Does monoclonal antibody treatment for COVID-19 impact short and long-term outcomes in a large generalisable population? A retrospective cohort study in the USA.

OBJECTIVES: To explore whether monoclonal antibodies (MAb) administered to high-risk patients with COVID-19 during the first week of illness prevent postacute sequelae of SARS-CoV-2 infection. DESIGN: Retrospective cohort study. SETTING: USA. PARTICIPANTS: A sample of 3809 individuals who received MAbs and a matched one-to-one comparison group from a set of 327 079 eligible patients who did not receive MAb treatment were selected from a deidentified administrative data set from commercial and Medicare Advantage health plan enrollees in the USA, including claims and outpatient laboratory data. RESULTS: Individuals who received MAb were 28% less likely to be hospitalised (HR=0.72, 95% CI 0.58 to 0.89) and 41% less likely to be admitted to the intensive care unit (HR=0.59, 95% CI 0.38 to 0.89) 30 days from SARS-CoV-2 diagnosis compared with individuals who did not receive MAb. A higher proportion of individuals given MAb therapy received care for clinical sequelae in the postacute phase (p=0.018). CONCLUSIONS: While MAb therapy was associated with benefits in the acute period, the benefit of therapy did not extend into the postacute period and did not reduce risk for clinical sequelae.

Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection. DESIGN: Retrospective cohort study. SETTING: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results. PARTICIPANTS: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490). MAIN OUTCOME MEASURES: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19. RESULTS: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae. CONCLUSIONS: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65. DESIGN: Retrospective cohort study. SETTING: Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database. PARTICIPANTS: Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness. MAIN OUTCOME MEASURES: More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated. RESULTS: 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group. CONCLUSIONS: The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Self-reported Prostate Cancer Progression Status Is Accurate: A Validation Study.

BACKGROUND: Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression. METHODS: We conducted a validation study of self-reported prostate cancer progression in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and in a prostate cancer cohort enrolled in a Fred Hutchinson Cancer Research Center (FHCRC)-based study. We calculated measures of validity for self-reported progression, including sensitivity, specificity, positive predictive value, and negative predictive value using medical records as the gold standard. RESULTS: Our results suggest that ascertaining prostate cancer progression-related events (i.e., prostate-specific antigen elevation, recurrence, metastasis, and use of secondary treatment) through self-report may be a viable option for identifying men whose disease has progressed after diagnosis or initial therapy, particularly when multiple questions related to progression are included in the assessment (aggregate cluster of questions: sensitivity = 0.76 [PLCO]; 0.93 [FHCRC], specificity = 0.80 [PLCO]; 0.97 [FHCRC]). With an aggregate positive predictive value of 0.50 (PLCO), however, our PLCO results suggest that additional medical record verification of self-reported progression events may be necessary to rule out false positives. Most individuals reporting no evidence of progression-related events, however, were true negatives (aggregate negative predictive value = 0.92 [PLCO]; 0.98 [FHCRC]). Thus, there may be limited utility to investing resources in chart review to confirm self-reported nonevents. CONCLUSION: Ascertaining prostate cancer progression through self-report provides an efficient and valid approach to enhancing existing cancer cohorts with updated data on progression status. See video abstract at, http://links.lww.com/EDE/B658.

Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial.

Importance: Determining the right dosage of aspirin for the secondary prevention treatment of atherosclerotic cardiovascular disease (ASCVD) remains an unanswered and critical question. Objective: To report the rationale and design for a randomized clinical trial to determine the optimal dosage of aspirin to be used for secondary prevention of ASCVD, using an innovative research method. Design, Setting, and Participants: This pragmatic, open-label, patient-centered, randomized clinical trial is being conducted in 15 000 patients within the National Patient-Centered Clinical Research Network (PCORnet), a distributed research network of partners including clinical research networks, health plan research networks, and patient-powered research networks across the United States. Patients with established ASCVD treated in routine clinical practice within the network are eligible. Patient recruitment began in April 2016. Enrollment was completed in June 2019. Final follow-up is expected to be completed by June 2020. Interventions: Participants are randomized on a web platform in a 1:1 fashion to either 81 mg or 325 mg of aspirin daily. Main Outcomes and Measures: The primary efficacy end point is the composite of all-cause mortality, hospitalization for nonfatal myocardial infarction, or hospitalization for a nonfatal stroke. The primary safety end point is hospitalization for major bleeding associated with a blood-product transfusion. End points are captured through regular queries of the health systems' common data model within the structure of PCORnet's distributed data environment. Conclusions and Relevance: As a pragmatic study and the first interventional trial conducted within the PCORnet electronic data infrastructure, this trial is testing several unique and innovative operational approaches that have the potential to disrupt and transform the conduct of future patient-centered randomized clinical trials by evaluating treatments integrated in clinical practice while at the same time determining the optimal dosage of aspirin for secondary prevention of ASCVD. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Metastatic prostate cancer at diagnosis and through progression in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial assessed the effect of screening with prostate-specific antigen and a digital rectal examination on prostate cancer mortality. Another endpoint of interest was the burden of total metastatic disease. METHODS: All men in PLCO were assessed for metastatic prostate cancer at diagnosis; men with clinical stage I/II disease were assessed for metastatic progression. The rate of total metastatic disease was defined as metastases found either at diagnosis or through progression divided by person-years (PYs) of follow-up for all men in the trial. Metastatic progression rates were computed among men with clinical stage I/II prostate cancer. Survival among men with metastases at diagnosis was compared with survival among men with metastatic progression. RESULTS: Among 38,340 men in the intervention arm and 38,343 men in the control arm in PLCO, there were 4974 and 4699 prostate cancer cases, respectively. The rates of total metastatic disease were 4.72 and 4.83 per 10,000 PYs in the intervention and control arms, respectively (rate ratio, 0.98; 95% CI, 0.81-1.18). The rates of metastatic progression among men with clinical stage I/II prostate cancer were 43.7 and 50.5 per 10,000 PYs in the intervention and control arms, respectively (P = .30). Prostate cancer-specific 5- and 10-year survival rates were significantly worse for men with metastatic progression (24% and 19%, respectively) than men with metastases at diagnosis (40% and 26%, respectively). CONCLUSIONS: Rates of total metastatic disease and metastatic progression were similar across arms in PLCO. Survival was worse for men with metastatic progression in comparison with those with metastatic disease at diagnosis.

Aspirin Use and Mortality in Two Contemporary US Cohorts.

BACKGROUND: Daily aspirin use has been recommended for secondary prevention of cardiovascular disease, but its use for primary prevention remains controversial. METHODS: We followed 440,277 men and women from the NIH-AARP Diet and Health Study (ages 50-71) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (ages 55-74) for mortality for 13 years on average. Frequency of aspirin use was ascertained through self-report, and cause of death by death certificates. We calculated multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality using Cox proportional hazards models for each cohort and combined by meta-analysis. RESULTS: We found a consistent U-shaped relationship between aspirin use and mortality in both studies, with differential risk patterns for cardiovascular mortality by disease history. Among individuals with a history of cardiovascular disease, daily aspirin use was associated with reduced cardiovascular mortality [HR = 0.78 (95% CI, 0.74, 0.82)]. However, among those without a previous history, we observed no protection for daily aspirin users [HR = 1.06 (1.02, 1.11)], and elevated risk of cardiovascular mortality for those taking aspirin twice daily or more [HR = 1.29 (1.19, 1.39)]. Elevated risk persisted even among participants who lived beyond 5 years of follow-up and used aspirin without other nonsteroidal antiinflammatory drugs [HR = 1.31 (1.17, 1.47)]. CONCLUSIONS: Results from these 2 large population-based US cohorts confirm the utility of daily aspirin use for secondary prevention of cardiovascular mortality; however, our data suggest that caution should be exercised in more frequent use, particularly among individuals without a history of cardiovascular disease.

Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts.

Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer-specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75-0.90) and 15% (HR = 0.85; 95% CI = 0.77-0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72-0.95) and 25% (HR = 0.75; 95% CI = 0.66-0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410-20. ©2017 AACR.

A prospective study of alcohol consumption and renal cell carcinoma risk.

Recent epidemiological studies suggest that alcohol consumption may reduce renal cell carcinoma (RCC) risk, although inconsistent findings have been reported by sex and alcoholic beverage type. To better understand the relationship between alcohol consumption and RCC risk, we conducted an analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We followed up participants in the analytic cohort (N = 107,998) through 2010 for incident RCC (N = 408), and computed hazard ratios (HRs) and 95% confidence intervals (CIs) for alcohol intake using Cox regression with adjustment for age, sex, race, study center, hypertension, body mass index, and smoking status. In this study population increasing alcohol consumption was associated with reduced RCC risk compared to non-drinkers (>9.75 g day(-1) : HR, 0.67; 95%CI, 0.50 to 0.89; p trend = 0.002). We observed similar patterns of association for men and women as well as by alcohol beverage type. In analyses stratified by smoking status, the inverse association with consumption was apparent for ever smokers (HR, 0.51; 95%CI, 0.36 to 0.73; p trend<0.0001) but not among never smokers (HR, 1.08; 95%CI, 0.66 to 1.76; P trend = 0.78; p interaction = 0.01). Our study findings offer further support that alcohol consumption is associated with reduced RCC risk, regardless of sex or alcoholic beverage type. The finding of interaction with smoking is novel and requires confirmation.

Patient-powered research networks: building capacity for conducting patient-centered clinical outcomes research.

The Patient-Centered Outcomes Research Institute (PCORI) recently launched PCORnet to establish a single inter-operable multicenter data research network that will support observational research and randomized clinical trials. This paper provides an overview of the patient-powered research networks (PPRNs), networks of patient organizations focused on a particular health condition that are interested in sharing health information and engaging in research. PPRNs will build on their foundation of trust within the patient communities and draw on their expertise, working with participants to identify true patient-centered outcomes and direct a patient-centered research agenda. The PPRNs will overcome common challenges including enrolling a diverse and representative patient population; engaging patients in governance; designing the data infrastructure; sharing data securely while protecting privacy; prioritizing research questions; scaling small networks into a larger network; and identifying pathways to sustainability. PCORnet will be the first distributed research network to bring PCOR to national scale.

The risk of amyotrophic lateral sclerosis after cancer in U.S. elderly adults: a population-based prospective study.

Although epidemiologic studies have examined the risk of amyotrophic lateral sclerosis (ALS) in relation to cancer, none have been large population-based studies using incident ALS and adjusting for medical surveillance. Addressing those limitations, all first primary cancer cases from the Surveillance, Epidemiology and End Results (SEER) Program (1992-2005), linked to Medicare claims data were used. Cases were followed from cancer diagnosis until the earliest date of ALS diagnosis, a break in Medicare claims data, death, age 85 or December 31, 2005. A comparison group from a 5% random Medicare sample in the SEER areas who were cancer-free and censored as above, or until a cancer diagnosis were selected. ALS outcomes were derived from medical claims. The proportional hazards models to estimate ALS hazard ratios (HRs), using age as the time scale, adjusting for sex, race and physician visits, and stratifying the baseline hazard on birth year and SEER registry were used. A total of 303 ALS cases were ascertained in cancer patients (2,154,062 person-years) compared with 246 ALS cases (2,467,634 person-years) in the reference population. There was no overall relationship between cancer and ALS (HR = 0.99; 95% CI = 0.81-1.22), nor by gender or race. Except for an elevated ALS risk in the first year after a leukemia diagnosis, the relationship between site-specific cancers and ALS was null after correcting for multiple comparisons. Having a cancer diagnosis was not associated with an overall risk of incident ALS. The short-term ALS risk after leukemia may reflect screening or reporting errors.

Analgesic use and patterns of estrogen metabolism in premenopausal women.

Analgesic use has been hypothesized to reduce the risk of some cancers, with inverse associations between analgesics and colon cancer, and suggestive inverse associations for breast cancer. Estrogen metabolites (EM) have genotoxic and estrogenic potential; genotoxicity may differ by hydroxylation pathway. Analgesic use may impact patterns of estrogen metabolism; effects of analgesics on disease risk could be mediated through these patterns. We conducted a cross-sectional study among 603 premenopausal women in the Nurses' Health Study II. Frequency of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen use was reported via questionnaire; average frequency in 1997 and 1999 was calculated. Women provided urine samples between 1996 and 1999, collected during the mid-luteal phase of the menstrual cycle. Urinary EM were quantified using high-performance liquid chromatography-tandem mass spectrometry. We observed no association between analgesic use and estradiol, estrone, or specific pathways of estrogen metabolism. Women reporting more frequent aspirin use had lower methylated 2-catechols (e.g., 2-hydroxyestrone-3-methyl ether, 2+ days/week vs. non-use: 0.95 vs. 1.21 pmol/mg creatinine; p difference = 0.01, p trend = 0.07). Non-aspirin NSAID use was positively associated with 17-epiestriol (4+ days/week vs. non-use: 2.48 vs. 1.52 pmol/mg creatinine; p difference = 0.01, p trend = 0.11). Acetaminophen use was positively associated with total EM (2+ days/week vs. non-use: 236 vs. 198 pmol/mg creatinine; p difference = 0.02, p trend = 0.11), 2-hydroxyestrone-3-methyl ether (1.6 vs. 1.1 pmol/mg creatinine; p difference < 0.01, p trend = 0.02), and 16α-hydroxyestrone (17 vs. 12 pmol/mg creatinine; p difference = 0.01, p trend = 0.05). This study provides the first assessment of analgesic use and patterns of estrogen metabolism in women. While we observed some associations between analgesics and individual EM, no clear patterns emerged.

Hysterectomy and kidney cancer risk: a meta-analysis.

Recent cohort findings suggest that women who underwent a hysterectomy have an elevated relative risk of kidney cancer, although evidence from past studies has been inconsistent. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating hysterectomy and kidney cancer. Studies published from 1950 through 2012 were identified through a search of PubMed and of references from relevant publications. Meta-analyses were conducted using random-effects models to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for hysterectomy, age at hysterectomy (<45, 45+ years) and time since hysterectomy (<10, 10+ years). The SRR for hysterectomy and kidney cancer for all published studies (seven cohort, six case-control) was 1.29 (95% CI, 1.16-1.43), with no evidence of between-study heterogeneity or publication bias. The summary effect was slightly weaker, although still significant, for cohorts (SRR, 1.26; 95% CI, 1.11-1.42) compared with case-control findings (1.37; 95% CI, 1.09-1.73) and was observed irrespective of age at hysterectomy, time since the procedure and model adjustment for body mass index, smoking status and hypertension. Women undergoing a hysterectomy have an approximate 30% increased relative risk of subsequent kidney cancer. Additional research is needed to elucidate the biological mechanisms underlying this association.

Reproductive factors and kidney cancer risk in 2 US cohort studies, 1993-2010.

Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of Health-AARP Diet and Health Study (NIH-AARP), 1995-2006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 1993-2010). Cohort-specific and aggregated hazard ratios and 95% confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio = 1.28, 95% confidence interval: 1.09, 1.50) and PLCO (hazard ratio = 1.41, 95% confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend = 0.02) and increasing years of oral contraceptive use (P for trend = 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation.

Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP Diet and Health Study.

The incidence of bladder cancer among women is at least one-third to one-fourth that observed among men in many countries. Even after accounting for known risk factors, the reason for this gender disparity remains unexplained. We conducted a comprehensive evaluation of reproductive factors and exogenous hormone use with a primary focus on menopausal hormone therapy use and risk of bladder cancer in women in the NIH-AARP Diet and Health Study. Reproductive and hormonal factors were ascertained on the baseline questionnaire in 1995-1996 among 201,492 females who were followed until December 31, 2006. During follow-up, 651 cases of bladder cancer were diagnosed. A subset of women provided detailed information on use of MHT in a second questionnaire in 1996-1997. In this analysis, 127,361 females were followed through June 30, 2002 and 198 incident bladder cancer cases were identified. Cox proportional hazard models, adjusted for smoking status, cigarettes per day and body mass index using age as the time metric, were used to obtain hazard ratios (HRs). A reduced risk was observed among parous women (HR=0.76; 95% CI 0.62-0.93) and women who reported late age at menarche (≥15 years) (HR=0.57; 95% CI 0.39-0.84). Women who reported ever using estrogen and progestin therapy had a decreased risk (HR=0.53; 95% CI: 0.34-0.83) compared with women who did not report MHT use. No association was observed for estrogen only users (HR=0.82; 95% CI: 0.58-1.15). Our results suggest a putative role for sex hormones in the etiology of bladder cancer among women.

The association between cancer and amyotrophic lateral sclerosis.

OBJECTIVE: Increasing evidence suggests that some neurodegenerative disorders, such as Parkinson's disease, are inversely related to cancer. Few epidemiologic studies have examined the relationship between cancer and amyotrophic lateral sclerosis (ALS), another major neurodegenerative disease. This study addresses that gap. METHODS: Using data from 16 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the U.S. National Cancer Institute and death certificates, we followed 2.7 million cancer survivors who were diagnosed between 1973 and 2007, and who survived at least 1 year following cancer diagnosis. The standardized mortality ratio (SMR) of observed to expected ALS deaths in cancer survivors was calculated. RESULTS: A total of 1,216 ALS deaths were reported among 1 year survivors of cancer over 16.6 million person-years of follow-up. ALS mortality was not significantly associated with the incidence of total cancers [SMR = 1.00 (95 % confidence interval (CI), 0.95-1.06)]. There was, however, a significantly elevated risk of ALS death among survivors of melanoma [SMR = 1.49 (95 % (CI), 1.17-1.85)] and of tongue cancer [SMR = 2.57 (95 % CI, 1.41-4.32)], and a significantly reduced ALS death risk among prostate cancer survivors [SMR = 0.86 (95 % CI, 0.76-0.96)]. CONCLUSIONS: Cancer at certain sites may be related to risk of ALS death. Possible biologic factors linking ALS to these cancers are discussed. Future studies should attempt to confirm these associations using incident ALS outcomes. Establishing relationships between cancer and neurodegenerative diseases, such as ALS, opens new opportunities for understanding related pathophysiologic and therapeutic possibilities for these diseases.

Nonsteroidal anti-inflammatory drugs and glioma in the NIH-AARP Diet and Health Study cohort.

Several case-control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (>2 times/wk) of aspirin and risk of glioma (HR = 1.16; 95% CI, 0.87-1.56) or glioblastoma (HR = 1.17; 95% CI, 0.83-1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma = 0.90; 95% CI, 0.65-1.25 and HR for glioblastoma = 0.83; 95% CI, 0.56-1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma.

Nonsteroidal antiinflammatory drugs and bladder cancer: a pooled analysis.

Case-control studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk, but few cohort studies have evaluated this association. The authors investigated NSAID use and bladder cancer in 3 large prospective studies (NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists Study). Frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using self-administered questionnaires. Study-specific hazard ratios and 95% confidence intervals were estimated using Cox regression models and were combined using a fixed-effects meta-analytic model. Data from all studies were aggregated, and aggregated hazard ratios were estimated. The analysis included 508,842 individuals, with 2,489 incident cases of bladder cancer. A reduction in risk was observed for individuals who reported regular use (>2 times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). The risk reduction was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83) (P(trend) = 0.008) (P(interaction) = 0.02). No association was observed between regular aspirin use and bladder cancer risk (HR = 1.04, 95% CI: 0.94, 1.15). Results suggest that nonaspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers.

Variants in the alpha-Methylacyl-CoA racemase gene and the association with advanced distal colorectal adenoma.

BACKGROUND: alpha-Methylacyl-CoA racemase (AMACR), an enzyme involved in oxidation of branched chain fatty acids and cholesterol metabolites, as well as ibuprofen metabolism, is overexpressed in colorectal adenomas and cancer. AMACR gene variants have been associated with hereditary prostate cancer, but no studies have evaluated their etiologic role in colorectal carcinogenesis. METHODS: We conducted a case-control study of 725 advanced distal colorectal adenoma cases and 729 frequency-matched controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Seven AMACR polymorphisms were genotyped. Unconditional logistic regression models were used to evaluate the associations adjusting for age at randomization and gender. RESULTS: The 201L allele of S201L [TT versus CC: odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.15-2.62; TC versus CC: OR, 1.17; 95% CI, 0.93-1.49] and the 277E allele of K277E (GG versus AA: OR, 1.66; 95% CI, 1.03-2.68; GA versus AA: OR, 1.21; 95% CI, 0.96-1.53) were associated with increased risk of advanced distal colorectal adenoma (both P(trend)

Polymorphic variants in alpha-methylacyl-CoA racemase and prostate cancer.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), which prepares branched chain fatty acids to be metabolized for energy and is implicated in the activation of the COX-inhibiting form of ibuprofen, is overexpressed in prostate cancer and its precursor lesions. Significant differences in AMACR allele frequencies have been reported for hereditary prostate cancer (HPC), but the relevance of AMACR in the context of its substrates have not been studied. METHODS: We conducted a nested case-control study of 1,318 prostate cancer cases and 1,842 controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Five non-synonymous (nsSNP) and two intronic AMACR polymorphisms were genotyped. Conditional logistic regression models were used to evaluate the associations between the genetic variants and prostate cancer. RESULTS: Overall, prostate cancer was not related to AMACR gene variants; however, risks for prostate cancer were significantly reduced among regular ibuprofen users who carried allele variants at four nsSNP loci (M9V, D175G, S201L, and K277E; all P(trend) < 0.05) or carried the TGTGCG haplotype (OR = 0.65; 95% CI 0.44-0.97). No AMACR-related associations were noted among nonregular ibuprofen users (all P(interaction) > 0.33). CONCLUSION: AMACR gene variants were unrelated to prostate cancer overall in this study. The protective associations observed among ibuprofen users suggest that AMACR gene variants may enhance the chemopreventive effects of ibuprofen on prostate cancer risk.