Rishi D. S. Nandoe Tewarie’s research while affiliated with Haaglanden Medisch Centrum and other places

Background/Objectives: Neurosurgical resection is the standard treatment for large brain metastases (BMs). Postoperative stereotactic radiotherapy (SRT) is used to reduce local recurrence (LR) but does not always prevent leptomeningeal disease (LMD). This study aims to analyze patterns of tumor recurrence and to identify opportunities for the further improvement of treatment efficacy. Methods: We included 147 patients who underwent resection and SRT for BMs. The distance between the resection cavity target volume and the new tumor growth was calculated. Cox regression analyses were used to assess associations of LMD with various patient characteristics. Results: Median survival after postoperative SRT was 14 months (IQR 6–30) with a 3-year actuarial survival rate of 21%. LR occurred in 20/147 patients (14%). After total resection, LR occurred in 21% of patients after 3 years of follow-up compared to 36% after subtotal resection. Marginal LR occurred in 5/147 patients (3%). LMD was found in 21/147 patients (14%; 3-year actuarial rate, 26%), and it was found more commonly in patients with resected cerebellar metastases (23%; 3-year actuarial rate, 46%) compared to those with cerebral metastases (11%; 3-year actuarial rate 17%) (HR 2.54, 95% CI 1.07–6.04, p = 0.034). Conclusions: This study examined patterns of recurrence after postoperative radiotherapy and its implications for radiation dose, radiation field size, and treatment sequence. Local control was high after total resection. Radiation field size appeared adequate given the low incidence of marginal recurrences. Patients with cerebellar metastases showed an increased risk of LMD, underscoring the need for preventive measures, particularly preoperative SRT.

Background In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. Materials and methods Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). Results The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. Conclusion The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

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 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, four anonymized recurrent glioblastoma cases were presented to neurosurgeons, neuro-oncologists, medical oncologists, and radiation oncologists in the Netherlands using a standardised 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%) neurosurgeons, 26 (46%) neuro-oncologists, 2 (4%) medical oncologists, and 13 (23%) radiation oncologists. In two of the four 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 two 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 of importance; to achieve this, adequate prospective studies are essential.

Introduction Awake craniotomy is increasingly used to resect intrinsic brain tumors while preserving language. The level of musical training might affect the speed and extend of postoperative language recovery, as increased white matter connectivity in the corpus callosum is described in musicians compared to non-musicians. Methods In this cohort study, we included adult patients undergoing treatment for glioma with an awake resection procedure at two neurosurgical centers and assessed language preoperatively (T1) and postoperatively at three months (T2) and one year (T3) with the Diagnostic Instrument for Mild Aphasia (DIMA), transferred to z -scores. Moreover, patients’ musicality was divided into three groups based on the Musical Expertise Criterion (MEC) and automated volumetric measures of the corpus callosum were conducted. Results We enrolled forty-six patients, between June 2015 and September 2021, and divided in: group A (non-musicians, n = 19, 41.3%), group B (amateur musicians, n = 17, 36.9%) and group C (trained musicians, n = 10, 21.7%). No significant differences on postoperative language course between the three musicality groups were observed in the main analyses. However, a trend towards less deterioration of language (mean/SD z -scores) was observed within the first three months on the phonological domain (A: −0.425/0.951 vs. B: −0.00100/1.14 vs. C: 0.0289/0.566, p -value = 0.19) with a significant effect between non-musicians vs. instrumentalists (A: −0.425/0.951 vs. B + C: 0.201/0.699, p = 0.04). Moreover, a non-significant trend towards a larger volume (mean/SD cm ³ ) of the corpus callosum was observed between the three musicality groups (A: 6.67/1.35 vs. B: 7.09/1.07 vs. C: 8.30/2.30, p = 0.13), with the largest difference of size in the anterior corpus callosum in non-musicians compared to trained musicians (A: 3.28/0.621 vs. C: 4.90/1.41, p = 0.02). Conclusion With first study on this topic, we support that musicality contributes to language recovery after awake glioma surgery, possibly attributed to a higher white matter connectivity at the anterior part of the corpus callosum. Our conclusion should be handled with caution and interpreted as hypothesis generating only, as most of our results were not significant. Future studies with larger sample sizes are needed to confirm our hypothesis.

Background Awake craniotomy is used to resect tumor while preserving language. However, differences between patients in post-operative speech/language outcome are observed despite careful intra-operative monitoring. Literature describes improved performance in language tasks during cognitive tests in musicians. Moreover increased white matter connectivity properties in the corpus callosum are described in musicians compared to non-musicians. We hypothesize better recovery of language in musical patients after awake glioma surgery, caused by higher connectivity properties from the corpus callosum. Material and Methods Adult patients undergoing resection for glioma with an awake resection procedure at two neurosurgical centers were prospectively included. Patients without standardized language tests at pre- and post-operative level, with a glioblastoma multiforme (WHO grade 4) or undergoing re-resection were excluded. Language was assessed with the Diagnostic Instrument for Mild Aphasia (DIMA) and corrected for age and education years from a healthy population. The patients’ musical skill was assessed through questionnaires, and divided in groups based on the Musical Expertise Criterion (MEC) which defines musicality based the duration and intensity of musical training. Volumetric measures of the corpus callosum, corrected for total brain volumes, was calculated of each included patient based on the pre-operative structural MRI. Results Forty-six patients, enrolled between June 2015 and September 2019, were followed-up (mean/SD; 240/174 days after craniotomy) and divided in: non-musician (41.3%, n = 19), amateur-musician (34.8%, n=16) and trained-musician (23.9%, n = 11). Overall a decrease in language was observed after craniotomy (mean/SD) of -0.361/0.771. Musical abilities correlated with less decrease in language (mean/SD) when comparing non-musicians (-0.543/0.683) to amateur (-0.272/0.910) and trained (-0.176/0.693) musicians. An increased but non-significant trend (p=0.28) between musicality and corpus callosum / brain ratio (mean/SD) was observed in non-musicians (0.763, 0.718;0.808), amateur musicians (0.792, 0.745;0.838) and trained musicians (0.835, 0.778;0.891). Conclusion Musicality seemed to improve language outcome after awake glioma surgery, possibly attributed due to a higher white matter connectivity in the corpus callosum. Future studies with larger sample sizes are needed to confirm our findings.

Background Non-enhancing glioma typically have a favorable outcome, but approximately 19-44% have a highly aggressive course due to a glioblastoma genetic profile. The aim of this retrospective study is to use physiological MRI parameters of both perfusion and diffusion to distinguish the molecular profiles of glioma without enhancement at presentation. Methods Ninety-nine patients with non-enhancing glioma were included, in whom molecular status (including 1p/19q co-deletion status and IDH mutation) and pre-operative MRI (T2w/FLAIR, dynamic susceptibility weighted and diffusion weighted imaging) were available. Tumors were segmented semi-automatically using ITK-SNAP to derive whole tumor histograms of relative Cerebral Blood Volume (rCBV) and Apparent Diffusion Coefficient (ADC). Tumors were divided into three clinically relevant molecular profiles: IDH mutation (IDHmt) with (n=40) or without (n=41) 1p/19q co-deletion, and (n=18) IDH-wildtype (IDHwt). ANOVA, Kruskal-Wallis and Chi-Square analyses were performed using SPSS. Results rCBV (mean, median, 75 th and 85 th percentile) and ADC (mean, median, 15 th and 25 th percentile) showed significant differences across molecular profiles (p<0.01). Post-hoc analyses revealed that IDHwt and IDHmt 1p/19q co-deleted tumors showed significantly higher rCBV compared to IDHmt 1p/19q intact tumors: mean rCBV (mean, SD) 1.46 (0.59) and 1.35 (0.39) versus 1.08 (0.31), p<0.05. Also, IDHwt tumors showed significantly lower ADC compared to IDHmt 1p/19q co-deleted and IDHmt 1p/19q intact tumors: mean ADC (mean, SD) 1.13 (0.23) versus 1.27 (0.15) and 1.45 (0.20), p<0.001). Conclusions A combination of low ADC and high rCBV, reflecting high cellularity and high perfusion respectively, separates IDHwt from in particular IDHmt 1p/19q intact glioma.

Introduction The synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR overactivation combined with MR underactivation may contribute to the neuropsychiatric adverse effects of dexamethasone. The DEXA-CORT trial aims to reactivate the MR using cortisol to reduce neuropsychiatric adverse effects of dexamethasone treatment. Methods and analysis The DEXA-CORT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients who undergo elective brain tumour resection treated perioperatively with high doses of dexamethasone to minimise cerebral oedema. 180 patients are randomised between treatment with either two times per day 10 mg hydrocortisone or placebo during dexamethasone treatment. The primary study outcome is the difference in proportion of patients scoring ≥3 points on at least one of the Brief Psychiatric Rating Scale (BPRS) questions 5 days postoperatively or earlier at discharge. Secondary outcomes are neuropsychiatric symptoms, quality of sleep, health-related quality of life and neurocognitive functioning at several time points postoperatively. Furthermore, neuropsychiatric history, serious adverse events, prescribed (psychiatric) medication and referrals or evaluations of psychiatrist/psychologist and laboratory measurements are assessed. Ethics and dissemination The study protocol has been approved by the Medical Research Ethics Committee of the Leiden University Medical Center, and by the Dutch competent authority, and by the Institutional Review Boards of the participating sites. It is an investigator-initiated study with financial support by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Brain Foundation. Results of the study will be submitted for publication in a peer-reviewed journal. Trial registration number NL6726 (Netherlands Trial Register); open for patient inclusion. EudraCT number 2017-003705-17.

Objective Steroids are commonly used against peritumoral edema and increased intracranial pressure in brain tumor patients. Despite the widespread use of steroids, relatively little evidence is available about their optimal perioperative dosing scheme. This study aims to increase insight into practice variation of perioperative steroid dosing and tapering schedules used in the neurosurgical community. Methods An electronic survey consisting of 27 questions regarding steroid dosing, tapering schedules, and adverse events was conducted among neurosurgeons between December 6th, 2019 and June 1st, 2020. The survey was distributed through the European Association of Neurosurgical Societies and social media platforms. Collected data were assessed for quantitative and qualitative analysis. Results The survey obtained 175 responses from 55 countries across six continents, including 30 from low- or middle-income countries; 152 (87%) respondents completed all questions. In total, 130 respondents (80%) indicated prescribing perioperative steroids. Reported doses ranged from 2 to 64 mg/day in schedules ranging from one to four times daily. The most prescribed steroid was dexamethasone in a dose of 16 mg/day (n = 49; 31%), followed by 12 mg/day (n = 31; 20%) and 8 mg/day (n = 18; 12%). No significant association was found between prescribed dose and physician and institutional characteristics. Conclusion Steroids are commonly prescribed perioperatively in brain tumor patients. However, there is a great practice variation in dosing and schedules among neurosurgeons. Future investigation in a prospective and preferably randomized manner is needed to identify an optimal dosing scheme and implement (inter)national guidelines for steroid use.

Purpose The present study aims to conduct a systematic review of literature reporting on the dose and dosing schedule of dexamethasone (DXM) in relation to clinical outcomes in malignant brain tumor patients, with particular attention to evidence-based practice. Methods A systematic search was performed in PubMed, Embase, Web of Science, Cochrane, Academic Search Premier, and PsycINFO to identify studies that reported edema volume reduction, symptomatic relief, adverse events and survival in relation to dexamethasone dose in glioma or brain metastasis (BM) patients. Results After screening 1812 studies, fifteen articles were included for qualitative review. Most studies reported a dose of 16 mg, mostly in a schedule of 4 mg four times a day. Due to heterogeneity of studies, it was not possible to perform quantitative meta-analysis. For BMs, best available evidence suggests that higher doses of DXM may give more adverse events, but may not necessarily result in better clinical condition. Some studies suggest that higher DXM doses are associated with shorter survival in the palliative setting. For glioma, DXM may lead to symptomatic improvement, yet no studies directly compare different doses. Results regarding edema reduction and survival in glioma patients are conflicting. Conclusions Evidence on the safety and efficacy of different DXM doses in malignant brain tumor patients is scarce and conflicting. Best available evidence suggests that low DXM doses may be noninferior to higher doses in certain circumstances, but more comparative research in this area is direly needed, especially in light of the increasing importance of immunotherapy for brain tumors.

Despite profound diagnostics, the aetiology of spinal epidural haematoma (SEH) often remains unknown. In this case, diagnostics revealed an SEH at the fifth and sixth thoracic levels due to a subclavian steal syndrome with a tortuous vascular loop between the sixth thoracic intercostal artery and the costocervical arteries deriving from the left subclavian artery with plump arteries in the epidural space. The patient underwent decompression surgery and a percutaneous transluminal angioplasty. The patient showed good recovery at follow-up. The SEH was a result of secondary formed thoracic collateral circuits with epidural involvement due to a subclavian steal syndrome.