HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N ‫؍‬ 145), whereas conventionally treated survivors (N ‫؍‬ 7207) and siblings (N ‫؍‬ 4020) were drawn from CCSS. Selfreported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported > 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/ life-threatening (relative risk [RR] ‫؍‬ 8.1, P < .01) and 2 or more (RR ‫؍‬ 5.7, P < .01) conditions, as well as functional impairment (RR ‫؍‬ 7.7, P < .01) and activity limitation (RR ‫؍‬ 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/lifethreatening conditions: RR ‫؍‬ 3.9, P < .01; multiple conditions: RR ‫؍‬ 2.6, P < .01; functional impairment: RR ‫؍‬ 3.5, P < .01; activity limitation: RR ‫؍‬ 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population. (Blood. 2011;118(5):1413-1420)

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Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.

Purpose This study was undertaken to determine the magnitude of pulmonary dysfunction in childhood cancer survivors when compared with healthy controls and the extent (and predictors) of decline over time. Patients and Methods Survivors underwent baseline (t1) pulmonary function tests, followed by a second comprehensive evaluation (t2) after a median of 5 years (range, 1.0 to 10.3 years). Survivors were also compared with age- and sex-matched healthy controls at t2. Results Median age at cancer diagnosis was 16.5 years (range, 0.2 to 21.9 years), and time from diagnosis to t2 was 17.1 years (range, 6.3 to 40.1 years). Compared with odds for healthy controls, the odds of restrictive defects were increased 6.5-fold (odds ratio [OR], 6.5; 95% CI, 1.5 to 28.4; P < .01), and the odds of diffusion abnormalities were increased 5.2-fold (OR, 5.2; 95% CI, 1.8 to 15.5; P < .01). Among survivors, age younger than 16 years at diagnosis (OR, 3.0; 95% CI, 1.2 to 7.8; P = .02) and exposure to more than 20 Gy chest radiation (OR, 5.6; 95% CI, 1.5 to 21.0; P = .02, referent, no chest radiation) were associated with restrictive defects. Female sex (OR, 3.9; 95% CI, 1.7 to 9.5; P < .01) and chest radiation dose (referent: no chest radiation; ≤ 20 Gy: OR, 6.4; 95% CI, 1.7 to 24.4; P < .01; > 20 Gy: OR, 11.3; 95% CI, 2.6 to 49.5; P < .01) were associated with diffusion abnormalities. Among survivors with normal pulmonary function tests at t1, females and survivors treated with more than 20 Gy chest radiation demonstrated decline in diffusion function over time. Conclusion Childhood cancer survivors exposed to pulmonary-toxic therapy are significantly more likely to have restrictive and diffusion defects when compared with healthy controls. Diffusion capacity declines with time after exposure to pulmonary-toxic therapy, particularly among females and survivors treated with high-dose chest radiation. These individuals could benefit from subsequent monitoring.