Mark Fluchel

The genomic landscape of juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists

Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.

Limitations in health care access and utilization among long-term survivors of adolescent and young adult cancer.

Health care outcomes for long‐term survivors of adolescent and young adult (AYA) cancer were compared with young adults without a cancer history, using the 2009 Behavioral Risk Factor Surveillance System data.

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis

OBJECTIVE To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use. RESULTS A total of 121 children at 28 childrens hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin-1 antagonists. CONCLUSION Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

Geography and the Burden of Care in Pediatric Cancers

Childhood cancers typically require rigorous treatment at specialized centers in urban areas, which can create substantial challenges for families residing in remote communities. We evaluated the impact of residence and travel time on the burden of care for families of childhood cancer patients.

Self and proxy-reported health status and health-related quality of life in survivors of childhood cancer in Uruguay†

The incidence of cancer in children in Uruguay is similar to that in industrialized societies but the survival rate is half as great. This study assesses another important measure of treatment effectiveness: the health‐related quality of life (HRQL) of survivors.

Cancer Risk in Children and Adolescents with Birth Defects: A Population-Based Cohort Study

Objective Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects. Methods and Findings This retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus. Conclusion Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.

Statewide Longitudinal Hospital Use and Charges for Pediatric and Adolescent Patients With Cancer

PURPOSE We investigated longitudinal hospitalization outcomes (total charges, hospital days and admissions) among pediatric and adolescent patients with cancer compared with individuals from the general population without cancer using a novel and efficient three-step regression procedure. METHODS The statewide Utah Population Database, with linkages to the Utah Cancer Registry, was used to identify 1,651 patients who were diagnosed with cancer from 1996 to 2009 at ages 0 to 21 years. A comparison group of 4,953 same-sex and -age individuals was generated from birth certificates. Claims-based hospitalization data from 1996 to 2012 were retrieved from the Utah Department of Health. Using the regression method, we estimated survival (differences due to survival) and intensity (differences due to resource accumulation) effects of the cancer diagnosis on hospitalization outcomes within 10 years after diagnosis. RESULTS At 10 years after diagnosis, on average, patients with cancer incurred

A population-based study of childhood cancer survivors' body mass index.

51,723 (95% CI,

Endoscopy in the diagnosis of intestinal graft-versus-host disease: Is lower endoscopy with biopsy as effective in diagnosis as upper endoscopy combined with lower endoscopy?

48,100 to