External validation of the lung-molGPA to predict survival in patients treated with stereotactic radiotherapy for brain metastases of non-small cell lung cancer.

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.

Practice variation in re-resection for recurrent glioblastoma: A nationwide survey among Dutch neuro-oncology specialists.

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, 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.

Combined molecular subtyping, grading, and segmentation of glioma using multi-task deep learning.

BACKGROUND: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is time-consuming. Previously, deep learning methods have been developed that can either non-invasively predict the genetic or histological features of glioma, or that can automatically delineate the tumor, but not both tasks at the same time. Here, we present our method that can predict the molecular subtype and grade, while simultaneously providing a delineation of the tumor. METHODS: We developed a single multi-task convolutional neural network that uses the full 3D, structural, preoperative MRI scans to predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using a patient cohort containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes. RESULTS: In the independent test set, we achieved an IDH-AUC of 0.90, an 1p/19q co-deletion AUC of 0.85, and a grade AUC of 0.81 (grade II/III/IV). For the tumor delineation, we achieved a mean whole tumor Dice score of 0.84. CONCLUSIONS: We developed a method that non-invasively predicts multiple, clinically relevant features of glioma. Evaluation in an independent dataset shows that the method achieves a high performance and that it generalizes well to the broader clinical population. This first-of-its-kind method opens the door to more generalizable, instead of hyper-specialized, AI methods.

Cost-Utility of the eHealth Application 'Oncokompas', Supporting Incurably Ill Cancer Patients to Self-Manage Their Cancer-Related Symptoms: Results of a Randomized Controlled Trial.

Evidence on the cost-effectiveness of eHealth in palliative care is scarce. Oncokompas, a fully automated behavioral intervention technology, aims to support self-management in cancer patients. This study aimed to assess the cost-utility of the eHealth application Oncokompas among incurably ill cancer patients, compared to care as usual. In this randomized controlled trial, patients were randomized into the intervention group (access to Oncokompas) or the waiting-list control group (access after three months). Healthcare costs, productivity losses, and health status were measured at baseline and three months. Intervention costs were also taken into account. Non-parametric bootstrapping with 5000 replications was used to obtain 95% confidence intervals around the incremental costs and quality-adjusted life years (QALYs). A probabilistic approach was used because of the skewness of cost data. Altogether, 138 patients completed the baseline questionnaire and were randomly assigned to the intervention group (69) or the control group (69). In the base case analysis, mean total costs and mean total effects were non-significantly lower in the intervention group (-€806 and -0.01 QALYs). The probability that the intervention was more effective and less costly was 4%, whereas the probability of being less effective and less costly was 74%. Among patients with incurable cancer, Oncokompas does not impact incremental costs and seems slightly less effective in terms of QALYs, compared to care as usual. Future research on the costs of eHealth in palliative cancer care is warranted to assess the generalizability of the findings of this study.

Effect of awake craniotomy in glioblastoma in eloquent areas (GLIOMAP): a propensity score-matched analysis of an international, multicentre, cohort study.

BACKGROUND: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). METHODS: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18-90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0-1 vs ≥2), and preoperative KPS (90-100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. FINDINGS: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0-24·0] vs 14·0 months [13·0-16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0-11·0] vs 7·3 months [6·0-8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0-1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90-100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0-31·0] vs 15·0 months [13·0-17·0]; p<0·0001), an NIHSS score of 0-1 (18·0 months [16·0-31·0] vs 14·0 months [13·0-16·5]; p=0·00047), and KPS of 90-100 (19·0 months [16·0-31·0] vs 14·5 months [13·0-16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0-12·0] vs 7·5 months [6·5-9·0]; p=0·0061), in those with an NIHSS score of 0-1 (9·5 months [9·0-12·0] vs 8·0 months [6·5-9·0]; p=0·0035), and in those with a KPS of 90-100 (10·0 months [9·0-13·0] vs 8·0 months [7·0-9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. INTERPRETATION: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). FUNDING: None.

Between-hospital variation in time to glioblastoma surgery: a report from the Quality Registry Neuro Surgery in the Netherlands.

OBJECTIVE: Patients with glioblastoma are often scheduled for urgent elective surgery. Currently, the impact of the waiting period until glioblastoma surgery is undetermined. In this national quality registry study, the authors determined the wait times until surgery for patients with glioblastoma, the risk factors associated with wait times, and the risk-standardized variation in time to surgery between Dutch hospitals. The associations between time to surgery and patient outcomes were also explored. METHODS: Data from all 4589 patients who underwent first-time glioblastoma surgery between 2014 and 2019 in the Netherlands were collected by 13 hospitals in the Quality Registry Neuro Surgery. Time to surgery comprised 1) the time from first MR scan to surgery (MTS), and 2) the time from first neurosurgical consultation to surgery (CTS). Long MTS was defined as more than 21 days and long CTS as more than 14 days. Potential risk factors were analyzed in multivariable logistic regression models. The standardized rate of long time to surgery was analyzed using funnel plots. Patient outcomes including Karnofsky Performance Scale (KPS) score change, complications, and survival were analyzed by multivariable logistic regression and proportional hazards models. RESULTS: The median overall MTS and CTS were 18 and 9 days, respectively. Overall, 2576 patients (56%) had an MTS within 3 weeks and 3069 (67%) had a CTS within 2 weeks. Long MTS was significantly associated with older age, higher preoperative KPS score, higher American Society of Anesthesiologists comorbidity class, season, lower hospital case volume, university affiliation, and resection. Long CTS was significantly associated with higher baseline KPS score, university affiliation, resection, more recent year of treatment, and season. In funnel plots, considerable practice variation was observed between hospitals in patients with long times to surgery. Fewer patients with KPS score improvement were observed after a long time until resection. Long CTS was associated with longer survival. Complications and KPS score decline were not associated with time to surgery. CONCLUSIONS: Considerable between-hospital variation among Dutch hospitals was observed in the time to glioblastoma surgery. A long time to resection impeded KPS score improvement, and therefore, patients who may improve should be identified for more urgent resection. Longer survival was observed in patients selected for longer time until surgery after neurosurgical consultation (CTS).

Noninvasive differentiation of molecular subtypes of adult nonenhancing glioma using MRI perfusion and diffusion parameters.

Background: Nonenhancing 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 nonenhancing glioma were included, in whom molecular status (including 1p/19q codeletion status and IDH mutation) and preoperative MRI (T2w/FLAIR, dynamic susceptibility-weighted, and diffusion-weighted imaging) were available. Tumors were segmented semiautomatically 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 codeletion, and (n = 18) IDH-wildtype (IDHwt). ANOVA, Kruskal-Wallis, and Chi-Square analyses were performed using SPSS. Results: rCBV (mean, median, 75th and 85th percentile) and ADC (mean, median, 15th and 25th percentile) showed significant differences across molecular profiles (P < .01). Posthoc analyses revealed that IDHwt and IDHmt 1p/19q codeleted 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 < .05. Also, IDHwt tumors showed significantly lower ADC compared to IDHmt 1p/19q codeleted 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 < .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.

Practice Variation in Perioperative Steroid Dosing for Brain Tumor Patients: An International Survey.

OBJECTIVE: Steroids are commonly used to treat peritumoral edema and increased intracranial pressure in patients with brain tumors. Despite widespread use of steroids, relatively little evidence is available about their optimal perioperative dosing scheme. This study aimed to increase insight into practice variation of perioperative steroid dosing and tapering schedules used in the neurosurgical community. METHODS: An electronic survey comprising 27 questions regarding steroid dosing, tapering schedules, and adverse events was administered to neurosurgeons between December 6, 2019, and June 1, 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 6 continents, including 30 from low- or middle-income countries; 152 (87%) respondents completed all questions. Of respondents, 130 (80%) indicated prescribing perioperative steroids. Reported doses ranged from 2 to 64 mg/day in schedules ranging from 1 to 4 times daily. The most prescribed steroid was dexamethasone in doses of 16 mg/day (n = 49; 31%), 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. CONCLUSIONS: Steroids are commonly prescribed perioperatively in patients with brain tumors. However, there is 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 international/national guidelines for steroid use.

The effect of musicality on language recovery after awake glioma surgery.

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 cm3) 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.

Atypical meningioma: patterns of postradiotherapy recurrences.

PURPOSE: There is no consensus on a target definition and optimal dose in radiotherapy for atypical meningioma (AM). Insight into the postradiotherapy recurrence pattern is needed for optimal target definition and local control. The objective was to describe the patterns of recurrence after postoperative or salvage radiotherapy in patients with AM. MATERIALS AND METHODS: A retrospective analysis was conducted of patients treated for intracranial AM with (fractionated) stereotactic radiotherapy (FSRT). The relationships between postradiotherapy recurrences, the dura and irradiated volume were established. Moreover, the dose prescriptions and fractionation schedules were converted to a reference to determine the relationship between dose and local control. RESULTS: The included patients received 57 (F)SRT treatments and 73 surgeries. Recurrent disease was found in 21 of 29 patients (72%) and after 39 of 57 (F)SRTs (68%). The median interval to first recurrence was 39.7 months. Of these recurrences, 25 were in-field, 11 were marginal, and 3 were out of field. In-field recurrence rates after biological equivalent doses < 60 Gy or ≥ 60 Gy were 50% and 21%. All recurrences were connected to the dura. Of the marginal recurrences, 64% were within 2 cm and 91% were within 3 cm of the volume receiving the prescribed dose. CONCLUSIONS: AM frequently recurs after radiotherapy. All postradiotherapy recurrences were connected to the dura. Most marginal recurrences occurred within 3 cm of the irradiated abnormal dura. The lowest rate of in-field recurrences occurred after equivalent doses of least 60 Gy in 2 Gy fractions suggesting a dose-effect relationship.

The DEXA-CORT trial: study protocol of a randomised placebo-controlled trial of hydrocortisone in patients with brain tumour on the prevention of neuropsychiatric adverse effects caused by perioperative dexamethasone.

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.

Topographical Mapping of 436 Newly Diagnosed IDH Wildtype Glioblastoma With vs. Without MGMT Promoter Methylation.

Introduction: O6 -methylguanine-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) mutation status are important prognostic factors for patients with glioblastoma. There are conflicting reports about a differential topographical distribution of glioblastoma with vs. without MGMT promoter methylation, possibly caused by molecular heterogeneity in glioblastoma populations. We initiated this study to re-evaluate the topographical distribution of glioblastoma with vs. without MGMT promoter methylation in light of the updated WHO 2016 classification. Methods: Preoperative T2-weighted/FLAIR and postcontrast T1-weighted MRI scans of patients aged 18 year or older with IDH wildtype glioblastoma were collected. Tumors were semi-automatically segmented, and the topographical distribution between glioblastoma with vs. without MGMT promoter methylation was visualized using frequency heatmaps. Then, voxel-wise differences were analyzed using permutation testing with Threshold Free Cluster Enhancement. Results: Four hundred thirty-six IDH wildtype glioblastoma patients were included; 211 with and 225 without MGMT promoter methylation. Visual examination suggested that when compared with MGMT unmethylated glioblastoma, MGMT methylated glioblastoma were more frequently located near bifrontal and left occipital periventricular area and less frequently near the right occipital periventricular area. Statistical analyses, however, showed no significant difference in topographical distribution between MGMT methylated vs. MGMT unmethylated glioblastoma. Conclusions: This study re-evaluated the topographical distribution of MGMT promoter methylation in 436 newly diagnosed IDH wildtype glioblastoma, which is the largest homogenous IDH wildtype glioblastoma population to date. There was no statistically significant difference in anatomical localization between MGMT methylated vs. unmethylated IDH wildtype glioblastoma.

Evidence-based dexamethasone dosing in malignant brain tumors: what do we really know?

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.

Complications corner: Anterior thoracic disc surgery with dural tear/CSF fistula and low-pressure pleural drain led to severe intracranial hypotension.

BACKGROUND: Thoracic disc surgery can lead to a life-threatening complication: intracranial hypotension due to a subarachnoid-pleural fistula. CASE DESCRIPTION: We report a 63-year-old male with paraparesis due to multiple herniated thoracic discs, with compressive myelopathy. The patient required a circumferential procedure including a laminectomy/fusion followed by an anterior thoracic decompression to address both diffuse idiopathic skeletal hyperostosis (DISH) anteriorly and posterior stenosis. The postoperative course was complicated by severe intracranial hypotension attributed to the erroneous placement of a low-pressure drain placed in the pleural cavity instead of a lumbar drain; this resulted in subdural hematoma's necessitating subsequent surgery. CONCLUSION: Severe neurological deterioration occurring after thoracic decompressive surgery may rarely be attributed to intracranial hypotension due to a subarachnoid-pleural fistula. Patients should be treated with external lumbar drainage of cerebrospinal fluid for 3-5 days rather than a low-pressure pleural drain to avoid the onset of intracranial hypotension leading to symptomatic subdural hematomas.

Bone marrow stromal cell-mediated tissue sparing enhances functional repair after spinal cord contusion in adult rats.

Bone marrow stromal cell (BMSC) transplantation has shown promise for repair of the spinal cord. We showed earlier that a BMSC transplant limits the loss of spinal nervous tissue after a contusive injury. Here, we addressed the premise that BMSC-mediated tissue sparing underlies functional recovery in adult rats after a contusion of the thoracic spinal cord. Our results reveal that after 2 months BMSCs had elicited a significant increase in spared tissue volumes and in blood vessel density in the contusion epicenter. A strong functional relationship existed between spared tissue volumes and blood vessel density. BMSC-transplanted rats exhibited significant improvements in motor, sensorimotor, and sensory functions, which were strongly correlated with spared tissue volumes. Retrograde tracing revealed that rats with BMSCs had twice as many descending brainstem neurons with an axon projecting beyond the contused spinal cord segment and these correlated strongly with the improved motor/sensorimotor functions but not sensory functions. Together, our data indicate that tissue sparing greatly contributes to BMSC-mediated functional repair after spinal cord contusion. The preservation/formation of blood vessels and sparing/regeneration of descending brainstem axons may be important mediators of the BMSC-mediated anatomical and functional improvements.

A clinical perspective of spinal cord injury.

Spinal cord injury (SCI) results in loss of nervous tissue in the spinal cord and consequently loss of motor and sensory function. The impairments are permanent because endogenous repair events fail to restore the damaged axonal circuits that are involved in function. There is no treatment available that restores the injury-induced loss of function. The consequences of SCI are devastating physically and socially. The assessment of functional loss after SCI has been standardized in the larger part of the world. For medical care however there are no standards available. During the early phase, treatments that stabilize the patient's health and attempt to limit further neurological deterioration need to be implemented. During the later phase of SCI, the focus needs to be on prevention and/or treatment of secondary complications such as pain, pressure ulcers, and infections. Neuroprotective, axon growth-promoting and rehabilitative repair approaches are currently being tested but, so far, none of these has emerged as an effective treatment that reverses the consequences of SCI. Promising new repair approaches have emerged from the laboratory during the last years and entered the clinical arena including stem cell transplantation and functional electrical stimulation.

Effect of electromagnetic-navigated shunt placement on failure rates: a prospective multicenter study.

OBJECT: As many as 40% of shunts fail in the first year, mainly due to proximal obstruction. The role of catheter position on failure rates has not been clearly demonstrated. The authors conducted a prospective cohort study of navigated shunt placement compared with standard blind shunt placement at 3 European centers to assess the effect on shunt failure rates. METHODS: All adult and pediatric patients undergoing de novo ventriculoperitoneal shunt placement were included (patients with slit ventricles were excluded). The first cohort underwent standard shunt placement using anatomical landmarks. All centers subsequently adopted electromagnetic (EM) navigation for routine shunt placements, forming the second cohort. Catheter position was graded on postoperative CT in both groups using a 3-point scale developed for this study: (1) optimal position free-floating in CSF; (2) touching choroid or ventricular wall; or (3) intraparenchymal. Episodes and type of shunt revision were recorded. Early shunt failure was defined as that occurring within 30 days of surgery. Patients with shunts were followed-up for 12 months in the standard group, for a median of 6 months in the EM-navigated group, or until shunt failure. RESULTS: A total of 75 patients were included in the study, 41 with standard shunts and 34 with EM-navigated shunts. Seventy-four percent of navigated shunts were Grade 1 compared with 37% of the standard shunts (p=0.001, chi-square test). There were no Grade 3 placements in the navigated group, but 8 in the standard group, and 75% of these failed. Early shunt failure occurred in 9 patients in the standard group and in 2 in the navigated group, reducing the early revision rate from 22 to 5.9% (p=0.048, Fisher exact test). Early shunt failures were due to proximal obstruction in 78% of standard shunts (7 of 9) and in 50% of EM-navigated shunts (1 of 2). CONCLUSIONS: Noninvasive EM image guidance in shunt surgery reduces poor shunt placement, resulting in a significant decrease in the early shunt revision rate.

Positron emission tomography for serial imaging of the contused adult rat spinal cord.

We investigated whether small-animal positron emission tomography (PET) could be used in combination with computed tomography (CT) imaging techniques for longitudinal monitoring of the injured spinal cord. In adult female Sprague-Dawley rats (n = 6), the ninth thoracic (T9) spinal cord segment was exposed by laminectomy and subsequently contused using the Infinite Horizon impactor (Precision System and Instrumentation, Lexington, KY) at 225 kDyn. In control rats (n = 4), the T9 spinal cord was exposed by laminectomy but not contused. At 0.5 hours and 3, 7, and 21 days postinjury, 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) was given intravenously followed 1 hour later by sequential PET and CT. Regions of interest (ROIs) at T9 (contused) and T6 (uninjured) spinal cord segments were manually defined on CT images and aided by fiduciary markers superimposed onto the coregistered PET images. Monte Carlo simulation revealed that about 33% of the activity in the ROIs was due to spillover from adjacent hot areas. A simulation-based partial-volume compensation (PVC) method was developed and used to correct for this spillover effect. With PET-CT, combined with PVC, we were able to serially measure standardized uptake values of the T9 and T6 spinal cord segments and reveal small, but significant, differences. This approach may become a tool to assess the efficacy of spinal cord repair strategies.

Reducing macrophages to improve bone marrow stromal cell survival in the contused spinal cord.

We tested whether reducing macrophage infiltration would improve the survival of allogeneic bone marrow stromal cells (BMSC) transplanted in the contused adult rat thoracic spinal cord. Treatment with cyclosporine, minocycline, or methylprednisolone all resulted in a significant decrease in macrophage infiltration at 3 days postinjury. However, when BMSC were injected at that time point, survival 7 days later was similar between treatment groups and saline-injected controls. In fact, we found that the presence of BMSC resulted in a significant increase in macrophage infiltration into the contusion.

Bone marrow stromal cells elicit tissue sparing after acute but not delayed transplantation into the contused adult rat thoracic spinal cord.

Bone marrow stromal cells (BMSC) transplanted into the contused spinal cord may support repair by improving tissue sparing. We injected allogeneic BMSC into the moderately contused adult rat thoracic spinal cord at 15 min (acute) and at 3, 7, and 21 days (delayed) post-injury and quantified tissue sparing and BMSC survival up to 4 weeks post-transplantation. BMSC survival within the contusion at 7 days post-transplantation was significantly higher with an acute injection (32%) and 3-day delayed injection (52%) than with a 7- or 21-day delayed injection (9% both; p < 0.01). BMSC survival at 28 days post-transplantation was close to 0 in all paradigms, indicating rejection. In contused rats without a BMSC transplant (controls), the volume of spared tissue gradually decreased until 46% (p < 0.001) of the volume of a comparable uninjured spinal cord segment at 49 days post-injury. In rats with BMSC, injected at 15 min, 3, or 7 days post-injury, spared tissue volume was significantly higher in grafted rats than in control rats at the respective endpoints (i.e., 28, 31, and 35 days post-injury). Acute and 3-day delayed but not 7- and 21-day delayed injection of BMSC significantly improved tissue sparing, which was strongly correlated (r = 0.79-1.0) to BMSC survival in the first week after injection into the contusion. Our data showed that neuroprotective effects of BMSC transplanted into a moderate rat spinal cord contusion depend strongly on their survival during the first week post-injection. Acutely injected BMSC elicit more tissue sparing than delayed injected BMSC.