Medical imaging utilization and associated radiation exposure in children with down syndrome.

OBJECTIVE: To evaluate the frequency of medical imaging or estimated associated radiation exposure in children with Down syndrome. METHODS: This retrospective cohort study included 4,348,226 children enrolled in six U.S. integrated healthcare systems from 1996-2016, 3,095 of whom were diagnosed with Down syndrome. We calculated imaging rates per 100 person years and associated red bone marrow dose (mGy). Relative rates (RR) of imaging in children with versus without Down syndrome were estimated using overdispersed Poisson regression. RESULTS: Compared to other children, children with Down syndrome received imaging using ionizing radiation at 9.5 times (95% confidence interval[CI] = 8.2-10.9) the rate when age <1 year and 2.3 times (95% CI = 2.0-2.5) between ages 1-18 years. Imaging rates by modality in children <1 year with Down syndrome compared with other children were: computed tomography (6.6 vs. 2.0, RR = 3.1[95%CI = 1.8-5.1]), fluoroscopy (37.1 vs. 3.1, RR 11.9[95%CI 9.5-14.8]), angiography (7.6 vs. 0.2, RR = 35.8[95%CI = 20.6-62.2]), nuclear medicine (6.0 vs. 0.6, RR = 8.2[95% CI = 5.3-12.7]), radiography (419.7 vs. 36.9, RR = 11.3[95%CI = 10.0-12.9], magnetic resonance imaging(7.3 vs. 1.5, RR = 4.2[95% CI = 3.1-5.8]), and ultrasound (231.2 vs. 16.4, RR = 12.6[95% CI = 9.9-15.9]). Mean cumulative red bone marrow dose from imaging over a mean of 4.2 years was 2-fold higher in children with Down syndrome compared with other children (4.7 vs. 1.9mGy). CONCLUSIONS: Children with Down syndrome experienced more medical imaging and higher radiation exposure than other children, especially at young ages when they are more vulnerable to radiation. Clinicians should consider incorporating strategic management decisions when imaging this high-risk population.

Modelling future usage and cost of factor and emicizumab to treat haemophilia A for the US Western States Region IX haemophilia treatment centres.

INTRODUCTION: Increased usage of emicizumab in the United States will affect standard half-life (SHL) and extended half-life (EHL) products usage and cost. AIM: To model the usage and cost of SHL and EHL products, and emicizumab to treat haemophilia A (HA) in the 13 Western States Region IX haemophilia treatment centres (HTCs.) (California, Nevada, Hawaii and Guam). METHODS: We modelled product usage and cost using decision analysis methods. VARIABLES: epidemiology/demographics, treatment and product cost. Data were from the US Western States Region IX, US Centers for Disease Control and Prevention, American Thrombosis and Hemostasis Network and the literature. RESULTS: Prior to EHL products and emicizumab, the usage of SHL products was ~300 million international units (IUs) or 6.8 IUs/capita and a cost of $430 million. With the uptake of EHL and emicizumab, the 2025 estimated usage of factor (SHL and EHL) was 270 million IUs (5.4 IU per capita) and 1,993 grams (40 micrograms/capita) for emicizumab and a cost of $532 million. As the number of HA patients in the region increases by 59%, factor usage increases by 20%, emicizumab usage increases by 26%, and cost increases to $650 million. CONCLUSION: The entrance of emicizumab into the market may radically change the use of SHL and EHL products. Our model suggests that emicizumab use will likely increase total product costs. While our estimates are most useful for the United States, the effect of emicizumab on factor use will likely be similar in other parts of the world.

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.

Children and adolescents with ALL are taller than expected at diagnosis.

We investigated whether the relative increased height of childhood acute lymphoblastic leukemia (ALL) survivors at diagnosis was due to referral bias, the height of California children, socio-economic status, or race/ethnicity. We reviewed the records of all Pediatric Oncology referrals to our institution from 1988 to 2007. Height at diagnosis, sex, age at and date of diagnosis, date of birth, diagnosis, race/ethnicity, and socio-economic status were evaluated. Heights were standardized by z score from age and sex norms for US children. Of the 883 cases, 180 were excluded (Down syndrome, noncancer diagnosis, data at relapse only, incorrect height measurement, or major growth disturbance). ALL patients were taller than those with other cancers and US children. Age at and date of diagnosis and date of birth had no effect. Whites, boys, and those with private insurance had higher height z scores. Multivariable analysis identified diagnosis and race/ethnicity as significant. ALL children and adolescents were taller and black and Asian children shorter than white children. The mean height increase for those with ALL was 1.3 cm. The reason for the increased height of these patients is unknown, but is not due to referral patterns, having childhood cancer, or the racial/ethnic makeup of California children.

Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model.

In this study, the efficacy of orally and parenterally administered curcumin was evaluated in non­obese diabetic/severe combined immunodeficient (NOD/SCID) mice (NOD.CB17-Prkdc(scid)/J mice) engrafted with the human t(4;11) acute lymphoblastic leukemia line, SEM. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, the chemotherapeutic potential was examined by injecting mice intraperitoneally with curcumin (5 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). The intraperitoneal administration of curcumin did not inhibit the growth of the leukemia cells. To determine the efficacy of oral curcumin, mice were fed a control diet or a diet containing 0.5% w/w curcumin 3 weeks prior to the injection of the leukemia cells and throughout the experimental period (n=16 per group). To determine whether dietary curcumin can enhance the efficacy of a conventional chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the different diets. Dietary curcumin did not delay the engraftment or growth of leukemia cells, or sensitize the cells to vincristine. Liquid chromatography­tandem mass spectrometry analyses of mouse sera showed that curcumin rapidly metabolized to glucuronidated and sulfated forms within 1 h post­injection and these were the major curcumin metabolites found in the sera of the mice fed the curcumin diet. In contrast to the findings in previous in vitro models, the current data indicate that orally or parenterally administered curcumin is not a potent preventive agent against high­risk t(4;11) acute lymphoblastic leukemia.

Dietary resveratrol does not delay engraftment, sensitize to vincristine or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice.

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. To evaluate the efficacy of dietary resveratrol in vivo, 5-week-old NOD.CB17-Prkdcscid/J mice were fed a control diet or a diet containing 0.2% w/w resveratrol. After 3 weeks of dietary treatment, mice were engrafted with the human t(4;11) ALL line SEM by tail vein injection. Engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry. Relative to control diet, dietary resveratrol did not delay the engraftment of the leukemia cells. To determine if dietary resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the control or supplemented diet. Survival curves and monitoring the percentage of human leukemia cells in peripheral blood showed that resveratrol did not inhibit leukemia cell growth or influence the activity of vincristine. Mass spectrometric analysis of mouse serum revealed that the majority of resveratrol was present as glucuronidated and sulfated metabolites. These data do not support the concept that dietary resveratrol has potential as a preventative agent against the growth of high-risk t(4;11) ALL.

Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model.

The efficacy of resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL SEM cell line. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with resveratrol (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit progression of the disease. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1 h post-injection, with low to no resveratrol or metabolites observed in sera by 24-48 h. These data indicate that in contrast to findings in in vitro models, parenterally administered resveratrol does not have potential as a preventive agent against high risk t(4;11) ALL.

Parthenolide treatment activates stress signaling proteins in high-risk acute lymphoblastic leukemia cells with chromosomal translocation t(4;11).

Parthenolide, the principal bio-active component of the herb feverfew (Tanacetum parthenium), has shown anti-leukemic activity. We evaluated the cell cycle status and the phosphorylation/activation of proteins involved in signal transduction in t(4;11) and non-t(4;11) acute lymphoblastic leukemia (ALL) cell lines after treatment with parthenolide. The cells were treated with the vehicle or 10 µM parthenolide for 2, 4, 6 and 8 h. As shown by flow cytometric analysis, parthenolide induced growth arrest at the S to G2/M phase transition. Using multiplex technology and Western blotting, we showed that the treatment with parthenolide within 0 to 10 h induced the phosphorylation of stress signaling proteins, including the p38 mitogen-activated protein kinase, the c-Jun N-terminal kinase, c-Jun, the heat shock protein 27 and protein kinase B. These data show that parthenolide induces a stress response leading to cell death and provide further evidence suggesting that parthenolide could be useful as a novel therapeutic agent against high risk ALL with chromosomal translocation t(4;11).

Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11).

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. Using the t(4;11) ALL line SEM, we evaluated chemotherapy resistance in NOD.CB17-Prkdcscid/J mice. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with phosphate-buffered saline (PBS), or vincristine (0.5mg/kg body weight) three times per week for 4weeks (n=8 per group). The level of P-glycoprotein in SEM cells was increased 3-fold by vincristine treatment compared to PBS-treated mice. Survival curves showed that leukemia cell growth was initially delayed by vincristine treatment, but the mice eventually succumbed to disease. These data describe a novel inducible model for investigating multi-drug resistance mechanisms in high-risk t(4;11) ALL.

Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia cells.

We investigated whether parthenolide, the principal bioactive component of the herb feverfew (Tanacetum parthenium) induced apoptosis in pre-B acute lymphoblastic leukemia (ALL) lines, including cells carrying the t(4;11)(q21;q23) chromosomal translocation. Parthenolide induced rapid apoptotic cell death distinguished by loss of nuclear DNA, externalization of cell membrane phosphatidylserine, and depolarization of mitochondrial membranes at concentrations ranging from 5 to 100 microM. Using reactive oxygen species (ROS)-specific dyes, an increase in nitric oxide and superoxide anion was detected in the cells by 4 h after exposure to parthenolide. Parthenolide-induced elevation of hypochlorite anion was observed only in the two t(4;11) lines. These data suggest parthenolide may have potential as a potent and novel therapeutic agent against pre-B ALLs.

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

PURPOSE: 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. PATIENTS AND METHODS: Forty-five patients were entered, 29 with T-ALL and 16 with higher-stage NHL. Forty-two of 45 patients achieved complete remission (CR), and 27 completed the therapy in continuous CR. Treatment consisted of 4-week induction then 6 weeks consolidation and ten 9-week maintenance cycles. Therapy primarily comprised antimetabolites, anthracyclines, alkylating agents, and asparaginase. Expected chemotherapy duration was 100 weeks. RESULTS: Forty-two of 45 patients achieved CR, and 27 completed therapy. The most common toxicities were Grade 3 or 4 myelosuppression after cyclophosphamide/cytarabine and allergic reactions to asparaginase. Two died of sepsis early in maintenance. Five-year EFS was 68.5% (SE 9.1%) for T-ALL and 81.3% (SE 9.8%) for NHL. Five-year EFS was 73.1% (SE 6.8%) for the entire cohort. No patients treated entirely on this study developed secondary neoplasms. One patient taken off study for asparaginase toxicity was treated with multiagent therapy that contained teniposide, and died from secondary myelodysplasia (sMDS)/AML. CONCLUSION: Substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase in a dose-intensive regimen was feasible in children and young adults with newly diagnosed T-ALL or higher-stage NHL. EFS was not compromised and secondary neoplasms were decreased.

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.

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.