Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials.

Children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia (AML) and 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non-Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non-Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow-up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed-lineage leukemia.

Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia.

BACKGROUND: The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm2 ), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors. PROCEDURE: A 2.5-year randomized controlled trial of 73 patients aged 4-18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T0 ) and end of therapy (T3 ), strength, range of motion, endurance, motor skills, and HRQL at baseline (T0 ), 8 (T1 ), 15 (T2 ), and 135 (T3 ) weeks. RESULTS: There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T3 or physical function and HRQL at T0 -T3 . While BMD declined in both the intervention (T0  = -0.21, T3  = -0.55) and usual care (T0  = -0.62, T3  = -0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T3 bone density with body mass index T1 (P = 0.01), T2 (P = <0.0001), T3 (P = 0.01), T3 ankle flexibility/strength (P = 0.001), and T2 parent (P = 0.02)/T0 child (P = 0.03) perceptions of less bodily pain. CONCLUSIONS: The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship.

Outcomes of children, adolescents, and young adults following allogeneic stem cell transplantation for secondary acute myeloid leukemia and myelodysplastic syndromes-The MD Anderson Cancer Center experience.

We conducted a retrospective analysis of outcomes for children and young adults with sAML/sMDS who underwent HSCT at our institution. Thirty-two patients (median age 20 years) with sAML (n=24) and sMDS (n=8) received HSCT between 1990 and 2013. The median time from sAML/sMDS diagnosis to HSCT was 4.1 months (range: 1.2-27.2 months). The transplant regimens were primarily busulfan based (n=19). BM was the primary donor source (n=15). Eleven recipients were transplanted with residual disease. At a median follow-up of 62.3 months (range: 0.4-250.9 months), 14 patients had disease recurrence. Acute GVHD, grade III/IV, occurred in three patients. Causes of death were as follows: disease relapse (n=12), infection (n=2), pneumonia (n=1), pulmonary hemorrhage (n=1), acute GVHD (n=1), and graft failure (n=1). A PS of ≥90% at the time of HSCT had a significant impact on PFS (P=.02). Patients achieving pretransplant primary CR (n=8) and those with sMDS and RA (n=6) had prolonged PFS (P=.04). On multivariate analysis, shorter time to transplantation (≤6 months from diagnosis of sAML/sMDS) was associated with superior OS (P=.0018) and PFS (P=.0005).

Symptom profiles in children with advanced cancer: Patient, family caregiver, and oncologist ratings.

BACKGROUND: Systematic symptom assessment is not routinely performed in pediatric oncology. The objectives of the current study were to characterize the symptoms of pediatric oncology outpatients and evaluate agreement between patient and proxy reports and the association between children's ratings and oncologists' treatment recommendations. METHODS: Two versions of the pediatric Memorial Symptom Assessment Scale (pMSAS) were translated into Spanish. An age-appropriate and language-appropriate pMSAS was administered independently before visits to the oncologist to patients and family caregivers (caregivers) and after visits to consenting oncologists. Statistical analysis included Spearman correlation coefficients and weighted kappa values. RESULTS: English and Spanish results were similar and were combined. A total of 60 children and their caregivers completed the pMSAS. The children had a median age of 10 years (range, 7-18 years); approximately 62% were male and 33% were Spanish-speaking. Fourteen oncologists completed the pMSAS for 25 patients. Nine patients (15%) had no symptoms and 38 patients (63%) reported ≥2 symptoms. The most common symptoms were fatigue (12 patients; 40%) and itch (9 patients; 30%) for the younger children and pain (15 patients; 50%) and lack of energy (13 patients; 45%) among the older children. Total and subscale score agreement varied by proxy type and subscale, ranging from fair to good for most comparisons. Agreement for individual symptoms between the patient and proxy ranged from a kappa of -0.30 (95% confidence interval, -0.43 to -0.01) to 0.91 (95% confidence interval, 0.75 to 1.00). Three of 51 symptomatic patients (6%) had treatment recommendations documented in the electronic health record. CONCLUSIONS: Symptoms are common and cross several functional domains. Proxy and child reports are often not congruent, possibly explaining apparent undertreatment among this group of patients.

A novel trial of topotecan, ifosfamide, and carboplatin (TIC) in children with recurrent solid tumors.

BACKGROUND: Ifosfamide, carboplatin, and etoposide (ICE) in children with refractory or recurrent solid tumors and lymphomas has resulted in good overall response rates (ORR). Etoposide, a topoisomerase-II inhibitor, however, has been associated with a significant increase in secondary leukemia. The rationale for substituting topotecan, a topoisomerase-I inhibitor, for etoposide in this regimen, a topoisomerase-II inhibitor, includes its limited toxicity profile and decreased leukemogenicity. Furthermore, topotecan in combination with both alkylators and platinating agents are additive and/or synergistic against a variety of solid tumors. PROCEDURE: Patients with relapsed/refractory solid tumors received ifosfamide (9 g/m2 ) and carboplatin (area under the curve: 3 mg/ml/min). Topotecan was also administered at 0.5 mg/m2 /day × 3 days (N = 12) and in a small cohort (N = 3) at 0.75 mg/m2 /day. RESULTS: Fifteen patients were entered onto study. Two patients developed seizures/encephalitis secondary to ifosfamide. One patient had dose-limiting thrombocytopenia secondary to TIC that resolved with supportive care. Patients received a median of three cycles (1-3) of TIC. Of the 14 evaluable patients for response, 4/14 had a complete response (CR), 2/14 had a partial response (PR), and 1/14 patients had stable disease (SD). The ORR (CR + PR) was 43%. CONCLUSION: TIC chemotherapy is feasible and tolerable in children and adolescents with refractory/recurrent solid tumors and lymphomas and results in a 43% excellent ORR in this poor-risk group of patients. A larger cohort of patients, especially in Wilms tumor and central nervous system (CNS) tumors, should be studied in the future to attempt to confirm these preliminary findings. Pediatr Blood Cancer 2015;62:274-278. © 2014 Wiley Periodicals, Inc.

An improved procedure to prepare 3-methyl-4-nitroalkylenethylisoxazoles and their reaction under catalytic enantioselective Michael addition with nitromethane.

Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding γ-nitroacids.

Symptom and Illness Experience for English and Spanish-Speaking Children with Advanced Cancer: Child and Parent Perspective.

Understanding the symptom and illness experience of children with advanced cancer facilitates quality care; yet, obtaining this understanding is complicated by the child's developmental level and physical and psychological health factors that affect communication. The purpose of this study was to describe the symptom and illness experience of English- and Spanish-speaking children with advanced cancer as described by the child and parent. We conducted hermeneutic phenomenological, descriptive, and interpretive interviews with eligible children and parents. The interdisciplinary research team analyzed transcripts hermeneutically until consensus on theme labels was reached. Four themes and associated subthemes were identified from the interviews of the 10 child-parent dyads: 1. symptoms disrupt life (path to diagnosis, life is disrupted), 2. isolation (lack of understanding, family separations/relationships), 3. protection, and 4. death is not for children. Children and parents readily described the impact symptoms and cancer treatment had on their lives and relationships. These findings underscore the salient aspects of daily life disrupted by cancer. With a deeper understanding of symptom burden and its interference, relationship and communication implications, and anticipatory grief, the treating team may better optimize care for children and their families living with advanced cancer.

Inhibition of Toll-like receptor 2-mediated interleukin-8 production in Cystic Fibrosis airway epithelial cells via the alpha7-nicotinic acetylcholine receptor.

Cystic Fibrosis (CF) is an inherited disorder characterised by chronic inflammation of the airways. The lung manifestations of CF include colonization with Pseudomonas aeruginosa and Staphylococcus aureus leading to neutrophil-dominated airway inflammation and tissue damage. Inflammation in the CF lung is initiated by microbial components which activate the innate immune response via Toll-like receptors (TLRs), increasing airway epithelial cell production of proinflammatory mediators such as the neutrophil chemokine interleukin-8 (IL-8). Thus modulation of TLR function represents a therapeutic approach for CF. Nicotine is a naturally occurring plant alkaloid. Although it is negatively associated with cigarette smoking and cardiovascular damage, nicotine also has anti-inflammatory properties. Here we investigate the inhibitory capacity of nicotine against TLR2- and TLR4-induced IL-8 production by CFTE29o- airway epithelial cells, determine the role of alpha7-nAChR (nicotinic acetylcholine receptor) in these events, and provide data to support the potential use of safe nicotine analogues as anti-inflammatories for CF.

All-trans-retinoic acid and arsenic trioxide as initial therapy for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML). Treatment of pediatric APL is based on the combination of all-trans-retinoic acid (ATRA), an anthracycline and cytosine arabinoside. Arsenic trioxide (ATO) has been studied in adults with newly diagnosed or relapsed APL with excellent response rates both when used as a single agent or in combination with ATRA or ATRA plus chemotherapy. There is little data on combination therapy with ATRA and ATO in pediatric APL. We present a case of an adolescent male with APL who was treated using ATRA and ATO without conventional chemotherapy agents.

Central neurocytoma responsive to topotecan, ifosfamide, carboplatin.

A 5-year-old male presented with spinal cord drop metastasis from a recurrent neurocytoma. Topotecan (0.5 mg/m(2)) and carboplatin (250 mg/m(2)) were administered on days 1-3 and ifosfamide (1,800 mg/m(2)) on days 1-5, every 21 days, for three cycles and resulted in complete response without severe complications. A literature review yielded 20 patients with central neurocytoma but no complete responses. The complete response of central neurocytoma to chemotherapy only reported here should be helpful to those caring for patients with this rare tumor.

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951.

PURPOSE: To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. PATIENTS AND METHODS: Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. RESULTS: Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). CONCLUSION: Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

Feasibility Study of a Novel Experimental Induction Protocol Combining B43-PAP (Anti-CD19) Immunotoxin With Standard Induction Chemotherapy in Children and Adolescents With Relapsed B-Lineage ALL: A Report From the Children's Oncology Group.

BACKGROUND: B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed. EXPERIMENTAL DESIGN: B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957. RESULTS: Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response. CONCLUSIONS: B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.

Skeletal, neuromuscular and fitness impairments among children with newly diagnosed acute lymphoblastic leukemia.

This study describes skeletal, neuromuscular and fitness impairments among 109 children (median age 10 [range 4-18] years, 65.1% male, 63.3% white) with acute lymphoblastic leukemia (ALL). Outcomes were measured 7-10 days after diagnosis and compared to age- and sex-specific expected values. Associations between function and health-related quality of life (HRQL) were evaluated with logistic regression. Children with ALL had sub-optimal bone mineral density (BMD) Z-score/height (mean ± standard error: - 0.53 ± 0.16 vs. 0.00 ± 0.14, p < 0.01), body mass index percentile (57.6 ± 3.15 vs. 50.0 ± 3.27%, p = 0.02), quadriceps strength (201.9 ± 8.3 vs. 236.1 ± 5.4 N, p < 0.01), 6 min walk distance (385.0 ± 13.1 vs. 628.2 ± 7.1 m, p < 0.001) and Bruininks-Oseretsky Test of Motor Proficiency scores (23 ± 2.5 vs. 50 ± 3.4%, p < 0.01). Quadriceps weakness was associated with a 20.9-fold (95% confidence interval 2.5-173.3) increase in poor physical HRQL. Children with newly diagnosed ALL have weakness and poor endurance and may benefit from early rehabilitation that includes strengthening and aerobic conditioning.

Quantitative nuclear magnetic resonance (QNMR) spectroscopy for assessing the purity of technical grade agrochemicals: 2,4-dichlorophenoxyacetic acid (2,4-D) and sodium 2,2-dichloropropionate (Dalapon sodium).

Comparison of quantitative NMR spectroscopy (QNMR) with chromatographic methods such as gas chromatography (GC) or high-pressure liquid chromatography (HPLC) for the determination of the purity of and impurities in technical grade agrochemicals, 2,4-dichlorophenoxyacetic acid (2,4-D), 1, and Dalapon sodium (sodium 2,2-dichloropropionate), 10, has revealed that QNMR is more precise and accurate than the chromatographic methods. Quantitative impurity profiling of technical grade 1 is rapid and accurate using 600 MHz (1)H NMR. Extra dispersion at the relatively high frequency allowed full assignment of the NMR spectrum of 1 and its related organic impurities in technical samples. The percentage purity of 1 was measured by the difference QNMR method, which involves summing the amounts of impurities and subtracting from 100%. Results are superior in consistency to those obtained by chromatographic methods. The percentage purity of Dalapon sodium, 10, in technical grade batches is readily obtained by (1)H QNMR, using either the difference method or the internal standard method, using dimethyl sulfone (DMSO2) internally as a reference material, that is chemically unrelated to the analyte. The latter method also allows the simultaneous identification and quantification of impurities, many of which are either not accessible to or detectable by the chromatographic methods. Uncertainty budgets for the QNMR method are presented and demonstrate that the major contributors to uncertainty lie in the weighing of the chemicals and in purity of the standard reference material prior to the QNMR experiment.