Uptake of Lung Cancer Screening CT After a Provider Order for Screening in the PROSPR-Lung Consortium.

BACKGROUND: Uptake of lung cancer screening (LCS) has been slow with less than 20% of eligible people who currently or formerly smoked reported to have undergone a screening CT. OBJECTIVE: To determine individual-, health system-, and neighborhood-level factors associated with LCS uptake after a provider order for screening. DESIGN AND SUBJECTS: We conducted an observational cohort study of screening-eligible patients within the Population-based Research to Optimize the Screening Process (PROSPR)-Lung Consortium who received a radiology referral/order for a baseline low-dose screening CT (LDCT) from a healthcare provider between January 1, 2015, and June 30, 2019. MAIN MEASURES: The primary outcome is screening uptake, defined as LCS-LDCT completion within 90 days of the screening order date. KEY RESULTS: During the study period, 18,294 patients received their first order for LCS-LDCT. Orders more than doubled from the beginning to the end of the study period. Overall, 60% of patients completed screening after receiving their first LCS-LDCT order. Across health systems, uptake varied from 41 to 87%. In both univariate and multivariable analyses, older age, male sex, former smoking status, COPD, and receiving care in a centralized LCS program were positively associated with completing LCS-LDCT. Unknown insurance status, other or unknown race, and lower neighborhood socioeconomic status, as measured by the Yost Index, were negatively associated with screening uptake. CONCLUSIONS: Overall, 40% of patients referred for LCS did not complete a LDCT within 90 days, highlighting a substantial gap in the lung screening care pathway, particularly in decentralized screening programs.

Risk of Disease Recurrence and Mortality Varies by Type of Fat Consumed before Cancer Treatment in a Longitudinal Cohort of Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: The associations between specific types of fat and head and neck squamous cell carcinoma (HNSCC) recurrence and mortality rates have not yet been examined. OBJECTIVES: The purpose of this study was to determine how intakes of various fat subtypes before cancer treatment are associated with recurrence and mortality in adults diagnosed with HNSCC. METHODS: This was a secondary analysis longitudinal cohort study of data collected from 476 newly diagnosed patients with HNSCC. Patients completed baseline FFQs and epidemiologic health surveys. Recurrence and mortality events were collected annually. Fat intakes examined included long-chain fatty acids (LCFAs), unsaturated fatty acids (FAs), PUFAs, ω-3 (n-3) PUFAs, ω-6 (n-6) PUFAs, MUFAs, animal fats, vegetable fats, saturated FAs, and trans fats. Associations between fat intake (categorized into tertiles) and time to event were tested using multivariable Cox proportional hazards models, adjusting for age, sex, smoking status, human papillomavirus status, tumor site, cancer stage, and total caloric intake. Intake of fats was compared with the lowest tertile. RESULTS: During the study period, there were 115 recurrent and 211 death events. High LCFA intake was associated with a reduced all-cause mortality risk (HR: 0.55; 95% CI: 0.34, 0.91; P-trend = 0.02). High unsaturated FA intake was associated with a reduced all-cause mortality risk (HR: 0.62; 95% CI: 0.40, 0.97; P-trend = 0.04) and HNSCC-specific mortality risk (HR: 0.51; 95% CI: 0.29, 0.90; P-trend = 0.02). High intakes of ω-3 PUFAs (HR: 0.56; 95% CI: 0.35, 0.91; P-trend = 0.02) and ω-6 PUFAs (HR: 0.57; 95% CI: 0.34, 0.94; P-trend = 0.02) were significantly associated with a reduced all-cause mortality risk. There were no significant associations between other fat types and recurrence or mortality risk. CONCLUSIONS: In this prospective survival cohort of 476 newly diagnosed patients with HNSCC, our data suggest that HNSCC prognosis may vary depending on the fat types consumed before cancer treatment. Clinical intervention trials should test these associations.

Vitamin D Receptor (VDR) Allelic Variants Correlating with Response to Vitamin D3 Supplementation in Breast Cancer Survivors.

We investigated how vitamin D receptor (VDR) allelic variants affect breast cancer survivors' responses to vitamin D3 supplementation to increase circulating 25-hydroxy vitamin D (25(OH)D) levels. Two hundred and fourteen patients who were diagnosed with breast cancer at least 6 mo, prior to the study and had completed all treatment regimens were assigned to consume 4000 IU of vitamin D3 daily for 12 weeks. Linear and multinomial logistic regression analyses were used to analyze the association of VDR single nucleotide polymorphism (SNPs) with changes in circulating 25(OH)D. The TaqI and BsmI VDR sequence variants modified the effect of vitamin D3 treatment on the plasma 25(OH)D changes (P value = 0.008 for TaqI and P value = 0.0005 for BsmI). Patients with the bb [Q4 vs. Q1 odds ratio(OR) 8.04, 95% confidence interval (CI) 1.55-41.57] and tt [Q4 vs. Q1 OR 4.64 95%CI 1.02-21.02] genotype of BsmI and TaqI had larger increases in plasma 25(OH)D levels compared to those with BB and TT genotype respectively after adjustment for potential confounders. Haplotype analyses suggested the existence of specific combination of alleles that might be associated with circulating 25(OH)D changes. VDR allelic variants modulate vitamin D3 supplementation to increase plasma 25(OH) levels in breast cancer survivors.

Statin use and head and neck squamous cell carcinoma outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and anti-inflammatory effects. The objective of our study is to identify the association between statin use among untreated HNSCC patients and overall death, disease-specific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR = 0.75, 95% CI = 0.63-0.88) and HNSCC-specific death (HR = 0.79, 95% CI = 0.63-0.99) and a nonstatistically significant inverse association for recurrence (HR = 0.85, 95% CI = 0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR = 0.41, 95% CI = 0.21-0.84; HPV-negative HR = 1.04, 95% CI = 0.71-1.51; p-int=0.02; recurrence: HPV-positive HR = 0.49, 95% CI = 0.29-0.84; HPV-negative HR = 1.03, 95% CI = 0.74-1.43; p=int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer.

Pretreatment Dietary Patterns, Serum Carotenoids and Tocopherols Influence Tumor Immune Response in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) aid in informing treatment for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of diet on TILs. METHODS: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pretreatment dietary patterns were evaluated using linear regression. Associations between baseline serum carotenoids, tocopherols and TILs were assessed using logistic regression. Cox models evaluated the association between diet and TILs on overall and recurrence-free survival. RESULTS: Consumption of a Western dietary pattern was associated with lower CD8+ and FOXP3+ infiltrates (p-value:0.03 and 0.02, respectively). Multivariable logistic regression models demonstrated significantly higher CD8+ (OR:2.21;p-value:0.001) and FOXP3+ (OR:4.26;p-value:<0.0001) among patients with high gamma tocopherol. Conversely, high levels of xanthophylls (OR:0.12;p-value:<0.0001), lycopene (OR:0.36;p-value:0.0001) and total carotenoids(OR:0.31;p-value: <0.0001) were associated with significantly lower CD68+. Among those with high CD4+ (HR:1.77;p-value:0.03), CD68+ (HR:2.42;p-value:0.004), CD103+ (HR:3.64;p-value:0.03) and FOXP3+ (HR:3.09;p-value:0.05), having a high Western dietary pattern increased the risk of overall mortality when compared to a low Western dietary pattern. CONCLUSION: Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC.

Global DNA (LINE-1) methylation is associated with lead exposure and certain job tasks performed by electronic waste workers.

OBJECTIVE: This study assessed the associations between blood and urine levels of toxic metals; cadmium (Cd) and lead (Pb), and methylation levels of the LINE-1 gene among e-waste and control populations in Ghana. METHODS: The study enrolled 100 male e-waste workers and 51 all-male non-e-waste workers or controls. The concentrations of Cd and Pb were measured in blood and urine using inductively coupled plasma mass spectrometry, while LINE1 methylation levels were assessed by pyrosequencing of bisulfite-converted DNA extracted from whole blood. Single and multiple metals linear regression models were used to determine the associations between metals and LINE1 DNA methylation. RESULTS: Blood lead (BPb) and urine lead (UPb) showed higher median concentrations among the e-waste workers than the controls (76.82 µg/L vs 40.25 µg/L, p ≤ 0.001; and 6.89 µg/L vs 3.43 µg/L, p ≤ 0.001, respectively), whereas blood cadmium (BCd) concentration was lower in the e-waste workers compared to the controls (0.59 µg/L vs 0.81 µg/L, respectively, p = 0.003). There was no significant difference in LINE1 methylation between the e-waste and controls (85.16 ± 1.32% vs 85.17 ± 1.11%, p = 0.950). In our single metal linear regression models, BPb was significantly inversely associated with LINE1 methylation in the control group (ßBPb = - 0.027, 95% CI - 0.045, - 0.010, p = 0.003). In addition, a weak association between BPb and LINE1 was observed in the multiple metals analysis in the e-waste worker group (ßBPb = - 0.005, 95% CI - 0.011, 0.000, p = 0.058). CONCLUSION: Continuous Pb exposure may interfere with LINE1 methylation, leading to epigenetic alterations, thus serving as an early epigenetic marker for future adverse health outcomes.

Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.

BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) has been historically low in the United States. Although etiological factors differ by histological subtype, Epstein-Barr virus is accepted as the primary risk factor for nonkeratinizing NPC. In light of the changing epidemiology of viral-associated cancers, it is important to evaluate the temporal incidence of NPC in the United States. METHODS: Incidence and survival data from 1973 through 2015 were obtained from the Surveillance, Epidemiology, and End Results program. Stratified analyses were conducted to assess temporal trends in NPC by histological subtype, sex, and race. The data were analyzed using SAS and Joinpoint Regression Software to determine age-adjusted incidence rates, determine trends in the annual percent change, and calculate 5-year relative survival estimates and Kaplan-Meier curves. RESULTS: Although overall NPC incidence is decreasing in the United States, the nonkeratinizing differentiated subtype is starkly increasing, with an annual percent change of approximately 4% among white males (95% CI, 2.5%-5.2%), white females (95% CI, 1.9%-6.2%), and black males (95% CI, 2.0%, 5.7%); 2.7% among black females (95% CI, 0.8%, 4.6%); and 1.8% among women in the "other" race category (95% CI, 0.4%-3.3%). Racial disparities were noted, with 32% of nonkeratinizing NPC cases among blacks occurring before the age of 40 years. In addition, black males displayed consistently worse survival across all histological subtypes, whereas individuals in the "other" race category, particularly females, experienced the highest 5-year relative survival estimates. CONCLUSIONS: The current results indicate that the Epstein-Barr virus-related, differentiated NPC subtype is increasing across all sexes and races in the United States, with distinct incidence and survival disparities among blacks.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Childhood cancer incidence and survival in Thailand: A comprehensive population-based registry analysis, 1990-2011.

BACKGROUND: Southeast Asia is undergoing a transition from infectious to chronic diseases, including a dramatic increase in adult cancers. Childhood cancer research in Thailand has focused predominantly on leukemias and lymphomas or only examined children for a short period of time. This comprehensive multisite study examined childhood cancer incidence and survival rates in Thailand across all International Classification of Childhood Cancer (ICCC) groups over a 20-year period. METHODS: Cancer cases diagnosed in children ages 0-19 years (n = 3574) from 1990 to 2011 were extracted from five provincial population-based Thai registries, covering approximately 10% of the population. Descriptive statistics of the quality of the registries were evaluated. Age-standardized incidence rates (ASRs) were calculated using the Segi world standard population, and relative survival was computed using the Kaplan-Meier method. Changes in incidence and survival were analyzed using Joinpoint Regression and reported as annual percent changes (APC). RESULTS: The ASR of all childhood cancers during the study period was 98.5 per million person-years with 91.0 per million person-years in 1990-2000 and 106.2 per million person-years in 2001-2011. Incidence of all childhood cancers increased significantly (APC = 1.2%, P < 0.01). The top three cancer groups were leukemias, brain tumors, and lymphomas. The 5-year survival for all childhood cancers significantly improved from 39.4% in 1990-2000 to 47.2% in 2001-2011 (P < 0.01). CONCLUSIONS: Both childhood cancer incidence and survival rates have increased, suggesting improvement in the health care system as more cases are identified and treated. Analyzing childhood cancer trends in low- and middle-income countries can improve understanding of cancer etiology and pediatric health care disparities.

Association between toxic and essential metals in blood and global DNA methylation among electronic waste workers in Agbogbloshie, Ghana.

Aberrant global DNA methylation status is a known biomarker for increased disease risk, especially cancer. There is little published data on the association between toxic and essential metal mixtures and global DNA methylation in electronic waste (e-waste) workers. We aimed to establish the association between toxic and essential metals in blood and the effect of their interactions on global DNA methylation among e-waste recyclers and a reference group in Ghana. We used ICP-MS to measure the level of five metals (Se, Zn, Mn, Cd, and Pb) in the blood of 100 e-waste workers and 51 controls. We quantified blood DNA methylation levels of LINE-1 as an indicator of global DNA methylation. Cd, Mn, and Se levels were significantly higher in the reference group than in e-waste workers. Only Pb was significantly higher in the e-waste workers compared to the controls. Our linear regression analysis results showed a significant inverse association between Zn and LINE-1 DNA methylation (ßZn = - 0.912; 95% CI, - 1.512, - 0.306; p = 0.003) which corresponds to a 0.009 decrease in %LINE-1 methylation (95% CI, - 0.015, - 0.003; p = 0.003) for a 1% increase in Zn concentration. Potential interactions between Cd and Zn on global DNA methylation were observed. In summary, co-exposure to toxic and essential metals is associated with global (LINE-1) DNA methylation.