP and lung cancer overall and by histologic subtype. Methods: The Los Angeles Ultrafines Study includes 45,012 participants aged ≤50 years in southern California at enrollment (1995-1996) followed through 2017 for incident lung cancer (n = 1,770). We estimated historical residential ambient UFP number concentrations via land use regression and back extrapolation using PM2.5. In Cox proportional hazards models adjusted for smoking and other confounders, we estimated associations between 10-year lagged UFP (per 10,000 particles/cm³ and quartiles) and lung cancer overall and by major histologic subtype (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma). We also evaluated relationships by smoking status, birth cohort, and historical duration at the residence. Measurements and Main Results: UFP was modestly associated with lung cancer risk overall (hazard ratio [HR], 1.03 [95% confidence interval (CI), 0.99-1.08]). For adenocarcinoma, we observed a positive trend among men; risk was increased in the highest exposure quartile versus the lowest (HR, 1.39 [95% CI, 1.05-1.85]; P for trend = 0.01) and was also increased in continuous models (HR per 10,000 particles/cm3, 1.09 [95% CI, 1.00-1.18]), but no increased risk was apparent among women (P for interaction = 0.03). Adenocarcinoma risk was elevated among men born between 1925 and 1930 (HR, 1.13 [95% CI, 1.02-1.26] per 10,000) but not for other birth cohorts, and was suggestive for men with ≤10 years of residential duration (HR, 1.11 [95% CI, 0.98-1.26]). We found no consistent associations for women or other histologic subtypes. Conclusions: UFP exposure was modestly associated with lung cancer overall, with stronger associations observed for adenocarcinoma of the lung. [ABSTRACT FROM AUTHOR]

Background The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. Methods Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. Results During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10–11 years; HR, 1.28; 95% CI, 1.00–1.64), younger (<40; HR, 1.31; 95% CI, 1.05–1.62) and older (≥55; HR, 1.33; 95% CI, 1.05–1.68) ages at menopause (vs 40–44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02–1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13–1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00–1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76–0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70–0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. Conclusions Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight. [ABSTRACT FROM AUTHOR]