Jonathan M. Ducore

Diagnostic X-rays and risk of childhood leukaemia

BACKGROUND The association between diagnostic X-ray exposures early in life and increased risk of childhood leukaemia remains unclear. METHODS This case-control study included children aged 0-14 years diagnosed with acute lymphoid leukaemia (ALL, n = 711) or acute myeloid leukaemia (AML, n = 116) from 1995 to 2008. Controls were randomly selected from the California birth registry and individually matched to cases with respect to date of birth, sex, Hispanic ethnicity and maternal race. Conditional logistic regression analyses were performed to assess whether ALL or AML was associated with self-reported childs X-rays after birth (post-natal), including number of X-rays, region of the body X-rayed and age at first X-ray, as well as maternal X-rays before and during pregnancy (preconception and prenatal). RESULTS After excluding X-rays in the year prior to diagnosis (reference date for matched controls), risk of ALL was elevated in children exposed to three or more post-natal X-rays [odds ratio (OR) = 1.85, 95% confidence interval (CI) 1.12-2.79]. For B-cell ALL specifically, any exposure (one or more X-rays) conferred increased risk (OR = 1.40, 95% CI 1.06-1.86). Region of the body exposed was not an independent risk factor in multivariable analyses. No associations were observed between number of post-natal X-rays and AML (OR = 1.05, 95% CI 0.90-1.22) or T-cell ALL (OR = 0.84, 95% CI 0.59-1.19). Prevalence of exposure to prenatal and preconception X-rays was low, and no associations with ALL or AML were observed. CONCLUSIONS The results suggest that exposure to post-natal diagnostic X-rays is associated with increased risk of childhood ALL, specifically B-cell ALL, but not AML or T-cell ALL. Given the imprecise measures of self-reported X-ray exposure, the results of this analysis should be interpreted with caution and warrant further investigation.

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Background The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. Methods We infused a single‐stranded adeno‐associated viral (AAV) vector consisting of a bioengineered capsid, liver‐specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. Results No serious adverse events occurred during or after vector infusion. Vector‐derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady‐state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow‐up of 492 weeks among all the participants (range of follow‐up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver‐enzyme levels developed in 2 participants and resolved with short‐term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. Conclusions We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene‐derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092.)

Tobacco Smoke Exposure and the Risk of Childhood Acute Lymphoblastic and Myeloid Leukemias by Cytogenetic Subtype

Background: Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect of tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of prenatal origin such as ALL with translocation t(12;21) or high-hyperdiploidy (51–67 chromosomes). Methods: We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996–2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in situ hybridization. Results: Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and childs passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL [95% confidence interval (CI), 1.01–2.23], compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR = 2.08; 95% CI, 1.04–4.16), but not high hyperdiploid B-cell ALL. Similarly, childs passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR = 2.76; 95% CI, 1.01–7.58), but not aneuploidy. Conclusions: Our data suggest that exposure to tobacco smoking was associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates. Impact: Parents should limit exposures to tobacco smoke before and after the childs birth. Cancer Epidemiol Biomarkers Prev; 22(9); 1600–11. ©2013 AACR.

Risk factors for the development of obesity in children surviving ALL and NHL.

We investigated obesity [body mass index (BMI) >95th percentile] and being heavy (BMI >85th percentile) in 95 children in first remission more than 2 years after treatment for acute lymphoblastic leukemia or non-Hodgkin lymphoma seen at our institution. Height, weight and BMI at diagnosis, end of treatment and follow-up, and blood pressure at diagnosis were adjusted by z-score for age and sex. At follow-up, obesity and overweight were not more prevalent than in the general population. Median BMI z-scores rose significantly between diagnosis (0.38) and treatment end (0.62) but not during follow-up (0.70). Median weight z-scores rose significantly during both periods (diagnosis 0.23, treatment end 0.49, and follow-up 0.68). Median height z-scores were 0.51, 0.14, and 0.16 for the same 3 time points, respectively. Repeated measures, multivariate logistic regression identified Hispanic ethnicity, younger age at diagnosis, and a positive age:weight interaction as being associated with obesity and being heavy at follow-up. There was no association with diagnosis, sex, age alone, radiation dose or field, metabolic diagnosis in patient/family, height z-score at diagnosis, duration of treatment, and systolic or diastolic blood pressure. Obesity and overweight were a combination of weight gain and height loss during treatment although weight continued to increase after treatment. We did not identify disease-related parameters associated with these effects.

Oral methotrexate for recurrent brain tumors in children: a Pediatric Oncology Group study.

PURPOSE Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied. METHODS Eight dosages of MTX 7.5 mg/m2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued. RESULTS The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable. CONCLUSION Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.

Surveillance Neuroimaging to Detect Relapse in Childhood Brain Tumors: A Pediatric Oncology Group Study

PURPOSE To investigate the prognostic significance of surveillance neuroimaging for detection of relapse among children with malignant brain tumors. PATIENTS AND METHODS A historical cohort study examined all children who experienced relapse from 1985 to 1999 on one of 10 Pediatric Oncology Group trials for malignant glioma, medulloblastoma, or ependymoma. RESULTS For all 291 patients (median age at diagnosis, 8.2 years), median time to first relapse was 8.8 months (range, 0.6 to 115.6 months). Ninety-nine relapses were radiographic, and 192, clinical; median time to relapse was 15.7 versus 6.6 months, respectively (P = .0001). When stratified by pathology, radiographic and clinical groups showed differences in median time to relapse for malignant glioma (7.8 v 4.3 months, respectively; P = .041) and medulloblastoma (23.6 v 8.9 months, respectively; P = .0006) but not ependymoma (19.5 v 13.3 months, respectively; P = .19). When stratified by early (< 8.8 months) or late (> or = 8.8 months) time to relapse, 115 early relapses were clinical, and 32, radiographic; for late relapses, 77 were clinical, and 67, radiographic (P = .001). Overall survival (OS) from relapse was significantly longer for radiographic compared with clinical detection (median, 10.8 months; 1-year OS, 46% v median, 5.5 months; 1-year OS, 33%; P = .002), but this trend did not retain significance when analyzed by pathology subgroups. CONCLUSION Surveillance neuroimaging detects a proportion of asymptomatic relapses, particularly late relapses, and may provide lead time for other therapies on investigational trials. During the first year after diagnosis, radiographic detection of asymptomatic relapse was infrequent. A prospective study is needed to formulate a rational surveillance schedule based on the biologic behavior of these tumors.

Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: A report of POG study 9296

A previous Pediatric Oncology Group (POG) study showed high incidence of secondary acute myelogenous leukemia (AML) in children treated for T‐cell acute lymphoblastic leukemia (T‐ALL) or higher‐stage lymphoblastic lymphoma. To prevent secondary neoplasms, induce prolonged asparagine depletion, and maintain high event‐free survival (EFS) in children with newly diagnosed T‐ALL or higher‐stage non‐Hodgkins lymphoma (NHL), we designed this pilot study to determine feasibility and safety of substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG‐asparaginase for native asparaginase.

Hydrogen peroxide induces DNA single strand breaks in respiratory epithelial cells.

The respiratory epithelium is often exposed to oxidant gases, including ozone from photochemical smog and toxic oxygen metabolites released from neutrophils recruited in conditions of airway inflammation. We evaluated DNA single strand break formation by alkaline elution as a measure of oxidant-induced DNA damage to bronchial epithelial cells. Human AdenoSV-40-transformed bronchial epithelial cells (BEAS), subclone R1.4 or nonhuman primate bronchial epithelial cells were cultured in growth factor supplemented Hams F12 medium on polycarbonate filters. DNA was labeled by incubation with [3H]thymidine. Cells were incubated for 1 h in HBSS or HBSS and increasing concentrations of hydrogen peroxide (H2O2). Cells incubated in H2O2 demonstrated dose-dependent increases in strand break formation, and BEAS cells were more sensitive to H2O2-induced injury than primary bronchial epithelial cells. The addition of catalase or preincubation of cells with the iron chelator desferoxamine prevented H2O2-induced strand breakage. DNA strand break formation may be an important mechanism of oxidant injury in respiratory epithelial cells.

Alprolix (recombinant Factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B

Hemophilia B is a genetic disease caused by mutation of the gene for coagulation protein Factor IX. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing Factor IX. Alprolix™ (recombinant Factor IX Fc fusion protein), is a therapeutic Factor IX preparation that has been engineered for a prolonged half-life in circulation, has completed pivotal clinical trials and has been approved recently in the USA, Canada, Australia and Japan for use in the clinic for patients with hemophilia B. This promising therapy should allow patients to use fewer infusions to maintain appropriate Factor IX activity levels in all clinical settings, and its use may be indicated in both on demand and prophylactic treatments.

Cancer occurrence in Southeast Asian children in California.

Objectives:To estimate misclassification of ethnicity and cancer incidence in Southeast Asian children using the population-based California Cancer Registry. Methods:Asian race/ethnicity was evaluated using lists of Asian surnames. Average annual incidence rates (per million) for 1988 to 1992 were calculated for non-Hispanic white, black, Hispanic, and Asian children (age <15 years). Proportional incidence ratios (PIRs) for 1988 to 1995 were used to compare Southeast Asian children to non-Hispanic white children. Results:Of the Asian children, 4.2% (30/722) were misclassified by subgroup, predominantly Hmong listed as Laotian. The Asian cancer rate was 134.2 versus 159.2 for non-Hispanic whites. The germ cell tumor rate was higher in Asians (9.9) than in non-Hispanic whites (4.8), but the Wilms tumor rate was two-thirds lower (3.1 vs. 9.2). The rates of Hodgkin lymphoma and central nervous system tumors were lower (2.8 vs. 5.6 and 20.0 vs. 33.8) in Asians than non-Hispanic whites. Compared with non-Hispanic whites, the PIR for Wilms tumor in Southeast Asian children was reduced (PIR = 0.1). Southeast Asian children had increased PIRs for Burkitt lymphoma (PIR = 2.6) and leukemias not classified as acute lymphocytic leukemia or acute nonlymphocytic leukemia (PIR = 3.5). Conclusions:Accurate race/ethnicity classification of Southeast Asian children is a concern. Marked differences were found in the incidence and PIRs of specific cancers among Southeast Asian children, other Asian children, and other children in California.