Long-term survivors of childhood Hodgkin lymphoma (HL) experience a high burden of chronic health morbidities. Correlates of neurocognitive and psychosocial morbidity have not been well established. A total of 1760 survivors of HL (mean ± SD age, 37.5 ± 6.0 years; time since diagnosis, 23.6 ± 4.7 years; 52.1% female) and 3180 siblings (mean age, 33.2 ± 8.5 years; 54.5% female) completed cross-sectional surveys assessing neurocognitive function, emotional distress, quality of life, social attainment, smoking, and physical activity. Treatment exposures were abstracted from medical records. Chronic health conditions were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.3 (1 = mild, 2 = moderate, 3 = severe/disabling, and 4 = life-threatening). Multivariable analyses, adjusted for age, sex, and race, estimated relative risk (RR) of impairment in survivors vs siblings and, among survivors, risk of impairment associated with demographic, clinical, treatment, and grade 2 or higher chronic health conditions. Compared with siblings, survivors had significantly higher risk (all, P < .05) of neurocognitive impairment (eg, memory, 8.1% vs 5.7%), anxiety (7.0% vs 5.4%), depression (9.1% vs 7%), unemployment (9.6% vs 4.4%), and impaired physical/mental quality of life (eg, physical function, 11.2% vs 3.0%). Smoking was associated with a higher risk of impairment in task efficiency (RR, 1.56; 95% confidence interval [CI], 1.02-2.39), emotional regulation (RR, 1.84; 95% CI, 1.35-2.49), anxiety (RR, 2.43; 95% CI, 1.51-3.93), and depression (RR, 2.73; 95% CI, 1.85-4.04). Meeting the exercise guidelines of the Centers for Disease Control and Prevention was associated with a lower risk of impairment in task efficiency (RR, 0.70; 95% CI, 0.52-0.95), organization (RR, 0.60; 95% CI, 0.45-0.80), depression (RR, 0.66; 95% CI, 0.48-0.92), and multiple quality of life domains. Cardiovascular and neurologic conditions were associated with impairment in nearly all domains. Survivors of HL are at elevated risk for neurocognitive and psychosocial impairment, and risk is associated with modifiable factors that provide targets for interventions to improve long-term functional outcomes.

Purpose: Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system–directed therapy, though little is known about the underlying mechanisms. Experimental Design: HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. Results: HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P’s < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P’s < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P’s < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed. Conclusions: Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.

Introduction: This study aimed to assess longitudinal associations between lifestyle and subsequent malignant neoplasms (SMNs) in young adult childhood cancer survivors. Methods: Members of the St. Jude Lifetime Cohort (SJLIFE) aged ≥18 years and surviving ≥5 years after childhood cancer diagnosis were queried and evaluated for physical activity, cardiorespiratory fitness (CRF), muscle strength, body mass index (BMI), smoking, risky drinking, and a combined lifestyle score. Time to first SMN, excluding nonmalignant neoplasms and nonmelanoma skin cancer, was the outcome of longitudinal analysis. Results: Survivors (n = 4072, 47% female, 29% smokers, 37% risky drinkers, 34% obese, and 48% physically inactive) had a mean (SD) time between baseline evaluation and follow-up of 7.0 (3.3) years, an age of 8.7 (5.7) years at diagnosis, and an age of 30 (8.4) years at baseline lifestyle assessment. Neither individual lifestyle factors nor a healthy lifestyle score (RR 0.8, 0.4–1.3, p = 0.36) were associated with the risk of developing an SMN. Conclusions: We did not identify any association between lifestyle factors and the risk of SMN in young adult childhood cancer survivors.

Objective To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors. Methods This study reports longitudinal data (baseline and follow-up) from 3969 adult siblings (median age = 29 [range 18–56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6–33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression. Results Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors’ diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), and 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12–2.20; grades 3–4 OR=1.86, 95% CI: 1.18–2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05–1.94; grades 3–4 OR=1.64, 95% CI: 1.09–2.47; compared to less than grade 2). Conclusions Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns. Implications for Cancer Survivors Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings.

Background: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors? Methods: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ. Results: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii). Conclusions: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants. Impact: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477