Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

What's missing in missing data? Omissions in survey responses among parents of children with advanced cancer.

BACKGROUND: Missing data is a common phenomenon with survey-based research; patterns of missing data may elucidate why participants decline to answer certain questions. OBJECTIVE: To describe patterns of missing data in the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) study, and highlight challenges in asking sensitive research questions. DESIGN: Cross-sectional, survey-based study embedded within a randomized controlled trial. SETTING: Three large children's hospitals: Dana-Farber/Boston Children's Cancer and Blood Disorders Center (DF/BCCDC); Children's Hospital of Philadelphia (CHOP); and Seattle Children's Hospital (SCH). MEASUREMENTS: At the time of their child's enrollment, parents completed the Survey about Caring for Children with Cancer (SCCC), including demographics, perceptions of prognosis, treatment goals, quality of life, and psychological distress. RESULTS: Eighty-six of 104 parents completed surveys (83% response). The proportion of missing data varied by question type. While 14 parents (16%) left demographic fields blank, over half (n=48; 56%) declined to answer at least one question about their child's prognosis, especially life expectancy. The presence of missing data was unrelated to the child's diagnosis, time from progression, time to death, or parent distress (p>0.3 for each). Written explanations in survey margins suggested that addressing a child's life expectancy is particularly challenging for parents. CONCLUSIONS AND RELEVANCE: Parents of children with cancer commonly refrain from answering questions about their child's prognosis, however, they may be more likely to address general cure likelihood than explicit life expectancy. Understanding acceptability of sensitive questions in survey-based research will foster higher quality palliative care research.

Psychological distress in parents of children with advanced cancer.

IMPORTANCE: Parent psychological distress can impact the well-being of childhood cancer patients and other children in the home. Recognizing and alleviating factors of parent distress may improve overall family survivorship experiences following childhood cancer. OBJECTIVES: To describe the prevalence and factors of psychological distress (PD) among parents of children with advanced cancer. DESIGN: Cohort study embedded within a randomized clinical trial (Pediatric Quality of Life and Evaluation of Symptoms Technology [PediQUEST] study). SETTING: Multicenter study conducted at 3 children's hospitals (Boston Children's Hospital, Children's Hospital of Philadelphia, and Seattle Children's Hospital). PARTICIPANTS: Parents of children with advanced (progressive, recurrent, or refractory) cancer. MAIN OUTCOME MEASURE: Parental PD, as measured by the Kessler-6 Psychological Distress Scale. RESULTS: Eighty-six of 104 parents completed the Survey About Caring for Children With Cancer (83% participation); 81 parents had complete Kessler-6 Psychological Distress Scale data. More than 50% of parents reported high PD and 16% met criteria for serious PD (compared with US prevalence of 2%-3%). Parent perceptions of prognosis, goals of therapy, child symptoms/suffering, and financial hardship were associated with PD. In multivariate analyses, average parent Kessler-6 Psychological Distress Scale scores were higher among parents who believed their child was suffering highly and who reported great economic hardship. Conversely, PD was significantly lower among parents whose prognostic understanding was aligned with concrete goals of care. CONCLUSIONS AND RELEVANCE: Parenting a child with advanced cancer is strongly associated with high to severe levels of PD. Interventions aimed at aligning prognostic understanding with concrete care goals and easing child suffering and financial hardship may mitigate parental PD.

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group.

BACKGROUND: Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of 3. Stratification of patients by risk group may allow toxic treatment to be avoided. METHODS: Seventy-six patients diagnosed with medulloblastoma and enrolled on CCG-9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or nondesmoplastic. Nonparametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates, and the log-rank test was used to compare survival according to histologic subtype. RESULTS: Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77% ± 9% and OS of 85% ± 8% compared with EFS of 17% ± 5% and OS of 29% ± 6% for patients with tumors in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy. CONCLUSIONS: Children less than 3 with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy.

The Seattle Pediatric Palliative Care Project: effects on family satisfaction and health-related quality of life.

PURPOSE: This paper presents the components of a pediatric palliative care demonstration program implemented in Seattle during the period 1999-2001. It reports findings from the evaluation of quality of life and family satisfaction among enrolled participants. The program was designed to enhance patient-provider communication using the Decision-making Tool (DMT) and experimented with co-management by clinicians and insurers to support decision making in advanced serious pediatric illness. DESIGN: The project design consisted of ethical decision-making, provider education, and flexible administration of health benefits through co-case management between insurers and care providers. The evaluation study design is a non-experimental pretest, posttest design comparison of pediatric quality of life and family satisfaction at program entry with repeated measures at 3 months post-program entry. Quality of life was measured with parent proxy reports of health-related quality of life using the PedsQL() Version 4.0, and family satisfaction was measured with a 31-item self-administered questionnaire designed by project staff. RESULTS: Forty-one patients ranging in age from infancy to 22 years old were enrolled in the program over a 2-year period. Parents consented to participate in the evaluation study. Thirty one specific diagnoses were represented in the patient population; 34% were some form of cancer. Improvements in health-related quality of life over baseline were observed for 21 matched pairs available for analysis in each domain of health-related quality of life; positive changes in reports of emotional well-being were statistically significant. Improvements over baseline in 14 of 31 family satisfaction items were statistically significant. CONCLUSIONS: Pediatric palliative care services that focus on effective communication, decision support, and co-case management with insurers can improve aspects of quality of life and family satisfaction.

BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.

The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.