The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Environmental and Occupational Exposures and Prognosis in Patients with Non-Muscle Invasive Bladder Cancer in the Be-Well Study.

Bladder cancer is primarily diagnosed as non-muscle invasive bladder cancer (NMIBC) with high recurrence and progression rates. Environmental and occupational exposures to carcinogens are well-known risk factors for developing bladder cancer, yet their effects on prognosis remain unknown. In the Be-Well Study, a population-based prospective cohort study of 1,472 patient with newly diagnosed NMIBC from 2015 to 2019, we examined history of environmental and occupational exposures in relation to tumor stage and grade at initial diagnosis by multivariable logistic regression, and subsequent recurrence and progression by Cox proportional hazards regression. Exposure to environmental and occupational carcinogens was significantly associated with increased risk of progression (HR = 1.79; 95% CI: 1.04, 3.09), specifically increased progression into muscle-invasive disease (HR = 2.28; 95% CI: 1.16, 4.50). Exposure to asbestos and arsenic were associated with increased odds of advanced stage at diagnosis (asbestos: OR = 1.43; 95% CI: 1.11, 1.84; arsenic, OR = 1.27; 95% CI: 1.01, 1.63), and formaldehyde exposure was associated with increased risk of recurrence (HR = 1.38; 95% CI: 1.12, 1.69). Our findings suggest that history of these exposures may benefit current risk stratification systems to tailor clinical care and improve prognosis in patients with NMIBC.

Chronic health conditions among long-term survivors of adolescent and young adult cancer: A comparison of outcomes in Israel and the United States.

BACKGROUND: There is a paucity of information on health outcomes of adolescent and young adult (AYA) cancer survivors living outside North America and Europe. This study compared outcomes in AYA cancer survivors in Israel with individuals without cancer and similar demographics and access to health care, and to AYA cancer survivors living in the United States. METHODS: This study included 12,674 2-year survivors of AYA (aged 15-39 years) cancer diagnosed between 2000 and 2018 at Clalit Health Services (CHS) in Israel. CHS participants without cancer (N = 50,696) were matched 4:1 to survivors on age, sex, ethnicity, and membership duration. Poisson regression was used to determine incidence rate ratios (IRRs) for chronic conditions. The US Kaiser Permanente Southern California AYA cohort (N = 6778) was used to estimate weighted (age, sex) standardized incidence ratios (SIRs) for CHS survivors. RESULTS: CHS AYA cancer survivors were more likely to have any chronic condition (IRR, 1.6 95% CI, 1.5-1.7), compared with participants without cancer. Survivors had an increased risk across nearly all conditions examined, with especially elevated risks for osteoporosis (IRR, 4.7; 95% CI, 4.1-5.5) and cardiomyopathy (IRR, 4.2 95% CI, 3.4-5.3). Compared with the Kaiser Permanente Southern California cohort, CHS survivors had an overall lower (SIR, 0.68; 95% CI, 0.65-0.72) incidence of developing any health condition, with noticeably lower incidence of hyperlipidemia (SIR, 0.7; 95% CI, 0.64-0.75). CONCLUSION: AYA cancer survivors in Israel are at increased risk for developing chronic conditions compared with individuals without cancer, but the overall incidence was lower than in US survivors. These findings may allow for refinement of surveillance recommendations for AYA survivors, taking into consideration regional differences in sociodemographic characteristics and cancer care. PLAIN LANGUAGE SUMMARY: The burden of chronic conditions was consistently greater in Israeli adolescent and young adult cancer survivors compared with individuals without cancer, with clear differences in risk of specific conditions by cancer diagnosis. However, the overall incidence of chronic conditions in Israeli survivors was generally lower than in US survivors.

Cause-specific mortality in survivors of adolescent and young adult cancer.

BACKGROUND: Few studies have adequately addressed long-term survival (>20 years from diagnosis) among survivors of adolescent and young adult (AYA) cancers. METHODS: In this retrospective, population-based cohort study in a US integrated health care system, the authors examined cause-specific mortality in 2-year survivors of AYA cancers (patients aged 15-39 years who were diagnosed between 1990 and 2012; N = 10,574) matched (by age, sex, and calendar year) to individuals without cancer (N = 136,683) to determine whether mortality rates changed over time. Incidence rate ratios (IRRs) for mortality were estimated using multivariable Poisson regression. A multivariable Cox model was used to examine predictors of cause-specific mortality among AYA cancer survivors. RESULTS: Through December 31, 2014, 1352 deaths were observed among AYA cancer survivors, yielding an overall survival rate of 78.5% at 25 years after diagnosis. Overall, AYA cancer survivors were at 10.4-fold increased risk for death (95% CI, 9.7-fold to 11.2-fold increased risk for death) compared with the matched noncancer cohort, and this risk remained elevated at >20 years after diagnosis (IRR, 2.9; 95% CI, 2.0-4.3). The absolute excess risk for death from any cause was 12.7 per 1000 person-years (95% CI, 11.9-13.4 per 1000 person-years). Starting at 15 years after diagnosis, the incidence of second cancer-related mortality exceeded the rate of recurrence-related mortality, and similar trends were observed for deaths from other health-related conditions. The 8-year cumulative incidence of mortality declined over time (before 2000, 12.6%; 2000-2006, 10.1%; after 2006, 7.3%; P < .001), largely because of declines in recurrence-related mortality. Age, sex, race/ethnicity, cancer stage at diagnosis, and cancer treatment predicted cause-specific mortality. CONCLUSIONS: The current data highlight the need for specialized, long-term follow-up care for AYA cancer survivors.

The Be-Well Study: a prospective cohort study of lifestyle and genetic factors to reduce the risk of recurrence and progression of non-muscle-invasive bladder cancer.

PURPOSE: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors. METHODS: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies. RESULTS: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection. CONCLUSIONS: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.

Neighborhood factors associated with late effects among survivors of adolescent and young adult cancer.

PURPOSE: The purpose of this study is to evaluate the associations between neighborhood income, education, and neighborhood racial composition (measured as a low percentage of white residents) and risk of developing cardiovascular diseases (CVD), diabetes (DM), and severe depression among survivors of AYA cancer and matched non-cancer peers. METHODS: Two-year survivors of AYA cancers diagnosed at age 15-39 yrs at Kaiser Permanente Southern California (diagnosed 2000-2012) and individually matched (1:13) non-cancer subjects were included. The development of CVD, DM, and severe depression was ascertained via electronic health records. Neighborhood characteristics were obtained from census-based geocoded data. Cox regression evaluated associations between neighborhood characteristics and the health outcomes of interest among both the cancer survivors and the non-cancer comparison cohort and effect modification by cancer survivor status on these relationships. RESULTS: Among cancer survivors (n = 6774), living in mostly non-white neighborhoods, was associated with risk of CVD (hazard ratio (HR) = 1.54 (95% CI 1.00-2.36)), while lower education level (HR = 1.41 (95% CI 1.02-1.94)) was associated with risk of severe depression. None of the neighborhood characteristics were associated with risk of DM. Effect modification was found for neighborhood education and risk of DM and severe depression. CONCLUSION: When jointly considered, cancer survivors who resided in the most disadvantaged neighborhoods were at the highest risk of developing these health outcomes compared to other subgroups. IMPLICATIONS FOR CANCER SURVIVORS: Our findings may inform screening strategy and addressing social determinants of health among AYA cancer survivors.

Impact of the Coronavirus Disease 2019 pandemic on neoadjuvant chemotherapy use in patients diagnosed with epithelial type ovarian cancer.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic posed critical challenges in providing care to ovarian cancer (OC) patients, including delays in OC diagnosis and treatment initiation. To accommodate for delays in OC surgery, the Society of Gynecologic Oncology (SGO) recommended preferential use of neoadjuvant chemotherapy during the pandemic. The purpose of this study was to assess the association of the COVID-19 pandemic with neoadjuvant chemotherapy use in patients diagnosed with OC. Methods: This retrospective cohort study included patients diagnosed with stage II-IV ovarian cancer of epithelial subtype between 01/01/2017-06/30/2021 at Kaiser Permanente Southern California (KPSC), a large integrated healthcare system in the United States. Ovarian cancer patients diagnosed between 2017-2020 were identified from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. Patients diagnosed in 2021 were identified from the electronic medical records (EMR) using ICD-10 diagnosis codes, followed by medical chart review to validate diagnosis and extract information on histology and stage at diagnosis. March 4, 2020 was used as the cut-off to define pre-pandemic and pandemic periods. Patients diagnosed with COVID-19 between OC diagnosis and treatment completion were excluded. Data on neoadjuvant chemotherapy use were extracted from the cancer registry and EMR, supplemented by chart review. Modified Poisson regression was used to evaluate the association of the pandemic with neoadjuvant chemotherapy use. Results: Of 566 OC patients, 160 (28.3%) were diagnosed in the pandemic period. Patients diagnosed in the pandemic period were slightly younger (mean age 62.7 vs 64.9 years, p=0.07) and had a higher burden of Charlson comorbidities (p=0.05) than patients diagnosed in pre-pandemic period. No differences in time to treatment initiation were observed by pandemic periods. Neoadjuvant chemotherapy use was documented in 58.7% patients during the pandemic period compared to 47.3% in pre-pandemic period (p=0.01). After adjusting for covariates, patients diagnosed in the pandemic period were 29% more likely to receive neoadjuvant chemotherapy than patients diagnosed in pre-pandemic period [RR(95%CI): 1.29(1.12-1.49)]. Discussions: Ovarian cancer patients diagnosed in the COVID-19 pandemic were more likely to receive neoadjuvant chemotherapy than patients diagnosed before the pandemic. Future research on patient outcomes and trends in the post-pandemic period are warranted.

DNA methylation markers for risk of metastasis in a cohort of men with localized prostate cancer.

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.

Modifying Effects of Genetic Variations on the Association Between Dietary Isothiocyanate Exposure and Non-muscle Invasive Bladder Cancer Prognosis in the Be-Well Study.

SCOPE: Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. METHODS AND RESULTS: In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. CONCLUSION: Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Changes in Fall Rates From Before to During the COVID-19 Pandemic: Findings From the Prospective AMBROSIA Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) social distancing policies resulted in reductions in community movement, however, fall rates during this time have not been described. METHODS: This prospective study included adults ≥65 years old participating in the Ambulatory Blood Pressure in Older Adults (AMBROSIA) cohort and who completed ≥1 monthly falls calendar (August 2019-March 2021; n = 250). Months were grouped to correspond to the fall 2020 phased reopening (August-October) and the shelter-in-place policy during the winter 2020 surge (November-January) in Los Angeles, California and compared to the same months, 1 year earlier (ie, before the pandemic). RESULTS: Participants had a mean (standard deviation [SD]) age of 75.2 (6.1) years, 49.6% were White, and 53.2% were women. We obtained 2 795 falls calendars during follow-up. Overall, 110 (44.0%) participants reported a total of 421 falls (rate 15.1 per 100 calendar months). The highest monthly fall rate during the pandemic was 22.9 (95% confidence interval [CI] 16.4-31.1) per 100 calendar-months in August 2020. The lowest fall rate during the pandemic was 8.6 (95% CI 3.5-17.8) per 100 calendar-months in February 2021. During the pandemic, fall rates in August, September, and October 2020 were higher than the previous year (rate ratio 1.8 [95% CI 1.1-2.9]), and fall rates in November and December 2020 and January 2021 were lower than the previous year (rate ratio 0.5 [95% CI 0.4-0.8]). CONCLUSION: As the pandemic continues and older adults resume community mobility after a shelter-in-place period, providers should pay attention to the risk of falls.

Exposure to statins post localized prostate cancer diagnosis and risk of metastasis among men who did not receive curative prostate cancer treatment.

BACKGROUND: Few studies have evaluated the effect of statin exposure on metastasis risk among prostate cancer patients not receiving curative treatment. METHODS: We included men diagnosed with localized prostate cancer at an integrated health care system between 1997 and 2006 who did not receive curative treatment within 6 months of diagnosis. We followed these men until a metastatic event, disenrollment, death, or 12/31/2016. We collected all data from electronic health records supplemented by chart review. We used Cox regressions to examine the association between post-diagnostic statin exposure and metastasis, controlling for clinical characteristics and pre-diagnostic statin exposure. RESULTS: There were 4245 men included. Mean age of diagnosis was 68.02 years. 46.6% of men used statins after prostate cancer diagnosis. During follow-up, 192 men developed metastasis (cumulative incidence rate: 14.5%). In the adjusted Cox model, statin use post-prostate cancer diagnosis was not significantly associated with a metastatic event (HR = 0.97, 95% CI = 0.69, 1.36). Pre-diagnostic statin use was also not associated with development of metastasis (HR = 0.76, 95% CI = 0.53, 1.10). We did not observe a dose-response for the proportion of person-time at-risk post-prostate cancer diagnosis on statins (HR = 0.98 per 10% increase in person-time exposed [95% CI = 0.93, 1.03]). CONCLUSIONS: We did not find an inverse association between post-diagnosis statin exposure and metastasis development in localized prostate cancer patients who did not receive active treatment. Our results did not offer support to the chemopreventive potential of post-diagnostic statin use among men on active surveillance.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non-muscle-invasive bladder cancer: findings from the Be-Well Study.

BACKGROUND: High recurrence and progression rates are major clinical challenges for non-muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. OBJECTIVES: This study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. METHODS: The study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015-2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC-albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. RESULTS: Over a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC-albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). CONCLUSIONS: Our findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Smoking Behaviors and Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer in the Be-Well Study.

Importance: Tobacco smoking is an established risk factor associated with bladder cancer, yet its impact on bladder cancer prognosis is unclear. Objective: To examine associations of use of tobacco (cigarettes, pipes, and cigars), e-cigarettes, and marijuana with risk of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) and to explore use of smoking cessation interventions. Design, Setting, and Participants: The Be-Well Study is a prospective cohort study of patients with NMIBC diagnosed from 2015 to 2019 and followed-up for 26.4 months in the Kaiser Permanente Northern and Southern California integrated health care system. Eligibility criteria were age at least 21 years, first NMIBC diagnosis (stages Ta, Tis, or T1), alive, and not in hospice care. Exclusion criteria were previous diagnosis of bladder cancer or other cancer diagnoses within 1 year prior to or concurrent with NMIBC diagnosis. Data were analyzed from April 1 to October 4, 2022. Exposures: Use of cigarettes, pipes, cigars, e-cigarettes, and marijuana was reported in the baseline interview. Use of smoking cessation interventions (counseling and medications) was derived from electronic health records. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs of recurrence and progression of bladder cancer were estimated by multivariable Cox proportional hazards regression. Results: A total of 1472 patients (mean [SD] age at diagnosis, 70.2 [10.8%] years; 1129 [76.7%] male patients) with NMIBC were enrolled at a mean (SD) of 2.3 (1.3) months after diagnosis, including 874 patients (59.4%) who were former smokers and 111 patients (7.5%) who were current cigarette smokers; 67 patients (13.7%) smoked pipes and/or cigars only, 65 patients (4.4%) used e-cigarettes, 363 patients (24.7%) used marijuana. Longer cigarette smoking duration and more pack-years were associated with higher risk of recurrence in a dose-dependent manner, with the highest risks for patients who had smoked for 40 or more years (HR, 2.36; 95% CI, 1.43-3.91) or 40 or more pack-years (HR, 1.97; 95% CI, 1.32-2.95). There was no association of having ever smoked, being a former or current cigarette smoker, and years since quit smoking with recurrence risk. No associations with pipes, cigars, e-cigarettes, or marijuana were found. Of 102 patients offered a smoking cessation intervention, 57 (53.8%) received an interventions after diagnosis, with female patients more likely than male patients to engage in such interventions (23 of 30 female patients [76.7%] vs 34 of 76 male patients [44.7%]; P = .003). Conclusions and Relevance: These findings suggest that longer duration and more pack-years of cigarette smoking were associated with higher risk of NMIBC recurrence. Cigarette smoking remains a critical exposure before and after diagnosis in survivors of NMIBC.

Long-term follow-up of a racially and ethnically diverse population of men with localized prostate cancer who did not undergo initial active treatment.

BACKGROUND: There is limited research on the racial/ethnic differences in long-term outcomes for men with untreated, localized prostate cancer. METHODS: Men diagnosed with localized, Gleason ≤7 prostate cancer who were not treated within 1 year of diagnosis from 1997-2007 were identified. Cumulative incidence rates of the following events were calculated; treatment initiation, metastasis, death due to prostate cancer and all-cause mortality, accounting for competing risks. The Cox model of all-cause mortality and Fine-Gray sub distribution model to account for competing risks were used to test for racial/ethnic differences in outcomes adjusted for clinical factors. RESULTS: There were 3925 men in the study, 749 Hispanic, 2415 non-Hispanic white, 559 non-Hispanic African American, and 202 non-Hispanic Asian/Pacific Islander (API). Median follow-up was 9.3 years. At 19 years, overall cumulative incidence of treatment, metastasis, death due to prostate cancer, and all-cause mortality was 25.0%, 14.7%, 11.7%, and 67.8%, respectively. In adjusted models compared to non-Hispanic whites, African Americans had higher rates of treatment (HR = 1.39, 95% CI = 1.15-1.68); they had an increased risk of metastasis beyond 10 years after diagnosis (HR = 4.70, 95% CI = 2.30-9.61); API and Hispanic had lower rates of all-cause mortality (HR = 0.66, 95% CI = 0.52-0.84, and HR = 0.72, 95% CI = 0.62-0.85, respectively), and API had lower rates of prostate cancer mortality in the first 10 years after diagnosis (HR = 0.29, 95% CI = 0.09-0.90) and elevated risks beyond 10 years (HR = 5.41, 95% CI = 1.39-21.11). CONCLUSIONS: Significant risks of metastasis and prostate cancer mortality exist in untreated men beyond 10 years after diagnosis, but are not equally distributed among racial/ethnic groups.

Chronic Comorbidities Among Survivors of Adolescent and Young Adult Cancer.

PURPOSE: To describe the incidence, relative risk, and risk factors for chronic comorbidities in survivors of adolescent and young adult (AYA) cancer. METHODS: This retrospective cohort study included 2-year survivors of AYA cancer diagnosed between age 15 and 39 years at Kaiser Permanente Southern California from 2000 to 2012. A comparison cohort without cancer was individually matched (13:1) to survivors of cancer on age, sex, and calendar year. Using electronic medical records, all participants were followed through December 31, 2014, for chronic comorbidity diagnoses. Poisson regression was used to evaluate the association between cancer survivor status and risk of developing each comorbidity. The associations between cumulative exposure to chemotherapy and radiation therapy and selected comorbidities were examined for survivors of cancer. RESULTS: The cohort included 6,778 survivors of AYA cancer and 87,737 persons without a history of cancer. The incidence rate ratio (IRR) for survivors of cancer was significantly increased for nearly all comorbidities examined. IRR ranged from 1.3 (95% CI, 1.2 to 1.4) for dyslipidemia to 8.3 (95% CI, 4.6 to 14.9) for avascular necrosis. Survivors of AYA cancer had a 2- to 3-fold increased risk for cardiomyopathy, stroke, premature ovarian failure, chronic liver disease, and renal failure. Among survivors of cancer, significant associations between chemotherapy and radiation therapy exposures and late effects of cardiomyopathy, hearing loss, stroke, thyroid disorders, and diabetes were observed from the multivariable analyses. Forty percent of survivors of AYA cancer had multiple (≥ 2) comorbidities at 10 years after index date, compared with 20% of those without cancer. CONCLUSION: Risk of developing comorbidities is increased in survivors of AYA cancer compared with the general population. Specific cancer treatment exposures were associated with risk of developing different comorbidities. These findings have important implications for survivorship care planning and patient education.

Incidence, Risk Factors, and Mortality Associated With Second Malignant Neoplasms Among Survivors of Adolescent and Young Adult Cancer.

Importance: Detailed data describing the epidemiology of second malignant neoplasms (SMN) are needed for survivors of adolescent and young adult (AYA) cancer to inform the development of age-appropriate survivorship care guidelines. Objective: To describe the incidence, risk factors, and mortality for SMN in survivors of AYA cancer. Design, Setting, and Participants: This retrospective matched cohort study included 10 574 two-year survivors diagnosed with cancer between January 1, 1990, and December 31, 2012, at age 15 to 39 years in an integrated health care delivery system in Southern California. A comparison cohort without a history of cancer was individually matched 13:1 to survivors of AYA cancer by age, sex, and calendar year. Data analysis was completed in July 2018. Exposures: Secondary malignant neoplasm risk factors of interest included age, stage, and calendar year at first cancer diagnosis; sex; race/ethnicity; radiation therapy; and chemotherapy. Main Outcomes and Measures: Diagnoses of SMN were ascertained using cancer registries from the National Cancer Institute Surveillance, Epidemiology, and End Results Program through December 31, 2014. Poisson regression was used to evaluate the association between cancer survivor status and developing SMN and risk factors for SMN, while risk of all-cause mortality by SMN status was examined in Cox regression. Results: A total of 10 574 survivors of AYA cancer (6853 [64.8%] female; median [range] age, 33 [15-39] years; 622 with SMN) and 136 683 participants in the comparison cohort (88 513 [64.8%] female; median [range] age, 33 [15-39] years; 3437 with first cancer) were included. In survivors of AYA cancer, 20-year cumulative incidence of SMN was 12.5%. The incidence rate ratio (IRR) of developing SMN in survivors of AYA cancer was 2.6 (95% CI, 2.4-2.9) compared with the comparison cohort. Survivors of breast cancer, melanoma, and testicular cancer had substantially elevated risk for SMN of the same organ (IRR, 5.6 [95% CI, 4.6-6.8], 11.2 [95% CI, 7.3-17.2], and 16.2 [95% CI, 6.8-38.4], respectively). Among survivors of AYA cancer, older age (IRR for age 30-39 years, 1.79 [95% CI, 1.21-2.65]), female sex (IRR, 1.31 [95% CI, 1.09-1.57]), white race/ethnicity (IRR for Asian race, 0.61 [95% CI, 0.43-0.87]), advanced stage at first cancer diagnosis (IRR for stage II, 1.29 [95% CI, 1.11-1.65]), and use of radiotherapy (IRR, 1.50 [95% CI, 1.26-1.79]) were associated with increased risk of SMN. Survivors of AYA cancer who developed SMN had an all-cause mortality rate 7.2 (95% CI, 6.1-8.5) times greater than survivors without SMN. Conclusions and Relevance: This study suggests that SMN risk is elevated in survivors of AYA cancer and varies across survivor subgroups. Survival following SMN may be significantly compromised. These data may form the basis for identifying individuals at high risk, as well as informing screening for SMN.