Use of Trametinib in Children and Young Adults With Progressive Low-grade Glioma and Glioneuronal Tumors.

Low-grade gliomas/glioneuronal tumors comprise one-third of all pediatric-type CNS tumors. These tumors are generally caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Targeted drugs, such as trametinib, have shown promise in other cancers and are being utilized in low-grade gliomas. A retrospective chart review was conducted to evaluate radiographic response, visual outcomes, tolerability, and durability of response in progressive circumscribed low-grade gliomas treated with trametinib. Eleven patients were treated with trametinib. The best radiographic response was 2/11 partial response, 3/11 minor response, 3/11 stable disease, and 3/13 progressive disease. In the patients with partial or minor response, the best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 9 months of therapy with a median of 21 months. Patients with optic pathway tumors showed at least stable vision throughout treatment, with 3 having improved vision on treatment. Trametinib is effective and well-tolerated in patients with progressive low-grade glioma. Best responses were seen after a longer duration of therapy in those with a positive response. Patients with optic pathway lesions showed stable to improved vision while on treatment.

Immunotherapy for the treatment of pediatric brain tumors: a narrative review.

Background and Objective: The goal of this narrative review is to report and summarize the completed pediatric immunotherapy clinical trials for primary CNS tumors. Pediatric central nervous system (CNS) tumors are the most common cause of pediatric solid cancer in children aged 0 to 14 years and the leading cause of cancer mortality. Survival rates for some pediatric brain tumors have improved, however, there remains a large portion of pediatric brain tumors with poor survival outcomes despite advances in treatment. Cancer immunotherapy is a growing field that has shown promise in the treatment of pediatric brain tumors that have historically shown a poor response to treatment. This narrative review provides a summary and discussion of the published literature focused on treating pediatric brain tumors with immunotherapy. Methods: MEDLINE via PubMed, Embase and Scopus via Elsevier were searched. The search utilized a combination of keywords and subject headings to include pediatrics, brain tumors, and immunotherapies. Manuscripts included in the analysis included completed clinical studies using any immunotherapy intervention with a patient population that consisted of at least half pediatric patients (<18 years) with primary CNS tumors. Conference abstracts were excluded as well as studies that did not include completed safety or primary outcome results. Key Content and Findings: Search results returned 1,494 articles. Screening titles and abstracts resulted in 180 articles for full text review. Of the 180 articles, 18 were included for analysis. Another two articles were ultimately included after review of references and inclusion of newly published articles, for a total of 20 included articles. Immunotherapies included dendritic cell vaccines, oncolytic virotherapy/viral immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, peptide vaccines, immunomodulatory agents, and others. Conclusions: In this review, 20 published articles were highlighted which use immunotherapy in the treatment of primary pediatric brain tumors. To date, most of the studies published utilizing immunotherapy were phase I and pilot studies focused primarily on establishing safety and maximum dose-tolerance and toxicity while monitoring survival endpoints. With established efficacy and toxicity profiles, future trials may progress to further understanding the overall survival and quality of life benefits to pediatric patients with primary brain tumors.

Mirtazapine for sleep disturbances in Angelman syndrome: a retrospective chart review of 8 pediatric cases.

STUDY OBJECTIVES: Angelman syndrome (AS) is a rare neurodevelopmental disorder that is characterized by developmental delay, intellectual disability, seizures, a characteristic happy personality, gait ataxia, tremulousness of the limbs, microcephaly, and anxiety. Severe sleep disturbances with the diminished need for sleep and abnormal sleep-wake cycles are seen in up to 90% of patients with AS. AS is caused by absent maternal expression of the gene UBE3A located in the 15q11.2-q13 locus. We hypothesized that selective antagonism of 5-HT2 and 5-HT3 serotonin receptors with mirtazapine would benefit sleep disturbances in patients with AS. METHODS: Institutional Review Board approval was obtained at Vanderbilt University Medical Center. Medical records of individuals seen in the Comprehensive Angelman Syndrome clinic were retrospectively reviewed to determine the use of mirtazapine for disordered sleep. Parents were asked to respond to a survey to assess the phenotypic features of sleep and behavioral disturbances in AS. They were asked about the use of medications for sleep, focusing on the benefits and risks of mirtazapine. RESULTS: A cohort of 8 individuals with AS, ranging in age from 3 to 16 years old with histories of sleep challenges, were treated with 3.75 to 30 mg of mirtazapine at bedtime for 0 to 36 weeks. Nocturnal awakenings were the most common sleep challenge reported. Seven of eight patients reported benefits from mirtazapine, including increased total sleep time, decreased nocturnal awakenings, and decreased time to fall asleep. The most significant side effects of mirtazapine were hyperphagia and weight gain. CONCLUSIONS: Individuals with AS have abnormal sleep-wake cycles and a high unmet medical need. Mirtazapine helped with sleep onset and nighttime awakenings in 7 of 8 patients, with 2 patients reporting a positive benefit with respect to behavior. These data suggest that mirtazapine may be considered for the treatment of sleep difficulties in patients with AS who remain refractory to more conventional therapies. Weight gain was a common side-effect and led to discontinuation of treatment in 1 patient.

Microcephaly.

Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. Congenital microcephaly is present at birth, whereas postnatal microcephaly occurs later in life. Genetic abnormalities, syndromes, metabolic disorders, teratogens, infections, prenatal, perinatal, and postnatal injuries can cause both congenital and postnatal microcephaly. Evaluation of patients with microcephaly begins with a thorough history and physical examination. In cases of worsening microcephaly or neurological signs or symptoms, neuroimaging, metabolic, or genetic testing should be strongly considered. Any further studies and workup should be directed by the presence of signs or symptoms pointing to an underlying diagnosis and are usually used as confirmatory testing for certain conditions. Neuroimaging with magnetic resonance imaging (MRI) is often the first diagnostic test in evaluating children with microcephaly. Genetic testing is becoming more common and is often the next step following neuroimaging when there is no specific evidence in the history or physical examination suggesting a diagnosis. Microcephaly is a lifelong condition with no known cure. The prognosis is usually worse for children who experienced an intrauterine infection or have a chromosomal or metabolic abnormality. Zika virus has rapidly spread since 2015, and maternal infection with this virus is associated with microcephaly and other serious brain abnormalities. Microcephaly has become much more prevalent in the news and scientific community with the recent emergence of Zika virus as a cause of congenital microcephaly.

A systematic review of neuropsychological outcomes following posterior fossa tumor surgery in children.

PURPOSE: Central nervous system tumors are the most common solid tumors in the pediatric population. As children with central nervous system (CNS) tumors are surviving into adolescence and adulthood, more research is being focused on the long-term cognitive outcomes of the survivors. This review examines the literature on different cognitive outcomes of survivors of different childhood posterior fossa CNS tumor types. METHODS: The authors reviewed the literature for articles published from 2000 to 2012 about long-term neuropsychological outcomes of children diagnosed with posterior fossa brain tumors before the age of 18, which distinguished between histological tumor types, and had a minimum follow-up of 3 years. RESULTS: The literature search returned 13 articles, and a descriptive analysis was performed comparing intelligence quotient (IQ), attention/executive function, and memory components of 456 survivors of childhood posterior fossa tumors. Four articles directly compared astrocytoma and medulloblastoma survivors and showed medulloblastoma survivors fared worse in IQ, attention/executive function, and memory measurements. Five articles reporting medulloblastomas found IQ, attention, and memory scores to be significantly below the standardized means. Articles examining astrocytoma survivors found IQ scores within the normal range for the population. Survivors of ependymomas reported 2/23 survivors impaired on IQ scores, while a second study reported a significant number of ependymoma survivors lower than the expected population norm. CONCLUSIONS: Tumor histopathology and the type of postoperative adjuvant therapy seem to have a significant impact on the long-term neuropsychological complications of pediatric posterior fossa CNS tumor survivors. Age at diagnosis and treatment factors are important variables that affect the outcomes of the survivors.

Multidisciplinary pediatric brain tumor clinics: the key to successful treatment?

Tumors of the CNS are the most common solid tumors diagnosed in childhood. As technology and research in cancer care are advancing, more specialties are involved in the diagnosis, treatment and follow-up of children with brain tumors. Multidisciplinary clinics have become the standard of care for cancer care throughout the USA, and specialty clinics focused on particular cancer types are gaining attention in improving the patient outcomes and satisfaction. We will discuss the role of multidisciplinary clinics, in an attempt to create preliminary guidelines on establishing and maintaining a multidisciplinary brain tumor clinic in order to optimize the care of the patients and their families.