BackgroundGlioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms... Show moreBackgroundGlioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood.ObjectivesTo identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq).MethodsThe tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis.ResultsOf the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls.ConclusionShh signaling may be involved in the development of glioblastoma-related VTE. Show less
BackgroundFocused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting... Show moreBackgroundFocused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this.Objectives and methodsA comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools.ResultsIn total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint.ConclusionFUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology. Show less
Solinge, T.S.V.; Friis, K.P.; O'Brien, K.; Verschoor, R.L.; Aarle, J. van; Koekman, A.; ... ; Broekman, M. 2023
In glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors... Show moreIn glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors influencing cellular uptake of liposomes in glioma cells are poorly understood. Heparin and heparin analogues are commonly used in glioma patients to decrease the risk of thrombo-embolic events. Our results show that heparin inhibits pegylated liposome uptake by U87 glioma and GL261 cells in a dose dependent manner in vitro, and that heparin-mediated inhibition of uptake required presence of fetal bovine serum in the media. In a subcutaneous model of glioma, Cy5.5 labeled liposomes could be detected with in vivo imaging after direct intra-tumoral injection. Ex-vivo analysis with flow cytometry showed a decreased uptake of liposomes into tumor cells in mice treated systemically with heparin compared to those treated with vehicle only. Show less
Background Despite current best treatment options, a glioblastoma almost inevitably recurs after primary treatment. However, in the absence of clear evidence, current guidelines on recurrent... Show moreBackground Despite current best treatment options, a glioblastoma almost inevitably recurs after primary treatment. However, in the absence of clear evidence, current guidelines on recurrent glioblastoma are not well-defined. Re-resection is one of the possible treatment modalities, though it can be challenging to identify those patients who will benefit. Therefore, treatment decisions are made based on multidisciplinary discussions. This study aimed to investigate the current practice variation between neuro-oncology specialists. Methods In this nationwide study among Dutch neuro-oncology specialists, we surveyed possible practice variation. Via an online survey, 4 anonymized recurrent glioblastoma cases were presented to neurosurgeons, neuro-oncologists, medical oncologists, and radiation oncologists in The Netherlands using a standardized questionnaire on whether and why they would recommend a re-resection or not. The results were used to provide a qualitative analysis of the current practice in The Netherlands. Results The survey was filled out by 56 respondents, of which 15 (27%) were neurosurgeons, 26 (46%) neuro-oncologists, 2 (4%) medical oncologists, and 13 (23%) radiation oncologists. In 2 of the 4 cases, there appeared to be clinical equipoise. Overall, neurosurgeons tended to recommend re-resection more frequently compared to the other specialists. Neurosurgeons and radiation oncologists showed opposite recommendations in 2 cases. Conclusions This study showed that re-resection of recurrent glioblastoma is subject to practice variation both between and within neuro-oncology specialties. In the absence of unambiguous guidelines, we observed a relationship between preferred practice and specialty. Reduction of this practice variation is important; to achieve this, adequate prospective studies are essential. Show less
Kapteijn, M.Y.; Kaptein, F.H.J.; Stals, M.A.M.; Klaase, E.E.; Eijk, R. van; Ruano, D.; ... ; Garcia-Ortiz, I. 2023
Background and objectives: Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the role of underlying genetic risk factors remains largely unknown.... Show moreBackground and objectives: Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the role of underlying genetic risk factors remains largely unknown. Therefore, the aim of this study was to discover whether genetic aberrations in glioblastoma associate with VTE risk.Methods: In this cohort study, all consecutive patients diagnosed with glioblastoma in two Dutch hospitals be-tween February 2017 and August 2020 were included. Targeted DNA next-generation sequencing of all glio-blastomas was performed for diagnostic purposes and included mutational status of the genes ATRX, BRAF, CIC, FUBP1, H3F3A, IDH1, IDH2, PIK3CA, PTEN and TP53 and amplification/gain or deletion of BRAF, CDKN2A, EGFR, NOTCH1 and PTEN. The primary outcome was VTE within three months before glioblastoma diagnosis until two years after. Cumulative incidences were determined using competing risk analysis adjusting for mor-tality. Univariable Cox regression analysis was performed to determine hazard ratios.Results: From 324 patients with glioblastoma, 25 were diagnosed with VTE. Patients with a CDKN2A deletion had a 12-month adjusted cumulative incidence of VTE of 12.5 % (95%CI: 7.3-19.3) compared with 5.4 % (95%CI: 2.6-9.6) in patients with CDKN2A wildtype (p = 0.020), corresponding to a HR of 2.53 (95%CI: 1.12-5.73, p = 0.026). No significant associations were found between any of the other investigated genes and VTE.Conclusion: This study suggests a potential role for CDKN2A deletion in glioblastoma-related VTE. Therefore, once independently validated, CDKN2A mutational status may be a promising predictor to identify glioblastoma patients at high risk for VTE, who may benefit from thromboprophylaxis. Show less
Glioma, a malignant brain tumor, is a serious condition with a large impact on patients’ life expectancy and Health-Related Quality of Life (HRQoL). This thesis aimed to improve knowledge on the... Show moreGlioma, a malignant brain tumor, is a serious condition with a large impact on patients’ life expectancy and Health-Related Quality of Life (HRQoL). This thesis aimed to improve knowledge on the prediagnostic symptoms, tmeasurement of HRQoL and care in the end-of-life phase of glioma patients.Regarding prediagnostic symptoms in glioma patients, it was found that several symptoms such as fatigue or headache were relatively common before diagnosis, but not more common than in patients with other conditions. Therefore, identification of patients with glioma in general practice based on their symptomatology seems extremely difficult.For the measurement of HRQoL in glioma it was demonstrated that patients, proxies and healthcare neuro-oncology professionals were overall positive about their routine implementation of its assessment in clinical practice. Regarding the timing of the measurements, the scores were not influenced by assessment either before or after the consultation with the physician.With respect to the optimization of care in the end-of-life phase, a feasibility study on the disease-specific Advanced Care Program was conducted among patients with glioblastoma, the most malignant type of glioma and their nearest. The relatively positive results of that study in terms of satisfaction warrant the need for a larger, controlled study. Show less
Background Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The... Show moreBackground Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. Methods The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. Discussion The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. Trial registration: ClinicalTrials.gov Identifier: NCT05186064. Show less
Purpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to... Show morePurpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to compare the use of laboratory tests in the perioperative care of glioblastoma patients between two tertiary academic centers-Brigham and Women's Hospital (BWH), Boston, USA, and University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. Methods All glioblastoma patients treated according to standard-of-care between 2005 and 2013 were included. We compared the number of blood drawings and laboratory tests performed during the 70-day perioperative period using a Poisson regression model, as well as the estimated laboratory costs per patient. Additionally, we compared the likelihood of an abnormal test result using a generalized linear mixed effects model. Results After correction for age, sex, IDH1 status, postoperative KPS score, length of stay, and survival status, the number of blood drawings and laboratory tests during the perioperative period were 3.7-fold (p < 0.001) and 4.7-fold (p < 0.001) higher, respectively, in BWH compared to UMCU patients. The estimated median laboratory costs per patient were 82 euros in UMCU and 256 euros in BWH. Furthermore, the likelihood of an abnormal test result was lower in BWH (odds ratio [OR] 0.75, p < 0.001), except when the prior test result was abnormal as well (OR 2.09, p < 0.001). Conclusions Our results suggest a substantially lower clinical threshold for ordering laboratory tests in BWH compared to UMCU. Further investigating the clinical consequences of laboratory testing could identify over and underuse, decrease healthcare costs, and reduce unnecessary discomfort that patients are exposed to. Show less
Clement, P.M.J.; Dirven, L.; Eoli, M.; Sepulveda-Sanchez, J.M.; Walenkamp, A.M.E.; Frenel, J.S.; ... ; Bent, M.J. van den 2021
Background: In the EORTC 1410/ INTELLANCE 2 randomised, phase II study (NCT02343406), with the antibody-edrug conjugate depatuxizumab mafodotin (Depatux-M, ABT-414) in patients with recurrent EGFR... Show moreBackground: In the EORTC 1410/ INTELLANCE 2 randomised, phase II study (NCT02343406), with the antibody-edrug conjugate depatuxizumab mafodotin (Depatux-M, ABT-414) in patients with recurrent EGFR-amplified glioblastoma, the primary end-point (overall survival) was not met, and the drug had ocular dose-limiting toxicity. This study reports results from the prespecified health-related quality of life (HRQoL) and neurological deterioration-free survival (NDFS) exploratory analysis.Patients and methods: Patients (n Z 260) were randomised 1:1:1 to receive either Depatux-M 1.25 mg/kg or 1.0 mg/kg intravenously every 2 weeks with oral temozolomide (TMZ) 150 mg/ m(2), Depatux-M alone, or TMZ or oral lomustine (CCNU) 110 mg/ m(2) ( TMZ/CCNU). HRQoL outcomes were recorded using the EORTC core Quality of Life QLQ-C30, and brain cancer-specific QLQ-BN20 questionnaires. Questionnaires were completed at baseline, weeks 8 and 16, and month 6, and changes from baseline to each time point were calculated. NDFS was defined as time to first deterioration in World Health Organisation performance status.Results: Compliance with HRQoL was 88.1% at baseline and decreased to 37.9% at month 6. Differences from baseline between Depatux-M arms and TMZ/CCNU in global health/QoL status throughout treatment did not reach clinical relevance (>= 10 points). Self-reported visual disorders deteriorated to a clinically relevant extent with Depatux-M arms versus TMZ/CCNU at all timepoints (mean differences range: 24.6-35.1 points). Changes from baseline for other HRQoL scales and NDFS were generally similar between treatment arms.Conclusions: Depatux-M had no impact on HRQoL and NDFS in patients with EGFRamplified recurrent glioblastoma, except for more visual disorders, an expected side- effect of the study drug. (C) 2021 Elsevier Ltd. All rights reserved. Show less
Introduction For decisions on glioblastoma surgery, the risk of complications and decline in performance is decisive. In this study, we determine the rate of complications and performance decline... Show moreIntroduction For decisions on glioblastoma surgery, the risk of complications and decline in performance is decisive. In this study, we determine the rate of complications and performance decline after resections and biopsies in a national quality registry, their risk factors and the risk-standardized variation between institutions. Methods Data from all 3288 adults with first-time glioblastoma surgery at 13 hospitals were obtained from a prospective population-based Quality Registry Neuro Surgery in the Netherlands between 2013 and 2017. Patients were stratified by biopsies and resections. Complications were categorized as Clavien-Dindo grades II and higher. Performance decline was considered a deterioration of more than 10 Karnofsky points at 6 weeks. Risk factors were evaluated in multivariable logistic regression analysis. Patient-specific expected and observed complications and performance declines were summarized for institutions and analyzed in funnel plots. Results For 2271 resections, the overall complication rate was 20 % and 16 % declined in performance. For 1017 biopsies, the overall complication rate was 11 % and 30 % declined in performance. Patient-related characteristics were significant risk factors for complications and performance decline, i.e. higher age, lower baseline Karnofsky, higher ASA classification, and the surgical procedure. Hospital characteristics, i.e. case volume, university affiliation and biopsy percentage, were not. In three institutes the observed complication rate was significantly less than expected. In one institute significantly more performance declines were observed than expected, and in one institute significantly less. Conclusions Patient characteristics, but not case volume, were risk factors for complications and performance decline after glioblastoma surgery. After risk-standardization, hospitals varied in complications and performance declines. Show less
Glioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual... Show moreGlioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual patient despite the increasing number of prognostic models. The aim of this study is to systematically review the literature on prognostic modeling in glioblastoma patients. A systematic literature search was performed to identify all relevant studies that developed a prognostic model for predicting overall survival in glioblastoma patients following the PRISMA guidelines. Participants, type of input, algorithm type, validation, and testing procedures were reviewed per prognostic model. Among 595 citations, 27 studies were included for qualitative review. The included studies developed and evaluated a total of 59 models, of which only seven were externally validated in a different patient cohort. The predictive performance among these studies varied widely according to the AUC (0.58-0.98), accuracy (0.69-0.98), and C-index (0.66-0.70). Three studies deployed their model as an online prediction tool, all of which were based on a statistical algorithm. The increasing performance of survival prediction models will aid personalized clinical decision-making in glioblastoma patients. The scientific realm is gravitating towards the use of machine learning models developed on high-dimensional data, often with promising results. However, none of these models has been implemented into clinical care. To facilitate the clinical implementation of high-performing survival prediction models, future efforts should focus on harmonizing data acquisition methods, improving model interpretability, and externally validating these models in multicentered, prospective fashion. Show less
Background It is unknown if the implementation of an advance care planning (ACP) program is feasible in daily clinical practice for glioblastoma patients. We aimed to develop an ACP program and... Show moreBackground It is unknown if the implementation of an advance care planning (ACP) program is feasible in daily clinical practice for glioblastoma patients. We aimed to develop an ACP program and assess the preferred content, the best time to introduce such a program in the disease trajectory, and possible barriers and facilitators for participation and implementation. Methods A focus group with health care professionals (HCPs) and individual semi-structured interviews with patients and proxies (of both living and deceased patients) were conducted. Results All predefined topics were considered relevant by participants, including the current situation, worries/fears, (supportive) treatment options, and preferred place of care/death. Although HCPs and proxies of deceased patients indicated that the program should be implemented relatively early in the disease trajectory, patient-proxy dyads were more ambiguous. Several patient-proxy dyads indicated that the program should be initiated later in the disease trajectory. If introduced early, topics about the end of life should be postponed. A frequently mentioned barrier for participation was that the program would be too confronting, while a facilitator was adequate access to information. Conclusion This study resulted in an ACP program specifically for glioblastoma patients. Although participants agreed on the program content, the optimal timing of introducing such a program was a matter of debate. Our solution is to offer the program shortly after diagnosis but let patients and proxies decide which topics they want to discuss and when. The impact of the program on several patient- and care-related outcomes will be evaluated in the next step. Show less
