Faculty Bibliography

OBJECTIVEThe authors describe the demographics and clinical characteristics of the first 517 patients enrolled in the Adult Hydrocephalus Clinical Research Network (AHCRN) during its first 2 years.METHODSAdults ≥ 18 years were nonconsecutively enrolled in a registry at 6 centers. Four categories of adult hydrocephalus were defined: transition (treated before age 18 years), unrecognized congenital (congenital pattern, not treated before age 18 years), acquired (secondary to known risk factors, treated or untreated), and suspected idiopathic normal pressure hydrocephalus (iNPH) (≥ age 65 years, not previously treated). Data include etiology, symptoms, examination findings, neuropsychology screening, comorbidities, treatment, complications, and outcomes. Standard evaluations were administered to all patients by trained examiners, including the Montreal Cognitive Assessment, the Symbol Digit Modalities Test, the Beck Depression Inventory-II, the Overactive Bladder Questionnaire Short Form symptom bother, the 10-Meter Walk Test, the Boon iNPH gait scale, the Lawton Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) questionnaire, the iNPH grading scale, and the modified Rankin Scale.RESULTSOverall, 517 individuals were enrolled. Age ranged from 18.1 to 90.7 years, with patients in the transition group (32.7 ± 10.0 years) being the youngest and those in the suspected iNPH group (76.5 ± 5.2 years) being the oldest. The proportion of patients in each group was as follows: 16.6% transition, 26.5% unrecognized congenital, 18.2% acquired, and 38.7% suspected iNPH. Excluding the 86 patients in the transition group, who all had received treatment, 79.4% of adults in the remaining 3 groups had not been treated at the time of enrollment. Patients in the suspected iNPH group had the poorest performance in cognitive evaluations, and those in the unrecognized congenital group had the best performance. The same pattern was seen in the Lawton ADL/IADL scores. Gait velocity was lowest in patients in the suspected iNPH group. Categories that had the most comorbidities (suspected iNPH) or etiologies of hydrocephalus that directly cause neurological injury (transition, acquired) had greater degrees of impairment compared to unrecognized congenital, which had the fewest comorbidities or etiologies associated with neurological injury.CONCLUSIONSThe clinical spectrum of hydrocephalus in adults comprises more than iNPH or acquired hydrocephalus. Only 39% of patients had suspected iNPH, whereas 43% had childhood onset (i.e., those in the transition and unrecognized congenital groups). The severity of symptoms and impairment was worsened when the etiology of the hydrocephalus or complications of treatment caused additional neurological injury or when multiple comorbidities were present. However, more than half of patients in the transition, unrecognized congenital, and acquired hydrocephalus groups had minimal or no impairment. Excluding the transition group, nearly 80% of patients in the AHCRN registry were untreated at the time of enrollment. A future goal for the AHCRN is to determine whether patients with unrecognized congenital and acquired hydrocephalus need treatment and which patients in the suspected iNPH cohort actually have possible hydrocephalus and should undergo further diagnostic testing. Future prospective research is needed in the diagnosis, treatment, outcomes, quality of life, and macroeconomics of all categories of adult hydrocephalus.

OBJECTIVEThe choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs.METHODSA retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed.RESULTSThe 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children.CONCLUSIONSApproximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.

OBJECTIVE: New onset hydrocephalus following foramen magnum decompression (FMD) for Chiari I malformation (CMI) is rare, and its natural history and pathophysiology is poorly understood. We describe a series of patients who presented with hydrocephalus following FMD for CMI, provide possible explanations of this condition, and outline treatment options. MATERIAL-METHODS: Of patients undergoing FMD for CMI from 6 different tertiary centres in North America, Europe and Middle East, we evaluated patients presenting with new onset hydrocephalus following the FMD. Retrospectively collected data included demographics, clinical and radiological findings of both the CMI and hydrocephalus, time from FMD and hydrocephalus onset, and treatment as well as surgical techniques. RESULTS: None of the patients had obvious symptoms related to idiopathic intracranial hypertension nor hydrocephalus prior to FMD. Of 367 patients who underwent FMD for CMI, 28 (7.6%) subsequently developed symptoms related to hydrocephalus (18 females-64.2%, and 10 males - 35.8%), (7 Le Bonheur Children's Hospital, 6 Tel Aviv Medical Center and Dana Children's Hospital, 6 Cincinnati Children's Hospital Medical Center, 5 Children's National Medical Center, 3 NYU Langone Medical Center, 1 Charite Universitatsmedizin) with a mean age of 11.7 +/- 11.9 years old (range 6 months to 52 years old). Hydrocephalus occurred on average 2.2 +/- 2.6 months after FMD (ranging from 1 week to 8 months). Presenting symptoms of hydrocephalus were headaches (41%), vomiting (24.4%), CSF leak/pseudomeningocele (17%), decreased level of consciousness (7.3%), cranial nerves signs (7.3%) and papilledema (2.4%). 23 patients (82.1%) underwent CSF shunting, 1 patient had an endoscopic third ventriculostomy (3.5%), 3 patients (10.7%) temporary CSF diversion only, and 1 patient (3.5%) acetazolamide. CONCLUSION: Hydrocephalus following FMD for CMI is uncommon. Based on our series and literature review, its incidence is ~7% and most likely will require further surgery. Considering different treatment options, shunting appears to be the favoured option

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.

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

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