Multifocal primary neuroblastoma tumor heterogeneity in siblings with co-occurring PHOX2B and NF1 genetic aberrations.

Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development. We performed comprehensive molecular characterization of neuroblastoma tumors from two siblings affected by familial multifocal neuroblastoma, including whole exome sequencing and single-nucleotide polymorphism (SNP) arrays of tumor and matched blood samples. Data were processed and analyzed using established bioinformatics algorithms to evaluate for germline and somatic mutations and copy number variations (CNVs). We confirmed the presence of a PHOX2B deletion and NF1 mutation across all tumor samples and the germline genome. Matched tumor-blood whole exome sequencing also identified 365 genes that contained nonsilent coding mutations across all tumor samples, with no recurrent mutations across all tumors. SNP arrays also showed significant heterogeneity with respect to CNVs. The only common CNV across all tumors was 17q gain, with differing chromosomal coordinates across samples but a common region of overlap distal to 17q21.31, suggesting this adverse prognostic biomarker may offer insight about additional drivers for multifocal neuroblastoma in patients with germline PHOX2B or NF1 aberrations. Molecular characterization of all tumors from patients with multifocal primary neuroblastoma has potential to yield novel insights on neuroblastoma pathogenesis.

Physician perspectives on compassionate use in pediatric oncology.

BACKGROUND: Targeted cancer treatments are almost always first studied in adults, even when there is a biologically plausible potential for efficacy in children. Through compassionate use programs, children who are not eligible for a clinical trial and for whom there are no known effective therapies may obtain access to investigational agents, including drugs under development for adults. However, little is known about pediatric oncologists' experiences with applying for and obtaining compassionate use agents. METHODS: This study surveyed 132 pediatric oncologists to assess awareness and utilization of compassionate use programs, to identify barriers to their use, and to evaluate available institutional support and resources. RESULTS: We found that the process of applying for access to drugs in development is poorly understood, which presents a barrier to obtaining investigational drugs. Fifty-seven percent of the pediatric oncologists applied for compassionate use. Providers from larger institutions or with more than 15 years of clinical experience were more likely to complete an application and obtain investigational agents for their patients. CONCLUSION: Identified perceived and actual barriers to compassionate use application submission suggest pediatric oncologists may benefit from educational resources and support to ensure children with cancer equal access to investigational agents and care.

Rapid-Acting Insulin Used to Treat a Case of Early Cystic Fibrosis-Related Diabetes Complicated by Post Prandial Hypoglycemia.

Background/Objective: Cystic fibrosis-related diabetes (CFRD) is one of the most common nonrespiratory complications of cystic fibrosis (CF). There is a lack of clinical research to provide guidance on optimal treatment regimens for various subtypes of CFRD. Case Report: This case describes an 18-year-old woman, diagnosed with CF in infancy, who presented to our clinic for evaluation of possible CFRD and episodes of hypoglycemia. Subsequent testing revealed normal fasting glucose with elevated blood glucose levels on oral glucose tolerance test, consistent with the diagnosis of CFRD without fasting hyperglycemia. She was found to have large glycemic excursions after carbohydrate-containing meals, followed by delayed postprandial hypoglycemia. Discussion: We initiated low-dose mealtime rapid-acting analog insulin and saw both a decrease in her postprandial hyperglycemia as well as resolution of her hypoglycemic episodes. Conclusion: This case highlights the spectrum of pancreatic dysfunction and insulin dysregulation in CFRD as well as the benefit of prandial insulin alone as a treatment option.

Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.

PURPOSE: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC. EXPERIMENTAL DESIGN: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib. RESULTS: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients. CONCLUSIONS: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC.