Peter Manley

Intensive Multimodality Treatment for Children With Newly Diagnosed CNS Atypical Teratoid Rhabdoid Tumor

PURPOSE Atypical teratoid rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a historic median survival ranging from 6 to 11 months. Based on a previous pilot series, a prospective multi-institutional trial was conducted for patients with newly diagnosed CNS ATRT. PATIENTS AND METHODS Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy. Intrathecal chemotherapy was administered, alternating intralumbar and intraventricular routes. Radiation therapy (RT) was prescribed, either focal (54 Gy) or craniospinal (36 Gy, plus primary boost), depending on age and extent of disease at diagnosis. RESULTS Between 2004 and 2006, 25 patients were enrolled; 20 were eligible for evaluation. Median age at diagnosis was 26 months (range, 2.4 months to 19.5 years). Gross total resection of the primary tumor was achieved in 11 patients. Fourteen patients had M0 disease at diagnosis, one patient had M2 disease, and five patients had M3 disease. Fifteen patients received radiation therapy: 11 focal and four craniospinal. Significant toxicities, in addition to the expected, included radiation recall (n = 2) and transverse myelitis (n = 1). There was one toxic death. Of the 12 patients who were assessable for chemotherapeutic response (pre-RT), the objective response rate was 58%. The objective response rate observed after RT was 38%. The 2-year progression-free and overall survival rates are 53% +/- 13% and 70% +/- 10%, respectively. Median overall survival has not yet been reached. CONCLUSION This intensive multimodality regimen has resulted in a significant improvement in time to progression and overall survival for patients with this previously poor-prognosis tumor.

Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.

Long‐term outcome of 4,040 children diagnosed with pediatric low‐grade gliomas: An analysis of the Surveillance Epidemiology and End Results (SEER) database

Children with pediatric low‐grade gliomas (PLGG) are known to have excellent 10‐year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG.

A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Preclinical models show that an antiangiogenic regimen at low‐dose daily (metronomic) dosing may be effective against chemotherapy‐resistant tumors. We undertook a prospective, open‐label, single‐arm, multi‐institutional phase II study to evaluate the efficacy of a “5‐drug” oral regimen in children with recurrent or progressive cancer.

Sexual Function in Childhood Cancer Survivors: A Report from Project REACH

INTRODUCTION Of the approximately 12,000 children and adolescents that will be diagnosed with cancer in 2013, it is expected that over 80% of them will become long-term adult survivors of childhood cancer. Although it has been well established that cancer treatment often has profound negative impact on sexual functioning, sexual functioning in adult survivors of childhood cancer is not well understood. AIM The aim of the current study was to examine the report of sexual function in adult survivors of childhood cancer in relationship to both physical and emotional functioning. METHODS Two hundred ninety-one participants enrolled in Project REACH, a longitudinal study of childhood cancer survivors, completed questionnaires as part of an annual health survey. MAIN OUTCOME MEASURE Primary outcome measures included the sexual functioning subscale of the Swedish Health-Related Quality of Life Survey, the SF-12, and the BSI-18. RESULTS Results indicate that 29% of young adult survivors reported two or more discrete symptoms of sexual dysfunction. Females were twice as likely to report sexual problems. Sexual problems were not related to specific types of childhood cancer treatments such as type of chemotherapy or radiation. Young adults with sexual dysfunction did report poorer functioning across the range of SF-12 subscales including physical functioning, general health, fatigue, and mental health. CONCLUSIONS Significant sexual dysfunction is common in adult survivors of childhood cancer. A greater understanding of the particular relationship between sexual dysfunction and both physical and emotional well-being in this relatively young population is needed. Even when long-term cancer survivors are young adults and report generally good health, results underscore the need for clinicians to specifically assess sexual functioning.

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

The determinants of outcomes for adult survivors of pediatric low‐grade glioma (PLGG) are largely unknown.

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

Background Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.

Seizures are common during and after treatment for a primary brain tumor. Our objective was to describe the incidence and risk factors for seizures in long‐term survivors of pediatric brain tumors.

Medical and Psychosocial Correlates of Insomnia Symptoms in Adult Survivors of Pediatric Brain Tumors

OBJECTIVE Children diagnosed with brain tumors are at risk for insomnia. We evaluated insomnia symptoms, medical and psychosocial correlates, and medical documentation of sleep-related issues in a neuro-oncology clinic. METHODS 98 adult survivors of pediatric brain tumors provided data about sleep, psychological distress, and health-related quality of life. Medical records were reviewed for treatment-related information and for documentation of sleep-related issues. RESULTS 26% of the sample reported insomnia symptoms as evidenced by poor sleep efficiency. Insomnia symptoms were associated with a migraine headache history, but not with other medical or psychosocial outcomes. Approximately one in three medical providers did not document discussing sleep during the survivorship visit. CONCLUSIONS A sizeable number of pediatric brain tumor survivors experience insomnia symptoms. The survivorship visit is an ideal opportunity for providers to conduct a sleep evaluation for this at-risk population and to provide referrals for evidence-based insomnia treatment.

Sleep Disorders in Children With Cancer

Approximately three-fourths of all pediatric cancer patients will be long-term survivors; however, there can be a steep cost for cancer survivorship. Cancer treatment involves exposure to chemotherapy, surgical intervention, and radiation, which can cause lasting long-term toxicities. Children with brain tumors have the highest prevalence of long-term morbidities. These effects can be attributed to direct neurologic damage to the developing brain caused by tumor, hydrocephalus, surgical removal of the tumor, and the effects of irradiation. The late effects experienced by childhood cancer survivors involve multiple domains, one of which is sleep disorders. Sleep dysfunction has an increased prevalence in the pediatric cancer survivor population. These issues are disruptive to patients and cause a decrease in quality of life. This review focuses on sleep disorders that occur in pediatric cancer survivors and discusses the possible causes, the assessments used to determine specific sleep disorders, and treatment modalities used to ameliorate this dysfunction with the hope of improving patients quality of life.