Smita Bhatia

Epidemiologic study of Langerhans cell histiocytosis in children

OBJECTIVEnThe etiology and pathogenesis of Langerhans cell histiocytosis (LCH) remain poorly understood. We conducted an exploratory epidemiologic study to investigate potential risk factors associated with LCH.nnnSTUDY DESIGNnWe used a case-control study design to obtain data from parents of children with LCH (n = 459) who were members of the Histiocytosis Association of America and Canada. The two control groups consisted of 683 community control subjects and 3719 children with childhood cancers treated at participating Childrens Cancer Group institutions.nnnRESULTSnThe median age at diagnosis of LCH was 1.8 years (range 0.1 to 14.6 years). Cases were categorized as multisystem LCH (MS-LCH) (n = 208) and single-system LCH (SS-LCH) (n = 198). Statistically significant associations included the following: infections in the neonatal period (MS-LCH, odds ratio (OR) = 2.2), solvent exposure (SS-LCH, OR = 54.9), childhood vaccinations (MS-LCH and SS-LCH, OR = 0.4), thyroid disease in the proband (MS-LCH and SS-LCH, OR = 21.6), and family history of thyroid disease (MS-LCH and SS-LCH, OR = 1.4). The association with thyroid disease in the proband was explained partially by the involvement of the pituitary, with the relative risk decreasing when patients with diabetes insipidus and thyroid involvement were excluded from analysis.nnnCONCLUSIONSnThis large hypothesis-generating study provides directions for future investigations in well-designed population-based or hospital-based epidemiologic studies.

Late Congestive Heart Failure After Hematopoietic Cell Transplantation

PURPOSEnTo examine the independent roles of pre-hematopoietic cell transplantation (HCT) therapeutic exposures, transplantation-related conditioning, and comorbidities (pre- and post-HCT) in the development of late congestive heart failure (CHF) after HCT.nnnMETHODSnThis was a nested case-control design. Individuals with late CHF (diagnosed >or= 1 year after HCT) were identified from a cohort of 2,938 1+ year survivors who underwent transplantation at City of Hope National Medical Center, Duarte, CA. This cohort formed the sampling frame for selecting controls (without CHF) matched for age and year of HCT, donor source (allogeneic v autologous), and length of follow-up.nnnRESULTSnSixty patients with late CHF were identified; median age at HCT was 45.3 years (range, 16.6 to 68.6 years); median time to CHF was 3.0 years (range, 1.03 to 18.9 years); 68% received autologous HCT. Median ejection fraction was 36.9% (range, 15% to 53%). Compared with matched controls (n = 166), patients with late CHF received more cycles of pre-HCT chemotherapy (8.6 v 4.9 cycles; P < .01), had greater body mass index at HCT (28.4 v 26.2 kg/m(2); P = .01), greater lifetime anthracycline exposure (285.3 v 175.6 mg/m(2); P < .01), and were more likely to have multiple chronic comorbidities (30.0% v 13.9%; P < .01). Multivariable analysis revealed number of pre-HCT chemotherapy cycles (odds ratio [OR] = 1.2; P < .01), anthracycline dose >/= 250 mg/m(2) (OR = 3.2; P = .05), and two or more chronic comorbidities (OR = 4.3; P = .01) to be independently associated with late CHF.nnnCONCLUSIONnPre-HCT exposure to anthracyclines and presence of comorbidities are primarily responsible for the risk associated with late CHF after HCT. Conditioning-related therapeutic exposure does not contribute significantly to the risk. These results form the basis for identifying high-risk individuals for targeted surveillance, as well as developing preventive strategies in the form of aggressive management of comorbidities.

Predicting and Preventing Anthracycline-Related Cardiotoxicity

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.