Faculty Bibliography

OBJECTIVE:Duraplasty is one technique successfully used to treat Chiari malformation type I (CM-I). This study describes the timely manner of clinical outcomes and the postoperative course after craniectomy and duraplasty for the treatment of symptomatic CM-I in pediatric children. METHODS:A retrospective chart review was done on 105 consecutive children who underwent surgical decompression of symptomatic CM-I with dural opening by a single surgeon between 1999 and 2015. RESULTS:In 16 of 28 children (57%) with typical Valsalva-related/tussive and mixed headaches, the symptoms resolved before discharge; by 6 months all children were headache free. Two of 28 children (7%) had recurrent headaches 9 months after surgery. In 78 children with syrinx, syrinx resolved or decreased in 68 children (87%), recurred in 8 children (10%), and was stable in 2 children (3%). In 51 children (65%), syrinx resolved or decreased by 3 months and in 62 children (79%) by 6 months. Complications included aseptic meningitis requiring reoperation in 3% and infection in one child (1%). Twelve reoperations occurred, none within the first 30 days. No child had a major morbidity or mortality. CONCLUSIONS:In carefully selected children with CM-I, a high success rate can be achieved with suboccipital decompression and duraplasty. Valsalva-related/tussive headaches resolved in the majority of children at discharge from the hospital; syrinx resolved or decreased in two thirds of the children by 3 months. By 6 months, headaches were resolved in all cases, and syrinx was resolved or decreased in 79% of cases.

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.

BACKGROUND: Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma

OBJECT: Gross-total resection (GTR) of craniopharyngioma is associated with high rates of complications that potentially affect quality of life (QoL). This study investigated the impact of GTR on the long-term QoL and sexual functioning in young adults. METHODS: 81 pediatric patients treated with primary GTR of craniopharyngioma were included in this retrospective cohort study. The Quality of Life Questionnaire SF36v1 and the Medical Outcomes Study family and sexual functioning scale were used to analyze follow-up data. RESULTS: 22 patients consented and completed the questionnaires. The median time of follow-up was 19 years (range 10-26). 55% of the patients reported to have excellent or very good health in general. The mean SF 36v total score was 51.63 for PCS and 49.26 for MCS. There was no significant difference between the patient cohort and the normal population. Twenty-one out of 22 subjects reported about sexual functioning, of whom 25% of women and 54% of men reported at least 'a little of a problem' in one or more areas of sexual functioning. Body mass index (BMI) values were: 14% normal, 41% overweight, 36% obese and 9% morbidly obese. Preoperative hypothalamic involvement and retrochiasmatic location of the tumor was significantly correlated with BMI. CONCLUSIONS: Young adults with childhood-onset craniopharyngioma report QoL and sexual functioning similar to that of the normal population. Overweight and obesity are more prevalent in the study population. Retrochiasmatic location of the tumor and hypothalamic involvement on the preoperative imaging correlate with higher BMI in long-term follow-up

INTRODUCTION: Liquid biopsy has the potential to revolutionize diagnosis and management of cancer. In brain tumors, detection of cell free tumor DNA (ctDNA) and circulating tumor cells (CTC) is challenging due to low level of the circulating material. We present a novel workflow for detection and capture of CTCs. METHODS: Peripheral blood was obtained from five pediatric patients with astrocytoma (n=2), ependymoma (n=1), dysembryoplastic neuroepithelial tumor (n=1), and medulloblastoma (n=1) at initial resection (n=3) and relapse (n=2). Samples were enriched using the Clear-Bridge ClearCell FX1 system and the suspension stained with antibodies against CD56 and CD45. Samples were analyzed using Silicon Biosystems DEPArray to capture single and pooled CTCs. CTCs were identified by CD56 positivity, while leukocytes were positive for CD45 and NK cells double-positive for CD56 and CD45. RESULTS: CTCs were identified in all 5 patient samples. The number of CD56-positive cells isolated from each sample ranged from 1 to 25 (mean 9). The CD56-positive cells were on average 11.8 mum in diameter (range 9.0-15.7 mum), and CD45-positive cells were on average 10.8 mum in diameter (range 8.9-15.9 mum). Single CTCs and CTC pools are amenable to molecular analysis after whole genome amplification. CONCLUSION: We report a novel integrated workflow for capturing CTCs in pediatric patients with brain tumors. While rare, CTCs circulate in peripheral blood of patients with brain tumors regardless of their grade and are amenable for molecular analysis. This method has the potential to serve as a non-invasive diagnostic and monitoring method for pediatric brain tumors

Optic pathway gliomas (OPGs) are relatively common and benign lesions in children; however, in adults these lesions are nearly always malignant and hold a very poor prognosis. In this report the authors present the case of an adult patient with a benign OPG who underwent subtotal resection without adjuvant therapy and has had no tumor progression for more than 20 years. A 50-year-old woman presented with a 2-year history of personality changes, weight gain, and a few months of visual disturbances. Ophthalmological evaluation showed incomplete right homonymous hemianopsia. MRI demonstrated a 2.5 × 2.5 × 2.5-cm enhancing left-sided lesion involving the hypothalamus with extension into the suprasellar cistern, extending along the left optic tract and anterior to the level of the optic chiasm. A biopsy procedure revealed a juvenile pilocytic astrocytoma. A subtotal resection of approximately 80% of the tumor was performed. Postoperatively, the patient experienced complete resolution of her personality changes, and her weight decreased back to baseline. Ophthalmological examination showed increased right homonymous hemianopsia. In the years following her surgery, there was a spontaneous decrease in tumor size without adjuvant therapy. The patient continues to have an excellent quality of life despite a visual field defect, and no further tumor growth has been observed.