Surgical morbidity and mortality of pediatric brain tumors: a single center audit

OBJECTIVES: The primary aim of this study is to perform an internal quality control of pediatric brain tumor surgery in the neurosurgical department of the VU University Medical Center Amsterdam (The Netherlands). Secondly, this study aims to contribute to the accumulating data concerning outcome in pediatric neurosurgery, in order to establish institutional practice benchmarks. METHODS: We report the surgical mortality and morbidity of 121 patients (0–18 years) surgically treated for a brain tumor from January 1999 to August 2007. Patients, in whom only a brain tumor biopsy was performed, were excluded. RESULTS: Mean age at first surgery was 8.2 years. Of the 121 patients, 14 had a second surgery, and two underwent a third surgery (for a total of 137 operations). Of all 121 primary surgeries, 66% were total resections, 26% subtotal resections, and 8% partial resections. The overall surgical morbidity rate in this study was 69% after first surgery, 50% after second surgery, and one out of two after third surgery. CONCLUSION: These overall morbidity rates are comparable to other published mixed case series. The surgical mortality rate was 0.8%; this is comparable to the lowest rates reported for high-volume neurosurgical centers. We encourage other neurosurgical centers to collect, analyze, and publish their data. These data can then serve as a basis for comparison with other pediatric neurosurgical centers and will eventually lead to an improvement of pediatric neurosurgical practice and patient care

Late neurocognitive sequelae in patients with WHO grade I meningioma

BACKGROUND: Information on the neurocognitive outcome following treatment of benign meningiomas is virtually lacking. This is remarkable considering these patientsś survival is the most favorable of all intracranial tumors. The aim of the present study is therefore to document the extent and nature of neurocognitive deficits in WHO grade I meningioma patients after treatment. METHODS: Eighty-nine WHO grade I meningioma patients who underwent surgery with or without adjuvant radiotherapy were individually matched to 89 healthy controls for age, sex, and educational level. Neurocognitive functioning of patients was assessed at least one year following treatment and compared to that of healthy controls using Student's t-tests. Additionally, associations between tumor characteristics (size, lateralization and localization), treatment characteristics (radiotherapy), and epilepsy burden (based on seizure frequency and antiepileptic drug use) and neurocognitive functioning were investigated. RESULTS: Compared to healthy controls meningioma patients showed significant impairments in executive functioning (p < 0.001), verbal memory (p < 0.001), information processing capacity (p = 0.001), psychomotor speed (p = 0.001), and working memory (p = 0.006). Patients with skull base meningiomas performed significantly lower on three out of six neurocognitive domains when compared to convexity meningiomas. Left-sided as opposed to right sided meningiomas were related to verbal memory deficits. A higher epilepsy burden was significantly associated with lower executive functioning, which primarily could be attributed to antiepileptic drug use. No significant associations were established between neurocognitive status and radiotherapy or tumor volume. CONCLUSIONS: Meningioma patients are characterized by long-term deficits in neurocognitive functioning that can partly be attributed to the use of antiepileptic drugs and tumor location, but not to the use of radiotherap

Health-related quality of life of long-term high-grade glioma survivors

The objective of this study was to compare the health-related quality of life (HRQOL) of long-term to short-term high-grade glioma (HGG) survivors, determine the prognostic value of HRQOL for overall survival, and determine the effect of tumor recurrence on HRQOL for long-term survivors. Following baseline assessment (after surgery, before radiotherapy), self-perceived HRQOL (using the Medical Outcomes Study Short Form 36 [SF-36]) and brain tumor-specific symptoms (using the 20-item Brain Cancer Module) were assessed every 4 months until 16 months after histological diagnosis. Kaplan-Meier survival analysis and the Cox proportional hazards model were performed to estimate overall survival of patients with impaired scores on the aggregated SF-36 higher-order summary scores measuring physical functioning on a physical component scale and on a mental component scale (MCS). Sixteen patients with a short-term survival (baseline and 4-month follow-up) and 16 with a long-term survival (follow-up until 16 months after diagnosis) were selected out of 68 initially recruited HGG patients. At baseline, the short-term and long-term survivors did not differ in their HRQOL. Between baseline and the 4-month follow-up, HRQOL of short-term survivors deteriorated, whereas the long-term survivors improved to a level comparable to healthy controls. Patients with impaired mental functioning (MCS) at baseline had a shorter median survival than patients with normal functioning. After accounting for differences in patient and tumor characteristics, however, mental functioning was not independently related to poorer overall survival. Not surprisingly, in the group of long-term survivors, the five patients with recurrence had a more compromised HRQOL at the 16-month follow-up compared to the 11 patients without recurrence. We concluded that baseline HRQOL is not related to duration of survival and that long-term survivors show improvement of HRQOL to a level comparable to that of the healthy

Mutational profiling of kinases in glioblastoma

Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.Methods: Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced. Results: Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway. Conclusions: The knowledge that at least 50% of glioblastoma tumors display mutational activation of the PI3K-AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas. However, due to the development of resistance mechanisms, kinase inhibition studies targeting the PI3K-AKT pathway for relapsing glioblastoma have mostly failed thus far. Other therapies should be investigated, targeting early events in gliomagenesis that involve both kinases and non-kinases

A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4),