Overweight-years and cancer risk: A prospective study of the association and comparison of predictive performance with body mass index (Atherosclerosis Risk in Communities Study).

Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight-years metric, which incorporates exposure time to BMI ≥25 kg/m2 , is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight-years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C-statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow-up. Hazard ratios for obesity-related cancers per standard deviation overweight-years were 1.15 (95% CI: 1.05-1.25) in men and 1.14 (95% CI: 1.08-1.20) in women. The difference in the C-statistic between models that incorporated BMI, or the overweight-years metric was non-significant in men and women. Overweight-years was associated with the risk of obesity-related cancers but did not outperform a single BMI measure in association performance characteristics.

Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study.

BACKGROUND: Multiple novel protein biomarkers have been shown to be associated with prostate cancer risk using genetic instruments. This study aimed to externally validate the associations of 30 genetically predicted candidate proteins with prostate cancer risk using aptamer-based levels in US Black and White men in the Atherosclerosis Risk in Communities (ARIC) study. Plasma protein levels were previously measured by SomaScan® using the blood collected in 1990-1992. METHODS: Among 4864 eligible participants, we ascertained 667 first primary prostate cancer cases through 2015. Hazard ratios (HRs) of prostate cancer and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for tertiles of each protein. We adjusted for age, race, and other risk factors. RESULTS: Of the 30 proteins and considering a nominal p trend < 0.05, two were positively associated with prostate cancer risk-RF1ML (tertile 3 vs. 1: HR = 1.23; 95% CI 1.02-1.48; p trend = 0.037) and TPST1 (1.28, 95% CI 1.06-1.55; p trend = 0.0087); two were inversely associated-ATF6A (HR = 0.80, 95% CI 0.65-0.98; p trend = 0.028) and SPINT2 (HR = 0.74, 95% CI 0.61-0.90; p trend = 0.0025). One protein, KDEL2, which was nonlinearly associated (test-for-linearity: p < 0.01) showed a statistically significant lower risk in the second tertile (HR = 0.79, 95% CI 0.65-0.95). Of these five, four proteins-ATF6A, KDEL2, RF1ML, and TPST1-were consistent in the direction of association with the discovery studies. CONCLUSION: This study validated some pre-diagnostic protein biomarkers of the risk of prostate cancer.

Determinants of receipt of prostate cancer screening among men living with HIV enrolled in an urban HIV Clinic in the United States over the period of 2000-2020.

BACKGROUND: Prostate cancer is projected to account for the greatest proportion of cancer-related burden among men with HIV. However, incidence is reportedly lower than in men without HIV, potentially due to differences in screening. Factors influencing receipt of screening in men with HIV are unknown. We described receipt of prostate-specific antigen (PSA) testing and assessed factors for association with receipt of PSA test. METHODS: Demographics, measures of HIV and related care, and non-HIV care were assessed for association with receipt of first PSA test in men ≥40 years old each calendar year in 2000-2020 using univariable and multivariable Poisson regression. Models were additionally stratified by calendar period to identify changes in determinants of PSA test as prostate cancer screening guidelines changed. RESULTS: Men (n = 2,063) 72% Non-Hispanic Black, median age of 47 (IQR: 41, 53), contributed median of 4.7 years (IQR: 2.3, 10.0) of follow-up. Receipt of antiretroviral therapy (aIRR = 1.33; 95% CI: 1.14, 1.55), engagement in HIV care (aIRR = 2.09; 95% CI: 1.66, 2.62), history of testosterone-replacement therapy (aIRR = 1.34; 95% CI: 1.19, 1.50), urologist evaluation (aIRR = 1.66; 95% CI: 1.35, 2.05), and receipt of PSA test in preceding two years (no elevated PSA aIRR = 2.37; 95% CI: 2.16, 2.61; elevated PSA aIRR = 4.35; 95% CI: 3.24, 5.84) were associated with PSA testing in men aged 50 or older. Associations varied across calendar time. CONCLUSION: Findings suggest men with greater interaction with healthcare are more likely to receive PSA test. Measures of control of HIV did not appear to influence the decision to screen.

Incidence of prostate cancer in Medicaid beneficiaries with and without HIV in 2001-2015 in 14 states.

Prostate cancer (PCa) incidence is reportedly lower in men with HIV compared to men without HIV for unknown reasons. We describe PCa incidence by HIV status in Medicaid beneficiaries, allowing for comparison of men with and without HIV who are similar with respect to socioeconomic characteristics and access to healthcare. Men (N = 15,167,636) aged 18-64 with ≥7 months of continuous enrollment during 2001-2015 in 14 US states were retained for analysis. Diagnoses of HIV and PCa were identified using non-drug claims. We estimated cause-specific (csHR) comparing incidence of PCa by HIV status, adjusted for age, race-ethnicity, state of residence, year of enrollment, and comorbid conditions, and stratified by age and race-ethnicity. Hazard of PCa was lower in men with HIV than men without HIV (csHR = 0.89; 95% CI: 0.80, 0.99), but varied by race-ethnicity, with similar observations among non-Hispanic Black (csHR = 0.79; 95% CI: 0.69, 0.91) and Hispanic (csHR = 0.85; 95% CI: 0.67, 1.09), but not non-Hispanic white men (csHR = 1.17; 95% CI: 0.91, 1.50). Findings were similar in models restricted to men aged 50-64 and 40-49, but not in men aged 18-39. Reported deficits in PCa incidence by HIV status may be restricted to specific groups defined by age and race ethnicity.

Retention in care and antiretroviral therapy adherence among Medicaid beneficiaries with HIV, 2001-2015.

Disparities in HIV care by socioeconomic status, place of residence, and race/ethnicity prevent progress toward epidemic control. No study has comprehensively characterized the HIV care cascade among people with HIV enrolled in Medicaid - an insurance source for low-income individuals in the US. We analyzed data from 246,127 people with HIV enrolled in Medicaid 2001-2015, aged 18-64, living in 14 US states. We estimated the monthly prevalence of four steps of the care cascade: retained in care/adherent to ART; retained/not adherent; not retained/adherent; not retained/not adherent. Beneficiaries were retained in care if they had an outpatient care encounter every six months. Adherence was based on medication possession ratio. We estimated prevalence using a non-parametric multi-state approach, accounting for death as a competing event and for Medicaid disenrollment using inverse probability of censoring weights. Across 2001-2015, the proportion of beneficiaries with HIV who were retained/ART adherent increased, overall and in all subgroups. By 2015, approximately half of beneficiaries were retained in care, and 42% of beneficiaries were ART adherent. We saw meaningful differences by race/ethnicity and region. Our work highlights an important disparity in the HIV care cascade by insurance status during this time period.

External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer-based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study.

Genetically predicted proteins have been associated with pancreatic cancer risk previously. We aimed to externally validate the associations of 53 candidate proteins with pancreatic cancer risk using directly measured, prediagnostic levels. We conducted a prospective cohort study of 10 355 US Black and White men and women in the Atherosclerosis Risk in Communities (ARIC) study. Aptamer-based plasma proteomic profiling was previously performed using blood collected in 1993 to 1995, from which the proteins were selected. By 2015 (median: 20 years), 93 incident pancreatic cancer cases were ascertained. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for protein tertiles, and adjust for age, race, and known risk factors. Of the 53 proteins, three were statistically significantly, positively associated with risk-GLCE (tertile 3 vs 1: HR = 1.88, 95% CI: 1.12-3.13; P-trend = 0.01), GOLM1 (aptamer 1: HR = 1.98, 95% CI: 1.16-3.37; P-trend = 0.01; aptamer 2: HR = 1.86, 95% CI: 1.07-3.24; P-trend = 0.05), and QSOX2 (HR = 1.96, 95% CI: 1.09-3.58; P-trend = 0.05); two were inversely associated-F177A (HR = 0.59, 95% CI: 0.35-1.00; P-trend = 0.05) and LIFsR (HR = 0.55, 95% CI: 0.32-0.93; P-trend = 0.03); and one showed a statistically significant lower risk in the middle tertile-endoglin (HR = 0.50, 95% CI: 0.29-0.86); by chance, we expected significant associations for 2.65 proteins. FAM3D, IP10, sTie-1 (positive); SEM6A and JAG1 (inverse) were suggestively associated with risk. Of these 11, 10 proteins-endoglin, FAM3D, F177A, GLCE, GOLM1, JAG1, LIFsR, QSOX2, SEM6A and sTie-1-were consistent in direction of association with the discovery studies. This prospective study validated or supports 10 proteins as associated with pancreatic cancer risk.

Total-, LDL-, and HDL-cholesterol, apolipoproteins, and triglycerides with risk of total and fatal prostate cancer in Black and White men in the ARIC study.

BACKGROUND: Cholesterol reduction is considered a mechanism through which cholesterol-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations between total cholesterol and more advanced stage and grade in White men, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle) and A1 (HDL particle), and triglycerides are similar for fatal prostate cancer and in Black men, who experience a disproportionate burden of total and fatal prostate cancer, is unknown. METHODS: We conducted a prospective study of 1553 Black and 5071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. A total of 885 incident prostate cancer cases were ascertained through 2015, and 128 prostate cancer deaths through 2018. We estimated multivariable-adjusted hazard ratios (HRs) of total and fatal prostate cancer per 1-standard deviation increments and for tertiles (T1-T3) of time-updated lipid biomarkers overall and in Black and White men. RESULTS: Greater total cholesterol concentration (HR per-1 SD = 1.25; 95% CI = 1.00-1.58) and LDL cholesterol (HR per-1 SD = 1.26; 95% CI = 0.99-1.60) were associated with higher fatal prostate cancer risk in White men only. Apolipoprotein B was nonlinearly associated with fatal prostate cancer overall (T2 vs. T1: HR = 1.66; 95% CI = 1.05-2.64) and in Black men (HR = 3.59; 95% CI = 1.53-8.40) but not White men (HR = 1.13; 95% CI = 0.65-1.97). Tests for interaction by race were not statistically significant. CONCLUSIONS: These findings may improve the understanding of lipid metabolism in prostate carcinogenesis by disease aggressiveness, and by race while emphasizing the importance of cholesterol control.

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

P2X4 purinergic receptors offer a therapeutic target for aggressive prostate cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer- compared with benign-tissue spots, in prostatic intraepithelial neoplasia, and in PCa with ERG positivity or with PTEN loss. High-level P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with the P2X4-specific agonist cytidine 5'-triphosphate (CTP) increased Transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. The P2X4 antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identify P2X4 as a candidate for therapeutic targeting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Localization of macrophage subtypes and neutrophils in the prostate tumor microenvironment and their association with prostate cancer racial disparities.

BACKGROUND: Black men are two to three times more likely to die from prostate cancer (PCa) than White men. This disparity is due in part to discrepancies in socioeconomic status and access to quality care. Studies also suggest that differences in the prevalence of innate immune cells and heightened function in the tumor microenvironment of Black men may promote PCa aggressiveness. METHODS: We evaluated the spatial localization of and quantified CD66ce+ neutrophils by immunohistochemistry and CD68+ (pan), CD80+ (M1), and CD163+ (M2) macrophages by RNA in situ hybridization on formalin-fixed paraffin-embedded tissues from organ donor "normal" prostate (n = 9) and radical prostatectomy (n = 38) tissues from Black and White men. Neutrophils were quantified in PCa and matched benign tissues in tissue microarray (TMA) sets comprised of 560 White and 371 Black men. Likewise, macrophages were quantified in TMA sets comprised of tissues from 60 White and 120 Black men. The phosphatase and tensin homolog (PTEN) and ETS transcription factor ERG (ERG) expression status of each TMA PCa case was assessed via immunohistochemistry. Finally, neutrophils and macrophage subsets were assessed in a TMA set comprised of distant metastatic PCa tissues collected at autopsy (n = 6) sampled across multiple sites. RESULTS: CD66ce+ neutrophils were minimal in normal prostates, but were increased in PCa compared to benign tissues, in low grade compared to higher grade PCa, in PCa tissues from White compared to Black men, and in PCa with PTEN loss or ERG positivity. CD163+ macrophages were the predominant macrophage subset in normal organ donor prostate tissues from both Black and White men and were significantly more abundant in organ donor compared to prostatectomy PCa tissues. CD68,+  CD80,+ and CD163+ macrophages were significantly increased in cancer compared to benign tissues and in cancers with ERG positivity. CD68+ and CD163+ macrophages were increased in higher grade cancers compared to low grade cancer and CD80 expression was significantly higher in benign prostatectomy tissues from Black compared to White men. CONCLUSIONS: Innate immune cell infiltration is increased in the prostate tumor microenvironment of both Black and White men, however the composition of innate immune cell infiltration may vary between races.

Trends in breast cancer incidence rates by race/ethnicity: Patterns by stage, socioeconomic position, and geography in the United States, 1999-2017.

BACKGROUND: The incidence rate of breast cancer has been increasing over time across race/ethnicity in the United States. It is unclear whether these trends differ among stage, poverty, and geography subgroups. METHODS: Using data from the North American Association of Central Cancer Registries, this study estimated trends in age-adjusted breast cancer incidence rates among women aged 50 to 84 years from 1999 to 2017 by race/ethnicity (non-Hispanic Black, non-Hispanic White, and Hispanic) and across subgroups (stage, county-level poverty, county urban/rural status, and geographic region [West, Midwest, South, and Northeast]). RESULTS: From 2004 to 2017, breast cancer incidence rates increased across race/ethnicity and subgroups, with the greatest average annual percent increases observed for non-Hispanic Black women, overall (0.9%) and those living in lower poverty areas (0.8%), rural areas (1.2%), and all regions except the West (0.8%-1.0%). Stronger increases among non-Hispanic Black women were observed for local-stage disease and for some subgroups of distant-stage disease. Non-Hispanic Black women had the smallest decrease in regional-stage disease across most subgroups. Similarly, Hispanic women had the strongest increases in some subgroups, including areas with higher poverty (0.6%-1.2%) and in the West (0.8%), for local- and distant-stage disease. CONCLUSIONS: These trends highlight concerns for an increasing burden of breast cancer among subpopulations, with some already experiencing disparate breast cancer mortality rates, and they highlight the need for targeted breast cancer prevention and efforts to reduce mortality disparities in areas with increasing incidence.

Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer.

BACKGROUND: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. METHODS: An automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. RESULTS: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. CONCLUSIONS: The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. LAY SUMMARY: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.

Differential mast cell phenotypes in benign versus cancer tissues and prostate cancer oncologic outcomes.

We reported previously that high numbers of mast cells in benign (extra-tumoral) regions of the prostate are associated with worse outcomes after radical prostatectomy including biochemical recurrence and the development of metastases. Herein, with a cohort of 384 men, we performed mast cell subtyping and report that higher minimum number of the tryptase-only (MCT ) subset of extra-tumoral mast cells is associated with increased risk of biochemical recurrence (comparing highest to lowest tertiles: HR 2.32, 95% CI 1.37-3.93; P-trend = 0.002), metastases (HR 3.62, 95% CI 1.75-7.47; P-trend 0.001), and death from prostate cancer (HR 2.87, 95% CI 1.19-6.95; P-trend = 0.02). Preliminary RNA sequencing and comparison of benign versus cancer tissue mast cells revealed differential expression of additional site-specific genes. We further demonstrate that the genes CXCR4 and TFE3 are more highly expressed in tumor-infiltrating mast cells as well as other tumor-infiltrating immune cells and in tumor cells, respectively, and represent an altered tumor microenvironment. KIT variants were also differentially expressed in benign versus cancer tissue mast cells, with KIT variant 1 (GNNK+ ) mast cells identified as more prevalent in extra-tumoral regions of the prostate. Finally, using an established mouse model, we found that mast cells do not infiltrate Hi-Myc tumors, providing a model to specifically examine the role of extra-tumoral mast cells in tumorigenesis. Hi-Myc mice crossed to mast cell knockout (Wsh) mice and aged to 1 year revealed a higher degree of pre-invasive lesions and invasive cancer in wild-type mice versus heterozygous and knockout mice. This suggests a dosage effect where higher numbers of extra-tumoral mast cells resulted in higher cancer invasion. Overall, our studies provide further evidence for a role of extra-tumoral mast cells in driving adverse prostate cancer outcomes. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

When Engagement Leads to Action: Understanding the Impact of Cancer (Mis)information among Latino/a Facebook Users.

Latinos/as - the largest minority group in the U.S. - are avid Facebook users, making this an opportune tool to educate on the uptake of cancer prevention and screening behaviors. However, there is a dearth in scholarship exploring how Latinos/as engage with and act upon health content encountered on social media, which may be influenced by cultural values. This qualitatively-driven, mixed-methods study explores how Latinos/as engage with and act upon cancer prevention and screening information (CPSI) on Facebook. During one-on-one, in-depth interviews, participants (n = 20) logged onto their Facebook account alongside the researcher and discussed cancer-related posts they engaged with during the past 12 months. Interview questions included the reasons for engagement, and whether engagement triggered further action. Interviews were analyzed thematically. In parallel, a content analysis of the CPSI posts identified during the interviews was conducted. The majority of CPSI posts participants engaged with contained food-related content and visual imagery. Engagement was most common when individuals had personal relationships to the poster, when posts included videos/images, and when posts contained content promoting the curative properties of popular Latin American foods. Engagement often led to information-seeking and sharing, discussing content with others, and/or changing health behaviors. Findings highlight the importance of adequately contextualizing how cultural values influence the ways in which Latinos/as engage with and act upon CPSI on Facebook, which may lead individuals to bypass evidence-based procedures. Multi-pronged efforts are necessary to adequately leverage social media to empower Latinos/as to partake in behaviors that effectively reduce cancer health disparities.

Contextualizing Engagement With Health Information on Facebook: Using the Social Media Content and Context Elicitation Method.

BACKGROUND: Most of what is known regarding health information engagement on social media stems from quantitative methodologies. Public health literature often quantifies engagement by measuring likes, comments, and/or shares of posts within health organizations' Facebook pages. However, this content may not represent the health information (and misinformation) generally available to and consumed by platform users. Furthermore, some individuals may prefer to engage with information without leaving quantifiable digital traces. Mixed methods approaches may provide a way of surpassing the constraints of assessing engagement with health information by using only currently available social media metrics. OBJECTIVE: This study aims to discuss the limitations of current approaches in assessing health information engagement on Facebook and presents the social media content and context elicitation method, a qualitatively driven, mixed methods approach to understanding engagement with health information and how engagement may lead to subsequent actions. METHODS: Data collection, management, and analysis using the social media content and context elicitation method are presented. This method was developed for a broader study exploring how and why US Latinos and Latinas engage with cancer prevention and screening information on Facebook. The study included 20 participants aged between 40 and 75 years without cancer who participated in semistructured, in-depth interviews to discuss their Facebook use and engagement with cancer information on the platform. Participants accessed their Facebook account alongside the researcher, typed cancer in the search bar, and discussed cancer-related posts they engaged with during the previous 12 months. Engagement was defined as liking, commenting, and/or sharing a post; clicking on a post link; reading an article in a post; and/or watching a video within a post. Content engagement prompted questions regarding the reasons for engagement and whether engagement triggered further action. Data were managed using MAXQDA (VERBI GmbH) and analyzed using thematic and content analyses. RESULTS: Data emerging from the social media content and context elicitation method demonstrated that participants mainly engaged with cancer prevention and screening information by viewing and/or reading content (48/66, 73%) without liking, commenting, or sharing it. This method provided rich content regarding how US Latinos and Latinas engage with and act upon cancer prevention and screening information on Facebook. We present 2 emblematic cases from the main study to exemplify the additional information and context elicited from this methodology, which is currently lacking from quantitative approaches. CONCLUSIONS: The social media content and context elicitation method allows a better representation and deeper contextualization of how people engage with and act upon health information and misinformation encountered on social media. This method may be applied to future studies regarding how to best communicate health information on social media, including how these affect assessments of message credibility and accuracy, which can influence health outcomes.

Association between pre-diagnostic circulating adipokines and colorectal cancer and adenoma in the CLUE II cohort.

OBJECTIVE: Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma. METHODS: We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma. RESULTS: Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women. CONCLUSION: In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.

Reversing the effects of androgen-deprivation therapy in men with metastatic castration-resistant prostate cancer.

OBJECTIVE: To investigate whether bipolar androgen therapy (BAT), involving rapid cyclic administration of high-dose testosterone, as a novel treatment for metastatic castration-resistant prostate cancer (mCRPC) promotes improvements in body composition and associated improvements in lipid profiles and quality of life. PATIENTS AND METHODS: Men from two completed trials with computed tomography imaging at baseline and after three cycles of BAT were included. Cross-sectional areas of psoas muscle, visceral and subcutaneous fat were measured at the L3 vertebral level. Functional Assessment of Chronic Illness Therapy - Fatigue questionnaire and 36-item short-form health survey were used to assess quality of life. RESULTS: The 60 included patients lost a mean (sd) of 7.8 (8.2)% of subcutaneous fat, 9.8 (18.2)% of visceral fat, and gained 12.2 (6.7)% muscle mass. Changes in subcutaneous and visceral fat were positively correlated with each other (Spearman's correlation coefficient 0.58, 95% confidence interval 0.35-0.71) independent of the effects of age, body mass index, and duration of androgen-deprivation therapy. Energy, physical function, and measures of limitations due to physical health were all significantly improved at 3 months. The improvements in body composition were not correlated with decreases in lipid levels or observed improvements in quality of life. CONCLUSIONS: In the present study, BAT was associated with significant improvements in body composition, lipid parameters, and quality of life. This has promising implications for the long-term health of men with mCRPC.

Albuminuria, Kidney Function, and Cancer Risk in the Community.

Few studies have comprehensively investigated the association of 2 key kidney disease measures, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), with cancer incidence. In 8,935 participants at the baseline (1996-1998) from the Atherosclerosis Risk in Communities study, we quantified the associations of eGFR (based on creatinine and cystatin C) and ACR with cancer risk using Cox regression models adjusted for potential confounders. Due to changing guidelines for prostate cancer screening during the follow-up period, we investigated overall cancer, overall nonprostate cancer, and site-specific cancer. During a median follow-up of 14.7 years, 2,030 incident cancer cases occurred. In demographically adjusted models, low eGFR and high ACR were associated with cancer incidence (both overall and overall nonprostate cancer). These associations were attenuated after adjusting for other shared risk factors, with a significant association remaining only for ACR (≥103 compared with 5 mg/g) and overall nonprostate cancer. For site-specific cancer, only high ACR showed a significant association with lung and urinary tract cancers. Of these, the association between ACR and lung cancer appeared most robust in several sensitivity analyses. Kidney disease measures, particularly high ACR, were independently associated with cancer risk. The association between ACR and lung cancer was uniquely robust, warranting future studies to explore potential mechanisms.

Neuroendocrine differentiation in usual-type prostatic adenocarcinoma: Molecular characterization and clinical significance.

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.