A B S T R A C T PurposeCarbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096GϾA) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and MethodsOne hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. 2 ) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low-to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P ϭ .003), as well as exposed to low-to moderate-dose anthracyclines (OR, 3.30; P ϭ .006). High-dose anthracyclines (Ͼ 250 mg/m 2 ) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Results ConclusionThis study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m 2 . Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low-to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

Purpose Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs). Patients and Methods Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes. Results Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% ± 1.0% with DRZ versus 0.85% ± 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% ± 1.2% versus CIR for non-DRZ of 0.85% ± 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231). Conclusion DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.

Infant acute lymphoblastic leukemia (ALL) has a poor therapeutic outcome despite attempts to treat it based on prognostic factor-guided therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/ 11q23 rearrangement. All infants enrolled on Children's Cancer Group (CCG) 1953 were tested for MLL rearrangement by Southern blot and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or "other") by reverse-transcriptase polymerase chain reaction (PCR).One hundred fifteen infants were enrolled; overall event-free survival (EFS) was 41.7% (SD ‫؍‬ 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL-rearranged cases was 33.6% and for MLL-nonrearranged cases was 60.3%. The difference in EFS between the 3 major MLL rearrangements did not reach statistical significance. Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis of CD10 negativity, age younger than 6 months, and MLL rearrangement,

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SUMMARY Background Sodium thiosulfate (STS) is an antioxidant shown in preclinical studies to prevent cisplatin-induced hearing loss (CIHL) but not compromise anti-tumour efficacy with timed administration post-cisplatin. The primary study aim was to evaluate STS for prevention of CIHL. Methods ACCL0431 was an open-label, phase 3 randomised cooperative group trial. Eligible participants 1–18 years old with newly diagnosed cancer and normal audiometry were randomly allocated (1:1) to receive STS or not in addition to their planned cisplatin-containing chemotherapy regimen using permuted blocks of 4. Randomisation was initially stratified by age (< or ≥ 5 years) and duration of cisplatin infusion (< or ≥ 2 hours). Stratification by prior cranial irradiation was added later. Sequence was computer-generated centrally and concealed to all personnel. If allocated to STS, participants received STS 16 grams/m2 intravenously 6 hours after each cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria. The primary endpoint was incidence of hearing loss 4 weeks post final cisplatin dose. Analysis was by intention to treat and restricted to evaluable participants. Enrollment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. Findings Between June 23, 2008 and September 28, 2012, 125 eligible participants were enrolled from 38 sites in the United States (US) and Canada. Of these, 104 were evaluable for the primary aim. The proportion with hearing loss for STS versus control (%, 95% confidence interval) was 14/49 (28.6%, 16.6, 43.3) and 31/55 (56.4%, 42.3, 69.7), respectively (p=0.00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the STS group compared with control group (odds ratio 0.31, 95% confidence interval 0.13, 0.73; p=0.0036). The most common grade 3–4 haematological adverse events (AE) reported in STS and control participants, irrespective of attribution, were neutropaenia in 117/177 (66.1%) and 145/223 (65.0%) participant-cycles, while the most common non-haematological AE was hypokalaemia in 25/147 (17.0%) and 22/187 (11.8%) participant-cycles, respectively. Of 194 serious AEs reported in STS recipients, none were considered probably or definitely related to STS; the most common was neutrophil count decreased in 26/194 (13.4%). Interpretation STS protects against CIHL in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for STS among emerging otoprotection strategies. Funding United States NCI; STS was provided at no cost by Fennec Pharmaceuticals.

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Purpose This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. Patients and Methods Patients with relapsed or refractory solid tumors were treated with 9 mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. Results One hundred and sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. Conclusion Cixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway.