Faculty Bibliography

A 1,2-dioxolane (FINO2) was identified as a lead compound from a screen of organic peroxides. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. Few compounds are known to induce primarily ferroptosis. In contrast to the perceived instability of peroxides, FINO2 was found to be thermally stable to at least 150 degrees C. FINO2 was more potent in cancer cells than nonmalignant cells of the same type. One of the enantiomers was found to be more responsible for the observed activity.

Standard risk acute lymphoblastic leukemia (SR-ALL) has high cure rates, but requires 2-3 years of therapy. We aimed to (i) prospectively evaluate health-related quality of life (HRQOL) during and after SR-ALL therapy, and (ii) identify associated predictors. Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. Mean PedsQL scores in physical, emotional and social functioning were impaired 1 month after diagnosis but steadily improved. Three months post-therapy, impaired physical and social functioning was observed in 27.8 and 25.8% of patients, respectively. In repeated-measures analysis, problematic family functioning predicted emotional (OR = 1.85, 95% CI 1.03-3.34) and social (OR = 1.99, 95% CI 1.21-3.27) impairment. Larger household size was associated with social impairment (OR = 1.21, 95% CI 1.02-1.45). Adverse neurological event(s) during therapy predicted post-therapy physical (OR = 5.17, 95% CI 1.61-16.63) and social (OR = 8.17, 95% CI 1.19-56.16) impairment. HRQOL 1 month after diagnosis was not predictive of HRQOL 3 months after therapy completion. In conclusion, children with SR-ALL experience considerable impairment in HRQOL at the end of induction, but rapidly improve. However, many still experience physical and social impairment 3 months post-therapy, suggesting a role for continued family and physical functioning support. Longer follow-up is needed to determine if post-therapy deficits change over time.

BACKGROUND: This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment. METHODS: This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated. RESULTS: The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea. CONCLUSIONS: Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized. Cancer 2016. (c) 2016 American Cancer Society.

PURPOSE OF REVIEW: The prognosis for children with the most common childhood malignancy, acute lymphoblastic leukemia (ALL), has improved dramatically. However, the burden of therapy can be substantial, with long-term side-effects, and certain subgroups continue to have a poor outcome. RECENT FINDINGS: The recent discovery of new genetic alterations in high-risk subsets provides targets for precision medicine-based interventions using existing Food and Drug Administration approved agents. Novel immunotherapeutic approaches are being deployed in relapsed ALL, one of the leading causes of cancer cell death in children. Moreover, genomic analysis has charted the evolution of tumor subclones, and relapse-specific alterations now provide a mechanistic explanation for drug resistance, setting the stage for targeted therapy. There is greater recognition that host factors - genetic polymorphisms - influence cancer risk, response to therapy, and toxicity. In the future, it is anticipated that they will be integrated into clinical decision making to maximize cure and minimize side-effects. Recent efforts to limit prophylactic central nervous system irradiation have been successful, thereby sparing many children late neurocognitive impairments. SUMMARY: Integration of advances in precision medicine approaches and novel agents will continue to increase the cure rate and decrease the burden of therapy for childhood ALL.

Primary neuroendocrine carcinomas (NEC) are rare tumors in children and young adults, resulting in a lack of standardized treatment approach. To refine the molecular taxonomy of these rare tumors, we performed whole exome sequencing in a pediatric patient with mediastinal NEC. We identified a somatic mutation in HRAS gene and LOH regions in NF2, MYO18B, and RUX3 genes. In addition, a germline heterozygous somatic variant in BRCA2 with LOH at that same position in the tumor tissue was also found. Our data provide valuable insight into the genomic landscape of this tumor, prompting further investigation of therapeutic targets.

BACKGROUND:Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. PROCEDURE/METHODS:AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). RESULTS:Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012). CONCLUSION/CONCLUSIONS:De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.

There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.