Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5′ arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 “hits” occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Background Pediatric oncology patients are at increased risk for blood stream infections (BSI). Risk in the absence of severe neutropenia (absolute neutrophil count (ANC) ≥500/µl) is not well defined. Procedure In a retrospective cohort of febrile (temperature ≥38.0° for > 1 hour or ≥38.3°) pediatric oncology patients with ANC≥500/µl , a diagnostic prediction model for BSI was constructed using logistic regression modeling and the following candidate predictors: age, ANC, absolute monocyte count, body temperature, inpatient/outpatient presentation, sex, central venous catheter type, hypotension, chills, cancer diagnosis, stem cell transplant, upper respiratory symptoms, and exposure to cytarabine, anti-thymocyte globulin, or anti-GD2 antibody. The model was internally validated with bootstrapping methods. Results Among 932 febrile episodes in 463 patients, we identified 91 cases of BSI. Independently significant predictors for BSI were higher body temperature (Odds ratio (OR) 2.36 p<0.001), tunneled external catheter (OR 13.79 p<0.001), peripherally inserted central catheter (PICC) (OR 3.95 p=0.005), elevated ANC (OR 1.19 p=0.024), chills (OR 2.09 p=0.031) and hypotension (OR 3.08 p=0.004). Acute lymphoblastic leukemia diagnosis (OR 0.34 p=0.026), increased age (OR 0.70 p=0.049) and drug exposure (OR 0.08 p<0.001) were associated with decreased risk for BSI. The risk prediction model had a C-index of 0.898; after bootstrapping adjustment for optimism, corrected C-index 0.885. Conclusions We developed a diagnostic prediction model for BSI in febrile pediatric oncology patients without severe neutropenia. External validation is warranted before use in clinical practice.

Background Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy. Procedure In a retrospective cohort of 183 pediatric ALL patients diagnosed from 2000-2008, prevalence, severity, and risk factors for obesity and hypertension were assessed during treatment. Results At diagnosis, 36% of patients were overweight and 19% were obese. Median BMI increased during induction therapy with a return to baseline soon after, but increased again over the first 22 months of maintenance therapy. At the end of therapy, 49% were overweight and 21% were obese. Increased BMI z-score at diagnosis was associated with increased z-score during maintenance (p<0.001). Elevated parental BMI was associated with elevated BMI at diagnosis. Median BMI z-score increased over the first 22 months of maintenance (p<0.001). Patients with high risk disease had lower BMI z-scores regardless of cranial radiotherapy exposure (p<0.001). Pre-hypertension was prevalent over the course of therapy (31.1% with systolic pre-hypertension and 18.6% with diastolic pre-hypertension). Hypertension was also highly prevalent with 41.5% meeting systolic criteria and 24.0% meeting diastolic criteria. Conclusions During ALL therapy, patients are at risk for early development of elevated BMI and blood pressure, which places them at potentially increased risk for future adverse health conditions. Future studies are needed to develop strategies to mitigate these risks, such as potential reduction of corticosteroid pulses or a family-based diet and exercise intervention during maintenance therapy.

Background 25-hydroxyvitamin D insufficiency is common in healthy children and adolescents. There have been limited studies of the 25-hydroxyvitamin D status of survivors of pediatric and adolescent acute lymphoblastic leukemia (ALL). Procedure In a cohort of 78 ALL survivors (52 chemotherapy-treated and 26 HCT-treated), we determined the prevalence of, and host, treatment and environmental risk factors for 25-hydroxyvitamin D insufficiency and deficiency. Results There were no differences in serum 25-hydroxyvitamin D levels between ALL survivors treated with conventional chemotherapy and those treated with HCT (median 26.0 vs 25.5 ng/ ml). Fifty-three percent of pediatric ALL survivors were 25-hydroxyvitamin D insufficient (15-29 ng/ dl), and 12% were deficient (<15 ng/ dl). Younger age, higher reported dietary vitamin D intake, use of vitamin D supplementation, and increased ambient ultraviolet light were associated with higher serum 25-hydroxyvitamin D levels. There was not enough evidence to suggest treatment type, gender, race, years since diagnosis or BMI were associated with serum 25-hydroxyvitamin D levels. Only 27% of conventional chemotherapy-treated ALL survivors and 8% of HCT-treated ALL survivors met RDA for dietary vitamin D intake. Conclusions The prevalence of vitamin D deficiency and insufficiency in ALL survivors is similar to that of the general pediatric population in the United States, and there is no difference in serum 25-hydroxyvitamin D status between chemotherapy-treated and HCT-treated ALL survivors. ALL survivors rarely meet the RDA requirements for vitamin D. Further studies are needed to determine whether dietary and behavioral interventions can improve the vitamin D status of ALL survivors.

IMPORTANCE Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. OBJECTIVE To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). INTERVENTIONS Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. MAIN OUTCOMES AND MEASURES The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. RESULTS The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). CONCLUSIONS AND RELEVANCE Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility.

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Purpose Children with acute lymphoblastic leukemia (ALL) are at increased risk of obesity and deconditioning from cancer therapy. This pilot study assessed feasibility/initial efficacy of an exercise intervention for ALL patients undergoing maintenance therapy. Methods Participants were children with ALL, age 5-10 years, receiving maintenance therapy, in first remission. A 6-month home-based intervention, with written and video instruction, was supervised with weekly calls from an exercise coach. Pre- and post-study testing evaluated strength, flexibility, fitness and motor function. Results Seventeen patients enrolled (participation 63%). Twelve (71%) finished the intervention, completing 81.7±7.2% of prescribed sessions. Improvements ≥5% occurred in 67% for knee and 75% for grip strength, 58% for hamstring/low-back and 83% for ankle flexibility, 75% for the 6-minute-walk-test, and 33% for performance on the Bruininks-Oseretsky Test of Motor Proficiency Version 2. Conclusions This pilot study demonstrated that exercise intervention during ALL therapy is feasible and has promise for efficacy.

Background Pediatric oncology patients are at increased risk for invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count (ANC) ≥500/μl) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical utility. Methods A six-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia, the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding two less clinically reliable variables was also created using the initial EsVan model derivative cohort, and validated using all five external validation cohorts. One dataset was only used in sensitivity analyses due to missing some variables. Results From the five primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C-statistic for predicting bacteremia was 0.695 with a 0.50 calibration slope for the original model and 1.0 calibration slope when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (Gram negative or Staphylococcus aureus infection) versus BSI alone with a C-statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across datasets with a C-statistic 0.733 for predicting BSI and 0.841 for high-risk BSI. Conclusions This external validation shows that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and could assist in decision making in clinical practice once validated and implemented prospectively.