Anderson B. Collier

Ewing sarcoma: prognostic criteria, outcomes and future treatment

Ewing sarcoma (EWS) is a bone tumor occurring primarily in adolescence and young adulthood. Multi-institutional clinical trials have improved the outcome for patients with nonmetastatic EWS, but not with metastatic EWS. Furthermore, although 30% of EWS recur, multi-institutional studies have not been completed for this high-risk group. Planning such studies has been hampered by both the lack of novel therapies and the inability to incorporate the biology of EWS. While the importance and detail of the EWS-FLI-1 translocation between chromosomes 11 and 22 are described, these have not yet led to new drug development for this orphan tumor. However, recent evidence supporting novel cytotoxic therapy, antiangiogenic therapy, and receptor-targeted therapy provides reason for optimism for patients with high-risk disease.

Pilot study of the effect of romiplostim on child health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP).

Childhood ITP can have a negative impact on the child and his/her family even though it is typically a benign disorder with low risk of serious bleeding. In adults and now children, romiplostim increases the platelet count without significant adverse effects. In this study, the impact of romiplostim treatment on the HRQoL of children with chronic ITP was assessed using the Kids ITP Tools (KIT).

Polymorphisms in CYP1A1 and Ethnic-Specific Susceptibility to Acute Lymphoblastic Leukemia in Children

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The U.S. Surveillance Epidemiology and End Results (SEER) registry reports that Hispanic children have the highest incidence of ALL, however, it is unclear if this is due to genetic factors, unique environmental exposures, or both. Previous reports have shown an association between CYP1A1 variants and ALL. Methods: To explore the contribution of CYP1A1 polymorphisms to ALL susceptibility in different ethnic groups, we conducted a case–control analysis in Caucasian, Hispanic, and African-American children. Results: Increased risk of developing ALL was found in the whole sample group for homozygosity of variant alleles at CYP1A1*2C (OR 2.51, 95% CI 1.18–5.33, P = 0.016) and CYP1A1*2B (OR 3.24, 95% CI 1.43–7.34, P = 0.005). Stratified analyses showed increased risks in the Hispanic group (CYP1A1*2A, OR 2.70, 95% CI 1.27–5.74, P = 0.010; CYP1A1*2C, OR 2.47, 95% CI 1.13–5.38, P = 0.023; and CYP1A1*2B, OR 3.28, 95% CI 1.40–7.69, P = 0.006) but not for the other ethnic groups. Hispanic control subjects were significantly more likely to be carriers of variant alleles as compared to Caucasians (P < 0.0001) and African Americans (P = 0.005). Conclusions: Our study suggests that polymorphisms in CYP1A1 may contribute to the increased risk of ALL in Hispanic children due to both their impact on leukemia susceptibility and the increased prevalence of the at-risk alleles in the Hispanic population. Impact: Our study provides a novel and specific link between CYP1A1 polymorphisms and ethnic influence on ALL risk that may help explain varying susceptibilities across groups to environmental toxins. Cancer Epidemiol Biomarkers Prev; 20(7); 1537–42. ©2011 AACR.

Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases.

Cutaneous Ewing sarcoma is a rare variant that has been poorly characterized and has no standard therapy. We report 2 patients with cutaneous Ewing sarcoma and review 76 other cases reported in the literature for demographics, presentation, treatment, and outcome. Only 2 patients presented with metastatic disease, and only 8 patients developed metastatic disease. Ninety-one percent of all patients are alive despite wide variations in treatment regimens. On the basis of this summary, treatment consisting of local control with surgery and/or radiation and abbreviated chemotherapy is proposed as a treatment option for this less aggressive Ewing sarcoma.

Exchange transfusion as treatment for rasburicase induced methemoglobinemia in a glucose‐6‐phosphate dehydrogenase deficient patient

To the Editor: A recent letter in this journal described methemoglobinemia and hemolysis due to rasburicase in a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency [1]. We would like to report on the management of a patient with rasburicase induced methemoglobinemia and G6PD deficiency. DS is a 12-year-old Laotian male who presented with a white blood cell count of 533,900/mm (89% blasts), hemoglobin 10.1 mg/dL, and platelets of 27,000/mm and was diagnosed with T-cell Acute Lymphoblastic Leukemia. Metabolic labs were normal except BUN 23 mg/dL, LDH 4,698 mg/dL, and uric acid 22.1 mg/dL. Rasburicase (Elitek) 10.5 mg (0.2 mg/kg) was administered. One hour later his uric acid was 18.1 mg/dL, and 10 hr later it was<0.2 mg/dL. During leukopheresis, his oxygen saturation level dropped to the 70s and did not improve with supplemental oxygen. Methemoglobin levels were found to be 7–10%. He received two doses of methylene blue, and a repeat methemoglobin level was 7% with persistently low oxygen saturation. A G6PD assay showed activity of 3 U/gm Hgb (normal 4.6–13.5 U/gm Hgb). He underwent a double-volume exchange transfusion, after which his methemoglobin level was 0% and his oxygen saturation was normal. Both remained normal throughout the remainder of his induction therapy. Methemoglobin is generated when hemoglobin iron is oxidized from the ferrous (Fe2þ) to the ferric (Fe3þ) state. Administered methylene blue is converted to leukomethylene blue by the NADPH-dependent methemoglobin reductase system, which then transfers an electron to ferric iron reducing it to ferrous iron [2]. As evidenced in our patient, this mechanism is ineffective in G6PDdeficient patients because of the inability to generate sufficient NADPH to drive the reaction [2,3]. Therefore, the only effective treatment is direct removal of the methemoglobin by exchange transfusion [4]. In our patient, this treatment was successful in lowering his methemoglobin level and resolving his hypoxia. Rasburicase has been reported to cause methemoglobinemia and hemolysis [1]. The package insert contains a recommendation for screening high-risk patients for G6PD deficiency prior to initiating rasburicase. However, in clinically emergent cases involving severe hyperuricemia and impending renal damage, waiting for a G6PD assay is usually not practical. Therefore, in patients at high risk for G6PD deficiency, we advocate close monitoring for hypoxia and methemoglobinemia when administering rasburicase. If the patient becomes hypoxic due to methemoglobinemia, avoid the use of methylene blue as this may precipitate a hemolytic anemia in a G6PD deficient patient while not treating the methemoglobinemia. Instead exchange transfusion is needed to remove the methemoglobinemia and improve oxygen saturations.

Initial vancomycin dosing in pediatric oncology and stem cell transplant patients.

Background Gram-positive bacteremia is a common infection in pediatric oncology and stem cell transplant (SCT) patients requiring therapy with vancomycin. Optimal dosing of vancomycin in this patient population has not been well established. Methods All pediatric oncology and SCT patients receiving vancomycin between October 2006 and March 2007 were included in this study. Therapeutic levels were defined as levels between 10 and 15 mg/dL and low therapeutic levels were between 5 and 9 mg/dL. Information regarding any recent or concurrent nephrotoxic medications was collected. Results Fifty-six patients received 82 courses of vancomycin during the study period. More patients (53.7%) received vancomycin for empiric therapy and 78% had recent or concurrent use of nephrotoxic medications. Using standardized vancomycin dosing guided by a computerized provider order entry system, there were significantly more patients who were in the subtherapeutic range than the supratherapeutic range (P=0.0023). There were also significantly more patients in the low therapeutic than the therapeutic range (P<0.0001). A small number of courses (3.5%) were associated with supratherapeutic levels. There was no association between the concurrent or recent use of nephrotoxic medications and vancomycin levels. Conclusions Pediatric oncology and SCT patients with normal renal function require higher daily vancomycin doses than other pediatric patients.

Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways.

Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.

Multilocus association of genetic variants in MLL, CREBBP, EP300, and TOP2A with childhood acute lymphoblastic leukemia in hispanics from Texas

Background: Hispanic children have both a higher incidence and a poorer outcome in acute lymphoblastic leukemia (ALL). Moreover, a higher incidence for therapy-related acute myeloid leukemia with 11q23 translocations after treatment with topoisomerase II (topo II) inhibitors has been observed in Hispanic children with ALL. We sought to determine the potential role of genetic variants within the topoisomerase IIα gene (TOP2A), within the mixed lineage leukemia gene (MLL) and two of its translocation partners, cyclin AMP response element-binding protein gene (CREBBP) and E1A binding protein gene (EP300) in the increased sensitivity of Hispanic children with ALL to topo II inhibitors. Methods: Fifty-two tagged single nucleotide polymorphisms (SNP) covering the four genes were genotyped in 241 samples (66 children with ALL and 175 age matched controls) of self-identified Hispanic origin. Results: Two SNPs within MLL (rs525549 and rs6589664) and three SNPs within EP300 (rs5758222, rs7286979, and rs20551) were significantly associated with ALL (P = 0.001–0.04). A significant gene-dosage effect for increasing numbers of potential high-risk genotypes (OR = 16.66; P = 2 × 10−5) and a major haplotype significantly associated with ALL (OR = 5.68; P = 2 × 10−6) were found. Replication in a sample of 137 affected White children and 239 controls showed that only rs6589664 (MLL) was significantly associated in this ethnic group. Conclusions: Our findings indicate that the association between ALL and common genetic variants within MLL and EP300 is population specific. Impact: Replication of our findings in independent Hispanic populations is warranted to elucidate the role of these variants in ALL susceptibility and define their importance in the ethnic specific differences in ALL risk. Cancer Epidemiol Biomarkers Prev; 20(6); 1204–12. ©2011 AACR.

Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 (LMO1)

To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.

Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia

Efficacy of therapeutic strategies relative to patient‐ and family‐centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at‐home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.