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Background Many patients with glioma suffer from deficits in executive functioning (EF), regardless of tumor location and size. While some patients experience improving EF after tumor resection, others deteriorate over time. This variability in cognitive trajectories is still poorly understood, but neuroscientific approaches that view the brain as a network may bear correlative and predictive value in this respect. Particularly integrative network connectivity of the fronto-parietal network are crucial for EF, but studies so far have only investigated isolated neural frequency bands of interest. Here, we synergize fronto-parietal network connectivity across frequency bands and test its explanatory power for EF at diagnosis and 1 year after tumor resection. Material and Methods Patients with diffuse glioma (n=37) underwent neuropsychological assessments, including three tests for EF, and resting-state magnetoencephalography (MEG) at both time points. Patients’ EF performance was standardized to z-scores using validated norm scores, adjusting for age, sex and education. MEG was source-reconstructed using patients’ MRI in combination with a beamformer approach and time series were filtered into six classical frequency bands. Band-specific functional connectivity between 78 cortical regions was estimated, after which an interconnected multilayer, multi-frequency network was created per patient. Multilayer centrality was then calculated as a measure of integrative network connectivity per region, and averaged over all fronto-parietal network regions to yield a single value reflecting integrative, multi-frequency network connectivity per patient at each time point. Results At diagnosis, eight patients had z-scores Conclusion Our results establish a significant relationship between poorer and decreasing EF with lower and decreasing multilayer, multi-frequency integrative connectivity of the fronto-parietal network in glioma patients. Studies with larger and more homogeneous samples may further explore the relevance of this multilayer approach in understanding and particularly predicting postoperative decline in EF in these patients, as our sample was characterized by large heterogeneity in cognitively relevant patient and tumor characteristics.

Background The prospects of a patient with suspected glioblastoma may rely heavily on the indication for surgical resection versus biopsy only. Biopsy percentages vary considerably across hospitals and guidelines for treatment of glioblastoma lack criteria for surgical decision-making. To identify patient and tumor characteristics associated with the decision to resect or biopsy a glioblastoma and to develop and validate a prediction model for decision support. Material and Methods Clinical data and pre-operative MRI scans were collected for adults who underwent first-time surgery for supratentorial glioblastoma from a registry-based cohort study of 12 hospitals from the Netherlands, Germany, France, Italy, and the United States between 1st of January 2007 and 31st of December 2011. The main outcome was the type of surgical procedure: surgical resection or biopsy only. Predictors were patient- and tumor-related characteristics. Radiological factors were extracted from MRI using an automated tumor segmentation method. A prediction model was constructed using multivariable logistic regression analysis. The model was cross-validated and externally validated with a leave-one-hospital-out approach. Results Out of 1053 patients treated for glioblastoma, 28% underwent biopsy only. Biopsy rates varied from 15-40% across hospitals. The prediction model showed excellent discrimination with an average area under the curve of 0.86. Of the patient-related characteristics, younger age was associated more with resection and Karnofsky Performance Score of 60 or less with biopsy. Of the tumor-related characteristics, a location in the right hemisphere, unifocality, no tumor midline crossing, and no involvement of the cortical spinal tract, were associated with resection, as well as a high expected resectability index, a location in the right occipital lobe, and a higher percentage of tumor in Schaefer’s dorsal or ventral attention, limbic, and default networks. External validation proved acceptable to outstanding discrimination with areas under the curve ranging between 0.79 and 0.92 for hospitals. Conclusion A prediction model is presented and validated to support the decision to resect or to biopsy a patient with a suspected supratentorial glioblastoma. In this prediction model, tumor-related characteristics were more informative than patient-related factors. This may support surgical decision-making for individual patients, or facilitate comparisons of patient cohorts between surgeons or institutions.

BACKGROUND Delay in cancer care may adversely affect emotional distress, treatment outcome and survival. Optimal timings in multidisciplinary glioblastoma care are a matter of debate and clear national guidelines only exist for time to neurosurgery. We evaluated the between-hospital variation in timings to neurosurgery and adjuvant radiotherapy and chemotherapy in newly diagnosed glioblastoma patients in the Netherlands. MATERIAL AND METHODS Data were obtained from the nation-wide Dutch Brain Tumor Registry between 2014 and 2018. All adult patients with glioblastoma were included, covering all 18 neurosurgical hospitals, 28 radiotherapy hospitals, and 33 oncology hospitals. Long time-to-surgery (TTS) was defined as >3 weeks from the date of first brain tumor diagnosis to surgery, long time-to-radiotherapy (TTR) as either >4 or >6 weeks after surgery, and long time-to-chemotherapy (TTC) as either >4 or >6 weeks after completion of radiotherapy. Between-hospital variation in standardized rate of long timings was analyzed in funnel plots after case-mix correction. RESULTS A total of 4203 patients were included. Median TTS was 20 days and 52.4% of patients underwent surgery within 3 weeks. Median TTR was 20 days and 24.6% of patients started radiotherapy within 4 weeks and 84.2% within 6 weeks after surgery. Median TTC was 28 days and 62.6% of patients received chemotherapy within 4 weeks and 91.8% within 6 weeks after radiotherapy. After case-mix correction, three (16.7%) neurosurgical hospitals had significantly more patients with longer than expected TTS. Three (10.7%) and one (3.6%) radiotherapy hospitals had significantly more patients with longer than expected TTR for >4 and >6 weeks, respectively. In seven (21.2%) chemotherapy hospitals, significantly less patients with TTC >4 weeks were observed than expected. In four (12.1%) chemotherapy hospitals, significantly more patients with TTC >4 weeks were observed than expected. CONCLUSION Between-hospital variation in timings to multidisciplinary treatment was observed in glioblastoma care in the Netherlands. A substantial percentage of patients experienced timings longer than anticipated.

BACKGROUND Besides early tumour progression, standard first-line radiation with concurrent and adjuvant temozolomide in de novo glioblastoma patients is abrogated frequently by severe haematological toxicity. This leads to treatment delays with unknown effect on efficacy and to more hospital visits with increased disease burden. In the present study, we identified clinical and pharmacological risk factors for temozolomide induced severe hematological toxicity. Furthermore, we describe the burden of toxicity for patients and evaluate the effect of severe toxicity on prognosis. METHODS A retrospective cohort study of adult patients with a histological confirmed glioblastoma (n=363), treated with standard treatment regimen at the Brain Tumor Center Amsterdam between 2000 and -2020. Severe haematological toxicity was defined as a CTCAE (version 5.0) grade ≥3. We used Pearson Chi-Square test to analyze differences in patient characteristics between the groups (no vs. severe toxicity) and paired samples T- Test to analyze fluctuations in cell counts. Univariate and multivariate logistic regression were used to identify patient- and treatment characteristics associated with severe hematological toxicity. Cox Proportional Hazards models were used to estimate Hazard Ratio’s for the association between survival and severe hematological toxicity. RESULTS Female gender (OR 8.05, 95%CI 2.96–21.89, p 70 years; OR 2.44, 95%CI 1.12–5.31, p=0.025) were independent risk factors for severe toxicity. Concurrent and adjuvant temozolomide was discontinued in respectively 56% and 35% of the patients. In general, patients with severe hematological toxicity had a treatment delay of 22 ± 48 days. Of all patients with severe hematological toxicity during chemoradiation, 96% developed toxicity after ≥4 weeks of treatment (p CONCLUSION Female gender and age >70 years are risk factors for severe hematological toxicity. Severe hematological toxicity relates to temozolomide exposure and results in a significant treatment burden for patients. Low temozolomide exposure results in decreased survival. Patient tailored therapy may result in better treatment outcomes.

BACKGROUND Over the past years, increasing worldwide attention towards centralization of complex cancer care has been pursued as higher volume centers have shown improved outcomes. Changes in distribution of care and the impact on travel distance in glioblastoma patients have not been determined yet. In this study, we determine trends in distribution of glioblastoma care in the Netherlands over the last three decades and assess whether the observed trends affected travel distance for individual patients. MATERIAL AND METHODS Data were obtained from the Dutch Brain Tumor Registry from 1989 to 2018. All glioblastoma patients (≥18 years) were included for analysis. Patients, neurosurgical centers and radiotherapy centers were geocoded. Data were analyzed in six time intervals of 5 years. High volume hospitals were defined as >50 cases per year. Travel distance was examined in two categories, ≤60km and >60km respectively. Trend analyses for proportions were used to analyze hospital volume changes and travel distances. RESULTS A total of 16.477 glioblastoma patients were registered, with an annual increase from 203 patients in 1989 to 917 patients in 2018. Neurosurgical centers increased from 16 to 17 and for radiotherapy from 19 to 22 centers between 1989–1993 and 2014–2018. Mean neurosurgical- and radiotherapy center volumes increased from 12 to 39 (P=0.025) and 7 to 27 (P=0.025) patients per hospital per year from 1989–1993 to 2014–2018. High volume neurosurgical centers were observed since 2004, and an increased number of patients were treated in these centers, 27.8%, 52.6% and 64.1% in the time periods 2004–2008, 2009–2013, and 2014–2018 (P60km to the neurosurgical center reduced from 15.8% to 13.2% (P=0.033). Travel distance >60km to the radiotherapy center did not reduce significantly (10.4% to 8.8%, P=0.601). CONCLUSION An increasing number of glioblastoma patients were differentially treated in high volume neurosurgery and radiotherapy centers. The observation that this did not translate into increased travel distances, indicates accessible specialized Neuro-Oncology care for glioblastoma patients in The Netherlands.

PURPOSE: To measure between-hospital variation in risk-standardized survival outcome after glioblastoma surgery and to explore the association between survival and hospital characteristics in conjunction with patient-related risk factors. METHODS: Data of 2,409 adults with first-time glioblastoma surgery at 14 hospitals were obtained from a comprehensive, prospective population-based Quality Registry for Neurological Surgery in the Netherlands between 2011 and 2014. We compared the observed survival with patient-specific risk-standardized expected early (30-day) mortality and expected late (2-year) survival, based on patient age, performance status, and year of treatment. Summarized outcomes per hospital were analyzed in funnel plots. Hospital characteristics were analyzed in logistic regression and Cox proportional hazards models. RESULTS: Overall 30-day mortality was 5.2% and overall 2-year survival was 13.5%. Median overall survival varied between 4.8 and 14.9 months among hospitals, and biopsy percentages ranged between 16% and 73%. One hospital had lower than expected early mortality, and four hospitals had lower than expected late survival. Higher hospital volume was related with lower early mortality (P=0.031). A 10% increase in volume was associated with 3.9% relative decrease in early mortality, but not with overall survival. Patient-related risk factors (lower age; better performance; more recent years of treatment) were significantly associated with longer overall survival. Of the hospital characteristics, longer overall survival was associated with lower biopsy percentage (HR: 2.09, 1.34–3.26, P=0.001), and not with academic setting (HR: 0.951, 0.858–1.05), nor with hospital volume (HR: 0.954, 0.866–1.05). CONCLUSION: Hospitals vary more in late survival than early mortality after glioblastoma surgery. Widely varying biopsy percentages indicate treatment variation. Patient-related factors have a stronger association with overall survival than hospital-related factors.

BACKGROUND Our previous study among 195 low-grade glioma (LGG) patients six years after initial diagnosis, showed that high radiation doses (>2 Gy) were associated with neurocognitive disability. Follow-up at 12 years in 64 LGG patients showed patients without radiotherapy to have stable neurocognitive and radiological status while attentional functioning deteriorated between 6 and 12 years in irradiated patients. The present assessment at a mean of 26 years after initial diagnosis and treatment, investigates the neurocognitive sequelae of radiotherapy in long-term survivors. METHODS Patients who were alive since the 12 year follow-up were invited for assessment of the same neurocognitive domains as tested at 6 and 12 years: attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed. Using a mixed model, standardized scores of neurocognitive performance were compared between treatment (radiotherapy versus no radiotherapy) and over time. FINDINGS: 32 patients, of whom 13 (41%) had received radiotherapy, completed the assessment at a mean of 26 years (range 20–35 years) after initial diagnosis. Patients who had radiotherapy had more attentional deficits at the present assessment, than those who did not (–1·0 [SD 1·6] vs 0·33 [0·65], p=0·01; mean difference 1·3, 95% CI 0·3–2·3). Furthermore, patients who had radiotherapy had reduced attentional functioning over time (p=0·03), regardless of antiepileptic drug use. Three (23%) patients who had radiotherapy developed neurocognitive disabilities deficits in at least four of the 20 neuropsychological test parameters compared with five (26%) patients who did not have radiotherapy. INTERPRETATION: Extreme long-term, and probably surviving LGG patients who had radiotherapy show relatively stable and adequate neurocognitive functioning when compared to patients who did not have radiotherapy. Apart from attentional functioning, no progression of neurocognitive deficits at 26 years after initial diagnosis were found.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutation (IDH-mut) is an important marker for survival in diffuse glioma patients. Patients with an IDH-mut glioma have a better prognosis but more often suffer from epilepsy. Patients with a wildtype glioma (IDH-wt) are generally older and more often have cognitive deficits. Regardless of IDH status, cognitive deficits in glioma patients are associated with altered functional connectivity throughout the brain as calculated through statistical correlations between regional neurophysiological activity patterns measured with magnetoencephalography (MEG). Cognitive variation in glioma patients is specifically related to altered theta (4–8 Hz) and alpha (8–13 Hz) band functional connectivity. We investigated whether global brain functional connectivity differs between patients with an IDH-mut and IDH-wt diffuse glioma, and whether this measure reflects variations in cognitive functioning in these subpopulations beyond the associated differences in age and epilepsy. MATERIAL AND METHODS: IDH mutation status was determined in 54 diffuse glioma patients via immunohistochemistry (31 IDH-mut, 23 IDH-wt). We recorded MEG and patients underwent cognitive testing. Global functional connectivity between 78 atlas regions spanning the entire cortex was calculated in the theta and alpha frequency bands. Group differences in cognition and global functional connectivity were tested. Next, the association between functional connectivity and cognitive performance was tested. RESULTS: As expected, patients with IDH-mut glioma were younger (P = 0.001) and more often had epilepsy (P = 0.010). Patients with IDH-wt glioma showed poorer verbal memory (P = 0.027, corrected for age, education and presence of epilepsy). More importantly, patients with IDH-wt glioma had lower functional connectivity in the alpha band than patients with IDH-mut glioma (P = 0.015, corrected for age and presence of epilepsy). Alpha band functional connectivity was positively associated with executive functioning (P = 0.049) and information processing speed (P = 0.009), regardless of IDH status and corrected for age, education, and presence of epilepsy. CONCLUSION: These results suggest that global functional connectivity is lower in patients with IDH-wt diffuse glioma compared to patients with IDH-mut diffuse glioma. Moreover, functional connectivity relates to cognitive performance in both IDH-wt and IDH-mut diffuse glioma patients, regardless of age, education and presence of epilepsy. These findings contribute to our understanding of cognitive functioning in patients with diffuse glioma in general, and cognitive deficits in patients with IDH-wt glioma specifically.

The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small-molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCbeta, and PDGFR.

BACKGROUND: Cognition is often affected in patients with brain tumors. Apart from language function, direct tumor effects on discrete cognitive functions have barely been studied. In this study, we quantify baseline cognitive functioning in seven cognitive domains and identify brain locations involved in these cognitive domains using tumor localization maps (TLMs), which is a new approach. METHODS: Adult patients with glioma treated at the VU University Medical Center between 2006-2011 with available preoperative neuropsychological assessment were included. Cognition was tested for verbal, visuospatial and working memory, attention, executive functioning, information processing speed, and visuoconstructive abilities. Cognitive performance was compared to matched healthy controls. Tumor volumes for TLMs were segmented on MRI fluid attenuated inversion recovery (FLAIR) hyperintense signal abnormality for low-grade gliomas, and MRI T1 contrast-enhanced abnormality for high-grade gliomas. For each cognitive domain, we applied TLMs to link cognitive performance with location throughout the brain at 1 mm resolution. Considerations for spatial dependence and multiple comparisons were taken into account. PRELIMINARY RESULTS: Seventy-four patients (50 with low-grade glioma, 22 with high-grade glioma and 2 with other histology) were included so far. Mean age of patients was 40 years. Compared to healthy controls, preoperative cognitive functioning was significantly impaired in five of seven domains. Most frequently affected were attention and working memory (30% and 21% of patients, respectively). We found no differences in cognitive domain scores between patients with low-grade and high-grade glioma. Tumor localization maps are currently being processed and statistically compared voxel-wise for each of the seven cognitive domains. Preliminary results of the TLMs demonstrate that performance in specific cognitive domains is associated with specific brain tumor locations. CONCLUSION: Empirical evidence on location of cognition can be used for optimizing brain tumor surgery and be integrated in counseling and cognitive rehabilitation for patients with newly-diagnosed glioma.