Justin N. Baker

Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

PURPOSE Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. PATIENTS AND METHODS Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. RESULTS Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. CONCLUSION DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.

“Trying to Be a Good Parent” As Defined By Interviews With Parents Who Made Phase I, Terminal Care, and Resuscitation Decisions for Their Children

PURPOSE When a childs cancer progresses beyond current treatment capability, the parents are likely to participate in noncurative treatment decision making. One factor that helps parents to make these decisions and remain satisfied with them afterward is deciding as they believe a good parent would decide. Because being a good parent to a child with incurable cancer has not been formally defined, we conducted a descriptive study to develop such a definition. METHODS In face-to-face interviews, 62 parents who had made one of three decisions (enrollment on a phase I study, do not resuscitate status, or terminal care) for 58 patients responded to two open-ended questions about the definition of a good parent and about how clinicians could help them fulfill this role. For semantic content analysis of the interviews, a rater panel trained in this method independently coded all responses. Inter-rater reliability was excellent. RESULTS Among the aspects of the definition qualitatively identified were making informed, unselfish decisions in the childs best interest, remaining at the childs side, showing the child that he is cherished, teaching the child to make good decisions, advocating for the child with the staff, and promoting the childs health. We also identified 15 clinician strategies that help parents be a part of making these decisions on behalf of a child with advanced cancer. CONCLUSION The definition and the strategies may be used to guide clinicians in helping parents fulfill the good parent role and take comfort afterward in having acted as a good parent.

Phase I Study of Vandetanib During and After Radiotherapy in Children With Diffuse Intrinsic Pontine Glioma

PURPOSE To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. PATIENTS AND METHODS Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy. RESULTS Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039). CONCLUSION The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

Providing Research Results to Participants: Attitudes and Needs of Adolescents and Parents of Children With Cancer

PURPOSE There is an increasing demand for researchers to provide research results to participants. Our aim was to define an appropriate process for this, based on needs and attitudes of participants. METHODS A multicenter survey in five sites in the United States and Canada was offered to parents of children with cancer and adolescents with cancer. Respondents indicated their preferred mode of communication of research results with respect to implications; timing, provider, and content of the results; reasons for and against providing results; and barriers to providing results. RESULTS Four hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n = 385; 94.2%) felt that they had a strong right to research results. For positive results, most wanted a letter or e-mail summary (n = 238; 58.2%) or a phone call followed by a letter (n = 100; 24.4%). If the results were negative, phone call (n = 136; 33.3%) or personal visits (n = 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n = 341; 83.4%), effect on future treatments (n = 341; 83.4%), and subsequent research steps (n = 284; 69.5%). Understanding the researcher was a main concern about receiving results (n = 145; 35.5%). Parents felt that results provide information to support quality of life (n = 315; 77%) and raise public awareness of research (n = 282; 68.9%). Adolescents identified similar preferences. CONCLUSION Parents of children with cancer and adolescents with cancer feel strongly that they have a right to be offered research results and have specific preferences of how and what information should be communicated.

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Purpose: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. Experimental Design: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated. Results: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. Conclusions: The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer. Clin Cancer Res; 19(11); 3050–8. ©2013 AACR.

Communicating and Understanding the Purpose of Pediatric Phase I Cancer Trials

PURPOSE Quality informed consent should provide a clear understanding of the purpose of the research. Given the ethical challenges of pediatric phase I cancer trials, it is important to investigate physician-parent communication during informed consent conferences (ICCs) and parental understanding of the purpose of these studies. METHODS In the multisite Informed Consent in Pediatric Phase I Cancer Trials study, 85 ICCs for phase I research between June 2008 and May 2011 were directly observed, and 60 parents were subsequently interviewed. The scientific purpose was defined as composite understanding of drug safety, dose finding, and dose escalation. We determined the frequency with which physicians explained these and other phase I-related concepts during the ICC. Parent interviews were analyzed to determine understanding. RESULTS The child was present at 83 of 85 ICCs. Only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I cancer trials; 35% demonstrated little or no understanding. Parents of higher socioeconomic status and racial majority status were more likely to understand the scientific purpose. Factors associated with understanding included physician explanation of the goal of the applicable phase I protocol offered (explained in 85% of ICCs) and explanation of the dose cohorts (explained in 43% of ICCs). Physicians explained drug safety in 23% of ICCs, dose finding in 52% of ICCs, and dose escalation in 53% of ICCs. CONCLUSION Many parents of children participating in phase I trials do not understand the purpose of these trials. Physician-parent communication about the purpose of phase I research is lacking during ICCs.

Decision-making by Adolescents and Parents of Children with Cancer Regarding Health Research Participation

BACKGROUND: Low rates of participation of adolescents and young adults (AYAs) in clinical oncology trials may contribute to poorer outcomes. Factors that influence the decision of AYAs to participate in health research and whether these factors are different from those that affect the participation of parents of children with cancer. METHODS: This is a secondary analysis of data from validated questionnaires provided to adolescents (>12 years old) diagnosed with cancer and parents of children with cancer at 3 sites in Canada (Halifax, Vancouver, and Montreal) and 2 in the United States (Atlanta, GA, and Memphis, TN). Respondents reported their own research participation and cited factors that would influence their own decision to participate in, or to provide parental authorization for their child to participate in health research. RESULTS: Completed questionnaire rates for AYAs and parents were 86 (46.5%) of 185 and 409 (65.2%) of 627, respectively. AYAs (n = 86 [67%]) and parents (n = 409 [85%]) cited that they would participate in research because it would help others. AYAs perceived pressure by their family and friends (16%) and their physician (19%). Having too much to think about at the time of accrual was an impediment to both groups (36% AYAs and 47% parents). The main deterrent for AYAs was that research would take up too much time (45%). Nonwhite parents (7 of 56 [12.5%]) were more apt to decline than white parents (12 of 32 [3.7%]; P < .01). CONCLUSIONS: AYAs identified time commitment and having too much to think about as significant impediments to research participation. Addressing these barriers by minimizing time requirements and further supporting decision-making may improve informed consent and impact on enrollment in trials.

Suggestions from adolescents, young adults, and parents for improving informed consent in phase 1 pediatric oncology trials.

Informed consent for a pediatric oncology phase 1 trial is a delicate process, and is made more complex by the difficulty of the information and the requirement for parental consent, and patient assent when applicable. This analysis identifies suggestions for improving the informed consent process received from parents and adolescent and young adult patients (aged 14 years‐21 years) who had the option of participating in a phase 1 pediatric oncology trial.

Use of epidural and peripheral nerve blocks at the end of life in children and young adults with cancer: the collaboration between a pain service and a palliative care service

Background:  Clinicians may avoid continuous pain blocks in pediatric cancer patients at the end of life for fear of complications or of interfering with the desired location of death.

Early Integration of Palliative Care for Children with High‐Risk Cancer and Their Families

Despite increasing data to support pediatric palliative care (PPC) as an integral component of high‐quality care for children with life‐threatening conditions and their families, timely integration of PPC is offered inconsistently to children with high‐risk cancer. In this review, we summarize the growing body of literature in support of early integration of PPC for children with high‐risk cancer and their families, advocating that PPC principles and resources are imperative to holistic cancer‐directed care and rooted in evidence‐based medicine. Finally, we offer possible strategies for optimizing integration of PPC into holistic cancer care for children and families.