Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Narcolepsy and Hypothalamic Region Tumors: Presentation and Evolution.

OBJECTIVE: Because most cases of brain tumor-associated narcolepsy have been published in the form of case reports or small series, the clinical presentation and evolution have not been well described. We sought to better define the epidemiology, etiology, and outcome of brain tumor-related narcolepsy. METHODS: We conducted an extensive review of the literature to identify cases of narcolepsy associated with brain tumors. Only cases of brain tumors involving the hypothalamic region including the suprasellar, sellar, and thalamus were included in this study. RESULTS: We report a child with possible narcolepsy in a child with a brain tumor. Through our literature review, we identified 25 additional cases of narcolepsy associated with brain tumors affecting the hypothalamic area. Most symptomatic narcolepsy cases were reported in children (70%). Half of the patients (13 of 25, 52%) developed narcolepsy after surgery, whereas 11 patients (44%) were symptomatic at the time of the tumor diagnosis. Ten patients had narcolepsy without cataplexy. Most cases were associated with craniopharyngioma (38%), adenoma (24%), and glioma (14%). Three, including our patient, experienced a complete resolution of symptoms. All patients underwent biopsy and were treated with adjuvant therapy. For patients with persistent symptoms, most (60%) improved following medical management of narcolepsy. CONCLUSION: This study represents the largest compilation of patients with this association. Our study allows us to better understand the etiology and outcome of patients with narcolepsy-related brain tumors.

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma.

Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63-17.55) and median survival was 6.43 (range, 0.01-27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups.

Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.

We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.

Pediatric thalamic tumors in the MRI era: a Canadian perspective.

BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13% for unithalamic tumors compared to 37 ± 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.

Cerebello-thalamo-cerebral connections in pediatric brain tumor patients: impact on working memory.

Brain tumors are the leading cause of death and disability from childhood disease in developed countries. Pediatric posterior fossa tumors are often effectively controlled with a combination of surgery, radiation, and chemotherapy, depending on tumor type. White matter injury following resection of tumor and radiation treatment is associated with cognitive declines, including working memory deficits. We investigated how brain injury following treatment for posterior fossa tumors results in deficits in working memory. We used diffusion tensor imaging and probabilistic tractography to examine the structural integrity of cerebello-thalamo-cerebral tracts in patients and healthy children. We also compared working memory outcome in patients versus controls, and related this function to integrity of cerebello-thalamo-cerebral tracts. Bilateral cerebello-thalamo-cerebral tracts were delineated in all participants. Patients treated with a combination of surgery and radiation had lower mean anisotropy and higher mean radial diffusivity within the cerebellar regions of the cerebello-thalamo-cerebral tract compared to patients treated with surgery only and healthy controls. Poorer working memory scores were observed for the cranial radiation group relative to controls. Reduced anisotropy and higher radial diffusivity within the entire cerebello-thalamo-cerebral pathway predicted lower working memory. Our finding that working memory function is related to the integrity of cerebello-thalamo-cerebral connections is a novel contribution to the understanding of cerebral-cerebellar communication. Identifying differences in the structural integrity of white matter for specific pathways is an essential step in attempting to localize the effects of posterior fossa tumors and their treatment methods.