Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events. OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations. METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors. RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95). CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Birth Outcomes and Rehospitalizations Among Pregnant Women With Rheumatoid Arthritis and Systemic Lupus Erythematosus and Their Offspring.

OBJECTIVE: To compare obstetric/birth outcomes and rehospitalization among women with and without rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and their infants. METHODS: This population-based retrospective cohort study identified women with RA (n = 1,223) and SLE (n = 1,354) and unexposed women with singleton births 1987-2014 in Washington State in linked vital hospital discharge records. Outcomes, including cause-specific hospitalizations <2 years postpartum, were compared by estimating adjusted relative risks (RRs) and cause-specific rehospitalization hazard ratios (HRs) with 95% confidence intervals (95% CIs). RESULTS: We observed increased risks of several adverse outcomes; RRs were often greatest for SLE. Women with RA/SLE more often required rehospitalization, most notably at <6 months postpartum (RA: 4% versus 2%; RR 2.22 [95% CI 1.62-3.04]; SLE: 6% versus 2%; RR 2.78 [95% CI 2.15-3.59]). Maternal postpartum rehospitalization was greatest for musculoskeletal conditions (RA: HR 19.1 [95% CI 13.6-26.8]; SLE: HR 29.8 [95% CI 22.1-40.1]). Infants of women with SLE more often had malformations (9% versus 6%; RR 1.46 [95% CI 1.21-1.75]), and increased mortality at <2 years (RR 2.11 [95% CI 1.21-3.67]). Infants of women with SLE also experienced more frequent rehospitalizations in their first year of life. CONCLUSION: Women with RA or SLE and their infants experienced adverse outcomes, particularly infants of women with SLE. Maternal/infant rehospitalization was more common; most marked in the early months postpartum. Close follow-up during these time periods is crucial to minimize adverse outcomes.

Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.

PURPOSE: For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. METHODS: Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m2 across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m2 ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status. RESULTS: From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m2). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m2. CONCLUSION: Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

Population-Based Impact of Rurality and Neighborhood-Level Socioeconomic Disadvantage on Pediatric Cancer Mortality in Washington State.

BACKGROUND: Childhood cancer-related mortality differs by socioeconomic factors, but the impact of residential location, including rurality and neighborhood-level socioeconomic disadvantage, is not well-characterized. METHODS: This retrospective cohort study linked Washington State cancer registry data (1992-2013) to state birth (1974-2013) and death records (1992-2013) to identify residents <20 years diagnosed with cancer (n = 4,306). Census-based rural-urban commuting area codes and Area Deprivation Index (ADI) defined rural residence and neighborhood socioeconomic disadvantage at time of cancer diagnosis, respectively. Neighborhoods in the highest state ADI quintile were classified as the most disadvantaged. Kaplan-Meier estimates and Cox hazards models, adjusted for key characteristics, were used to compare mortality by rural and ADI classification. RESULTS: Five-year overall survival for children from non-rural low ADI neighborhoods (referent) was 80.9%±0.8%, versus 66.4%±2.9% from non-rural high ADI neighborhoods, 69.4%±3.8% from rural low ADI neighborhoods, and 66.9%±3.8% from rural high ADI neighborhoods (P < 0.01 for each comparison versus referent). Compared with the referent group, children from comparator neighborhoods had a greater mortality risk: Rural low ADI [hazard ratio (HR), 1.50; 95% confidence interval (CI), 1.12-2.02], rural high ADI (HR, 1.53; 95% CI, 1.16-2.01), and non-rural high ADI (HR, 1.64; 95% CI, 1.32-2.04). Associations of ADI and rurality with mortality varied in sub-analyses by cancer type. CONCLUSIONS: Children with cancer living in rural and/or socioeconomically disadvantaged neighborhoods at diagnosis experienced greater mortality relative to those without either factor. IMPACT: Future investigation is needed to examine how rurality and poverty potentially impact healthcare utilization and health-related outcomes in pediatric oncology.

Morbidity and rehospitalization postpartum among women with epilepsy and their infants: A population-based study.

OBJECTIVE: We compared the relative occurrence of selected pregnancy outcomes and postpartum rehospitalizations among women with and without epilepsy and their infants. Using linked vital-hospital discharge records of women with deliveries in Washington State 1987-2014, comparisons were made overall, by epilepsy type, and by time periods related to antiepileptic drug (AED) marketing changes. METHODS: This population-based retrospective cohort study identified women with, and without epilepsy per diagnosis codes in the hospital discharge record from among all deliveries during 1987-2014 to examine maternal and infant outcomes, rehospitalization and mortality <2 years postpartum. Relative risks (RRs) and 95 % confidence intervals (CI) overall, and by epilepsy type were calculated using Poisson regression. We assessed the validity of epilepsy identification based on diagnosis codes by conducting a medical chart review for a sample of women. RESULTS: Women with epilepsy had increased risks of preeclampsia (RR 1.23; 95 % CI 1.08-1.41) and gestational diabetes (RR 1.18; 95 % CI 1.02-1.36). Their infants had increased malformation (RR 1.23; 95 % C: 1.08-1.42) and small for gestational age (SGA, RR 1.39; 95 % CI 1.25-1.54) risks, and were nearly three times as likely to not be breastfed. Affected mothers (RR 5.25; 95 % CI 2.46-11.23) and their infants (RR 1.64, 95 % CI 1.41-1.89) required more ICU admissions during the delivery hospitalizations, and more postpartum rehospitalization, with greatest risk in the first six months. Maternal mortality < 2 years after delivery was increased (RR 7.11; 95 % CI 2.47-20.49). Increased risks were observed for all epilepsy subtypes for nearly all outcomes examined. Risks of preterm delivery and low birthweight increased over time (p <.05). Suggestive, but not statistically significant temporal decreases in risks of gestational diabetes and malformations and increased risk of preterm labor were noted. We observed high sensitivity of diagnosis codes for identifying pregnant women with epilepsy. CONCLUSION: These population-based results emphasize the need for frequent postpartum monitoring of women with epilepsy. Increases in risks of low birthweight and preterm delivery over time are of concern. Possible temporal changes in other outcomes warrant further investigation.

Association of HSD3B1 Genotype and Clinical Outcomes in Postmenopausal Estrogen-Receptor-Positive Breast Cancer.

BACKGROUND: Homozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes. PATIENTS AND METHODS: Germline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I-III estrogen receptor-positive (ER+), HER2/neu-negative (HER2-) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks. RESULTS: Adrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32-18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27-9.59, p = 0.02). CONCLUSIONS: Inheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER+/HER2- breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression.

Hospitalization and Mortality Outcomes Among Childhood Cancer Survivors by Race, Ethnicity, and Time Since Diagnosis.

Importance: Cancer outcomes are relatively poor in adults who belong to minoritized racial and ethnic groups. Survival and long-term outcomes by race and ethnicity in individuals with childhood cancers are less studied. Objective: To evaluate survival and hospitalization among American Indian and Alaska Native, Asian, Black, and Hispanic children compared with non-Hispanic White children with cancer. Design, Setting, and Participants: This cohort study evaluated all individuals born in Washington State who were younger than 20 years (hereafter referred to as children) and had been diagnosed with cancer during 1987 to 2012, with follow-up ranging from 1 to 27 years. The data subset was built in 2019, and statistical analyses were completed in January 2022. Exposures: Race and ethnicity. Main Outcomes and Measures: Mortality and hospitalization events for all other racial and ethnic groups relative to non-Hispanic White children estimated by Cox proportional hazards regressions for the first 5 years after diagnosis and among cancer survivors 5 or more years after diagnosis. Results: A total of 4222 children (mean [SD] age, 8.4 [6.4] years; 2199 [52.1%] male; 113 American Indian and Alaska Native [2.7%], 311 Asian [7.4%], 196 Black [4.6%], 387 Hispanic [9.2%], and 3215 non-Hispanic White [76.1%]) with cancer diagnosed at younger than 20 years during 1987 to 2012 were included. Mortality was similar across all groups. Compared with non-Hispanic White survivors at less than 5 years after diagnosis, there were no greatly increased hazard ratios (HRs) for hospitalization. Among survivors at 5 or more years after diagnosis, hospitalization HRs were 1.7 (95% CI, 1.0-3.0) for American Indian and Alaska Native survivors and 1.5 (95% CI, 0.9-2.4) for Black survivors. Significantly increased HRs among Hispanic children were observed for infection-related (HR, 1.4; 95% CI, 1.2-1.6), endocrine-related (HR, 1.3; 95% CI, 1.1-1.6), hematologic-related (HR, 1.3; 95% CI, 1.1-1.5), respiratory-related (HR, 1.3; 95% CI, 1.0-1.5), and digestive-related (HR, 1.2; 95% CI, 1.0-1.5) conditions. American Indian and Alaskan Native children had increased HRs for infection-related (HR, 2.3; 95% CI, 1.2-4.5), hematologic-related (HR, 3.0; 95% CI, 1.4-6.5), and digestive-related (HR, 2.6; 95% CI, 1.3-5.4) conditions. Both American Indian and Alaska Native (HR, 3.6; 95% CI, 1.4-9.0) and Black (HR, 2.5; 95% CI, 1.2-5.5) children had increased mental health-related hospitalizations and death. Conclusions and Relevance: In this cohort study, disproportionately increased long-term risks of hospitalization for physical and mental conditions may have contributed to worse outcomes by race. A key component to bridging the morbidity gap by race is improved understanding of reasons for greater cause-specific hospitalizations in some groups, with development of culturally appropriate intervention strategies.

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group.

BACKGROUND: Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRF) among survivors compared with population-matched controls. METHODS: Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and Dana-Farber Cancer Institute 95-01 from 1996 to 2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 National Health and Nutrition Examination Survey (NHANES) population. We estimated future predicted cardiovascular risk based on general population (e.g., Framingham) and Childhood Cancer Survivor Study (CCSS) models. RESULTS: Compared with NHANES (n = 584), survivors [n = 164; 44.5% female, median age 28 years (range, 16-38 years); median 17.4 years (range, 13-22 years) since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation] had similar rates of obesity, diabetes, and dyslipidemia, but more prehypertension/hypertension (38.4% vs. 30.1%, P = 0.044). Survivors had fewer metabolic syndrome features compared with NHANES (≥2 features: 26.7% vs. 55.9%; P < 0.001). Survivors were more physically active and smoked tobacco less (both P < 0.0001). Therefore, general population cardiovascular risk scores were lower for survivors versus NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and >95% at moderate/high risk for heart failure, with a 9% to 12% predicted incidence of these conditions by age 50 years. CONCLUSIONS: Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically significant cardiovascular disease. IMPACT: Further strategies supporting optimal CRF control are warranted in survivors. See related commentary by Mulrooney, p. 515.

Time and geographic variations in human papillomavirus vaccine uptake in Washington state.

This study examines geographic variations of human papillomavirus (HPV) vaccine uptake, the most significant disparity in HPV vaccination, in Washington State. We evaluated Washington State Immunization Information System (WA-IIS) data on target age (11-12 year old adolescents) between 2008 and 2018. A Bayesian spatio-temporal analysis was conducted to examine uptake at the census tract level. Urban-rural disparities in vaccine rates were assessed using t-tests. Persistently high and low vaccine areas and their contributing sociodemographic factors were then identified using a multinomial logistic regression. HPV vaccine uptake gradually increased after 2010, but remained persistently low. Average vaccine uptake rates from 2010 through 2018 in urban areas were 11%-34% for initiation and 4-19% for completion. These rates were 9-22% initiation and 3-11% completion in rural areas. We observed statistically significant (p < 0.05) differences between the estimated vaccine rates for urban and rural census tracts. Race/ethnicity and socioeconomic status were associated with this urban-rural disparity. The odds of being in low vaccine rural areas increased with increase in Area Deprivation Index (ADI) (OR = 1.14, CI = (1.10, 1.19)), and decreased with percentage increase in Black (OR = 0.43, CI = (0.02, 0.85)) and Hispanic (OR = 0.97, CI = (0.94, 1.00)) population. Bayesian spatial analysis was effective in capturing spatio-temporal patterns in HPV vaccine rates and identifying areas with persistently low vaccination over time. This analytic approach can be used to guide public health policies and geographically target interventions to reduce HPV vaccine disparities and to prevent future HPV-related cancers.

Hospitalization and mortality outcomes in the first 5 years after a childhood cancer diagnosis: a population-based study.

PURPOSE: Children with cancer are frequently hospitalized. However, hospitalization and death by disease category are not well defined < 5 years from diagnosis. METHODS: We conducted a retrospective cohort study using linked cancer registry-hospital discharge-vital records to identify cancer cases < 20 years at diagnosis during 1987-2012 (n = 4,567) and comparison children without cancer, matched on birth year and sex (n = 45,582). Data linkage identified serious morbidities resulting in cancer- and non-cancer-related hospitalizations or deaths < 5 years from diagnosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare relative hospitalization and mortality by disease category and after excluding cancer-related outcomes. Among cancer cases, relative risks of these outcomes for children with solid tumors compared with children with leukemia/lymphoma were also estimated. RESULTS: Greater rates of all-cause hospitalization (281.5/1,000 vs. 6.2/1,000 person years) and death (40.7/1,000 vs. 0.15/1,000 person years) were observed in childhood cancer cases than comparators and across all diagnosis categories. Increased hospitalization (31.0/1,000 vs. 6.2/1,000 person years; HR 5.0, 95% CI 4.5-5.5) and death (1.0/1,000 vs. 0.15/1,000 person years; HR 10.4, 95% CI 5.6-19.1) rates remained when cancer-related outcomes were excluded. Although HRs for hospitalization and death did not differ greatly by treatment era, absolute rates of hospitalization were greater (1987-1999: 233.3/1,000; 2000-2012: 320.0/1,000 person years) and death were lesser (1987-1999: 46.3/1,000; 2000-2012: 36.8/1,000 person years) in the later treatment era among cases. Children with solid tumors were less likely to have a cancer-related hospitalization than were those with leukemia/lymphoma (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: Even after excluding cancer-related diagnoses, children with cancer experience greater rates of hospitalization and death in all disease categories. Results may guide future toxicity mitigation initiatives and inform anticipatory guidance for families of children with cancer.

Pregnancy outcomes among visually impaired women in Washington State, 1987-2014.

BACKGROUND: Women with visual impairment may have reduced ability to access standard care resources, however, information on their pregnancy and neonatal outcomes is limited. OBJECTIVE: To assess risk of adverse pregnancy and neonatal outcomes among visually impaired women in Washington State from 1987 to 2014. METHODS: We conducted a retrospective cohort study using linked Washington State birth/fetal death hospital discharge records to compare outcomes among women with and without visual impairment noted at their delivery hospitalization. Pregnancy conditions and outcomes evaluated included gestational diabetes, pre-eclampsia, labor induction and cesarean delivery. Neonatal outcomes included preterm delivery and birth weight <2500 g. We assessed length of maternal and infant delivery hospitalization. We performed Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CIs) for each outcome, adjusting for year of delivery, maternal age, and parity. RESULTS: Most adverse pregnancy and neonatal outcomes were similar for visually impaired (N = 232) and comparison women (N = 2362). However, visually impaired women had increased risks of severe pre-eclampsia (RR 3.77, 95% CI 1.69-8.43), labor induction (RR 1.33, 95% CI 1.10-1.61) and preterm delivery (RR 1.60, 95% CI 1.06-2.42). They were also more likely to have delivery hospitalizations of 3 or more days following a vaginal (RR 1.86, 95% CI 1.41-2.47). Among cesarean deliveries, infants of visually impaired women had increased risk (RR 1.24, 95% CI 1.02-1.51) of hospitalization for 3 or more days postpartum. CONCLUSION: Our findings may be useful for obstetric providers in counseling their visually impaired patients.

Health Care Cost Associated With Contemporary Chronic Myelogenous Leukemia Therapy Compared With That of Other Hematologic Malignancies.

PURPOSE: Given the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making. METHODS: A retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs. RESULTS: Mean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib's mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239). CONCLUSION: Contemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.

Adverse events among chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors: a real-world analysis of health plan enrollees.

With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p < 0.05). Increased risk of infections, cardiopulmonary and skin issues associated with later generation TKIs persisted in subsequent years. In this real-world population, TKI therapy was associated with a high burden of adverse events. Later generation TKIs may have greater toxicity than imatinib.

Feasibility of a behavioral intervention using mobile health applications to reduce cardiovascular risk factors in cancer survivors: a pilot randomized controlled trial.

PURPOSE: Determine the feasibility of a remotely delivered mobile health (mHealth)-supported intervention to improve diet and physical activity in hematologic malignancy survivors. METHODS: Pilot randomized controlled trial of a 16-week intervention for improving diet and physical activity: individualized goal-setting (daily steps, sodium, saturated fat, added sugar intake) per feedback from mHealth trackers (Fitbit for activity; Healthwatch360 for diet), supplemented by a Facebook peer support group. Controls accessed the trackers without goal-setting or peer support. Everyone received standardized survivorship counseling with tailored advice from a clinician. Actigraphy and food frequency questionnaires assessed activity and diet at baseline and follow-up. RESULTS: Forty-one participants (51.2% male; median age 45.1 years; 7.0 years from treatment) were randomized (24 intervention; 17 control). Fitbit and Healthwatch360 use were more common among intervention versus control participants (75.0% versus 70.6% and 50.0% versus 17.7% of eligible days, respectively). Most intervention participants (66.7%) engaged with Facebook; overall, 91.7% interacted with the study's mHealth applications. While no comparisons in activity or dietary outcomes between intervention versus control group met statistical significance, the intervention was associated with greater reductions in the targeted dietary factors and improvements in Healthy Eating Index-2015 score, moderate-vigorous physical activity time, and daily steps. Participant retention at 6 months was 90.2%. CONCLUSIONS: An intervention for cardiovascular risk reduction based on individualized goal-setting enhanced by mHealth and social media peer support was feasible and acceptable among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Effective and easily disseminated strategies that improve diet and physical activity in this population are needed. TRIAL REGISTRATION: Registered in ClinicalTrials.gov (NCT03574012) on June 29, 2018.

Humoral Response to HPV16 Proteins in Persons with Anal High-Grade Squamous Intraepithelial Lesion or Anal Cancer.

BACKGROUND: This study was launched to evaluate the association of early and late antibodies to human papillomavirus 16 (HPV16) detection and risk of anal high-grade squamous intraepithelial lesions (HSIL) or cancer. METHODS: We analyzed data from persons with anal HSIL or cancer and controls from a case-control study in Seattle, Washington. Sera were evaluated for HPV16 early (E1, E2, E4, E6, and E7) and late (L1) antibodies by multiplex serology. Logistic regression models were used to assess serologic associations with risk of anal HSIL or cancer. RESULTS: The study included 67 participants with anal HSIL, 116 with anal cancer, and 830 population-based controls. HPV16 seropositivity to L1 [adjusted OR (aOR), 13.8; 95% confidence interval (CI), 7.4-25.8], E4 (aOR, 2.3; 95% CI, 1.1-4.5), and E6 (aOR, 4.9; 95% CI, 1.1-21.2) was associated with HSIL; and detection of all antibodies to HPV16 late and early proteins was associated with increased risk of anal cancer ranging from aOR 1.7 to 32.5 [L1 aOR, 12.5 (95% CI, 7.3-21.7); E1 aOR, 24.9 (95% CI, 10.3-59.9); E2 aOR, 6.3 (95% CI, 3.4-11.7); E4 aOR, 2.8 (95% CI, 1.6-4.8); E6 aOR, 32.5 (95% CI, 14.2-74.4); and E7 aOR, 1.7 (95% CI, 1.0-3.0)]. CONCLUSIONS: HPV serologic markers proved to be specific for identifying anal cancer. HPV16 E6 seropositivity is relatively uncommon in persons without anal cancer. IMPACT: This large study comprehensively describes the distinct antibody responses to the HPV16 proteins in persons with anal HSIL or anal cancer. Antibodies to HPV16 E6 should be further evaluated as a potential biomarker for anal cancer prevention.

Dietary fat intake, erythrocyte fatty acids, and risk of uterine fibroids.

OBJECTIVE: To prospectively evaluate the association between dietary fat intake and risk of uterine fibroids; and to evaluate the association between erythrocyte membrane fatty acid (FA) levels and fibroid risk. DESIGN: Prospective cohort study. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence interval (CI). In a subset of participants 34 individual FAs were measured and logistic regression analysis was used to estimate odds ratios (ORs) and 95% CI for the association between FA tertiles and fibroids. SETTING: Not applicable. PATIENT(S): Premenopausal US women (81,590) in the Nurses' Health Study II, aged 25-42 years at enrollment in 1989 for whom diet was assessed by a food frequency questionnaire. A total of 553 participants with erythrocyte FA measurements. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cases of fibroids were defined on the basis of self-reported ultrasound or hysterectomy confirmation. RESULT(S): A total of 8,142 cases of ultrasound-confirmed or hysterectomy-confirmed were diagnosed during an 18-year period (1991-2009). No associations were observed between intake of any dietary fats and fibroids in the multivariable models. However, when erythrocyte FAs were examined, an inverse association was observed between total n-3 polyunsaturated FAs and likelihood of fibroids (OR for third versus first tertile, 0.41; 95% CI 0.19-0.89). In addition, total trans FAs were associated with more odds of fibroids (OR for third tertile, 3.33; 95% CI 1.50-7.38). CONCLUSION(S): Our findings provide preliminary suggestions that n-3 polyunsaturated FAs and trans FAs may play a role in fibroid etiology; however, these results should be confirmed in future studies.