Microdiscectomy for sciatica: reality check study of long-term surgical treatment effects of a Lumbosacral radicular syndrome (LSRS).

PURPOSE: It remains unclear whether the long-term results of RCTs regarding the outcome of microdiscectomy for lumbosacral radicular syndrome (LSRS) are generalizable. The purpose of this study was to determine the external validity of the outcome preseneted in RCTs after microdicectomy for LSRS in a patient cohort from a high-volume spine center. METHODS: Between 2007 and 2010, 539 patients had a single level microdiscectomy for MRI disk-related LSRS of whom 246 agreed to participate. Questionnaires included visual analogue scores (VAS) for leg pain, RDQ, OLBD, RAND-36 and Likert scores for recovery, leg and back pain. Lumbar re-operation(s) were registered. RESULTS: Mean age was 51.3, and median time of follow-up was 8.0 years. Re-operation occurred in 64 (26%) patients. Unfavorable perceived recovery was noted in 85 (35%) patients, and they had worse leg and back pain than the 161 (65%) patients with a favorable recovery: median VAS for leg pain 28/100 mm versus 2/100 mm and median VAS for back pain 9/100 mm versus 3/100 mm, respectively. In addition, the median RDQ and OLBD scores differed significantly: 9 vs 3 for RDQ and 26 vs 4 for OLBD, respectively (p < 0.001). CONCLUSION: In this cohort study, the long-term results after microdiscectomy for LSRS were less favorable than those obtained in RCTs, possibly caused by less strict patient selection than in RCTs. Our findings emphasize that patients, who do not meet the same inclusion criteria for surgery as in RCTs, should be informed about the chances of a less favorable result.

Tranexamic acid for chronic subdural hematoma.

BACKGROUND: There is no consensus on optimal treatment for a chronic subdural hematoma (cSDH). In patients with only moderate symptoms treatment with tranexamic acid (TXA) has been suggested. We report off-label use of TXA in seven patients. METHODS: Between August 2016 and May 2018 we identified seven patients for primary conservative treatment with TXA until satisfactory clinical and radiological status was achieved. Primary outcome was surgery for cSDH evacuation. Radiological follow-up was performed at regular intervals for hematoma volume measurements. RESULTS: Five patients experienced complete resolution of symptoms, one patient had a burr-hole craniostomy five days after initiation of TXA treatment due to an increase of left-sided weakness and dysarthria and in one patient symptoms did not improve. Median follow-up was 15 weeks (range 6-25, without the operated patient). The median total volume before start of treatment was 83 mL (range 11-137) for all patients. At the last follow-up, the median total volume in the non-operated patients decreased by 73% to 33 mL (range 0-77). CONCLUSIONS: TXA could be considered as primary medical treatment in patients with a cSDH and mild symptoms. The results of current randomized clinical trials must be awaited.

Neurological recovery after traumatic spinal cord injury: what is meaningful? A patients' and physicians' perspective.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: Most studies on neurological recovery after traumatic spinal cord injury (tSCI) assess treatment effects using the American Spinal Injury Association Impairment Scale (AIS grade) or motor points recovery. To what extent neurological recovery is considered clinically meaningful is unknown. This study investigated the perceived clinical benefit of various degrees of neurological recovery one year after C5 AIS-A tSCI. SETTING: The Netherlands. METHODS: By means of a web-based survey SCI patients and physicians evaluated the benefit of various scenarios of neurological recovery on a scale from 0 to 100% (0% no benefit to 100% major benefit). Recovery to AIS-C and D, was split into C/C+ and D/D+, which was defined by the lower and upper limit of recovery for each grade. RESULTS: A total of 79 patients and 77 physicians participated in the survey. Each AIS grade improvement from AIS-A was considered significant benefit (all p < 0.05), ranging from 47.8% (SD 26.1) for AIS-B to 86.8% (SD 24.3) for AIS-D+. Motor level lowering was also considered significant benefit (p < 0.05), ranging from 66.1% (SD 22.3) for C6 to 81.7% (SD 26.0) for C8. CONCLUSIONS: Meaningful recovery can be achieved without improving in AIS grade, since the recovery of functional motor levels appears to be as important as improving in AIS grade by both patients and physicians. Moreover, minor neurological improvements within AIS-C and D are also considered clinically meaningful. Future studies should incorporate more detailed neurological outcomes to prevent potential underestimation of neurological recovery by only using the AIS grade.

Do older patients with acute or subacute subdural hematoma benefit from surgery?

PURPOSE: According to the international guidelines, acute subdural hematomas (aSDH) with a thickness of >10 mm, or causing a midline shift of >5 mm, should be surgically evacuated. However, high mortality rates in older patients resulted in ongoing controversy whether elderly patients benefit from surgery. We identified predictors of outcome in a single-centre cohort of elderly patients undergoing surgical evacuation of aSDH or subacute subdural hematoma (saSDH). MATERIALS AND METHODS: This retrospective study included all patients aged ≥65 years undergoing surgical evacuation of aSDH/saSDH from 2000 to 2015. One-year outcome was dichotomized into favourable (Glasgow Outcome Scale (GOS) 4-5) and unfavourable (GOS 1-3). Predictors of outcome were identified by analysing patient characteristics. RESULTS: Eighty-four patients aged ≥65 years underwent craniotomy for aSDH/saSDH during the 16 year time period. Twenty-five percent regained functional independence, 11% survived severely disabled, and 64% died. Most patients died of respiratory failure following withdrawal of artificial respiration or following restriction of treatment. Age of the SDH or Glasgow Coma Scores ≤8/intubation did not predict unfavourable outcome. All patients with bilaterally absent pupillary light reflexes died, also those who still exhibited one normal-sized pupil. CONCLUSION: The low number of operated patients per year probably suggests that this cohort represents a selection of patients who were judged to have good chances of favouring from surgery. Functional independence at one-year follow-up was reached in 25% of patients, 64% died. Patients with bilaterally absent pupillary light reflexes did not benefit from surgery. The tendency to restrict treatment because of presumed poor prognosis may have acted as a self-fulfilling prophecy.

External validation of the diffuse intrinsic pontine glioma survival prediction model: a collaborative report from the International DIPG Registry and the SIOPE DIPG Registry.

We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age <3 years, longer symptom duration and receipt of chemotherapy as favorable predictors, and presence of ring-enhancement on MRI as unfavorable predictor. Model performance was evaluated by analyzing the discrimination and calibration abilities. External validation was performed using an unselected cohort from the International DIPG Registry, including patients from United States, Canada, Australia and New Zealand. Basic comparison with the results of the original study was performed using descriptive statistics, and univariate- and multivariable regression analyses in the validation cohort. External validation was assessed following a variety of analyses described previously. Baseline patient characteristics and results from the regression analyses were largely comparable. Kaplan-Meier curves of the validation cohort reproduced separated groups of standard (n = 39), intermediate (n = 125), and high-risk (n = 78) patients. This discriminative ability was confirmed by similar values for the hazard ratios across these risk groups. The calibration curve in the validation cohort showed a symmetric underestimation of the predicted survival probabilities. In this external validation study, we demonstrate that the DIPG survival prediction model has acceptable cross-cohort calibration and is able to discriminate patients with short, average, and increased survival. We discuss how this clinico-radiological model may serve a useful role in current clinical practice.

Factors associated with success of conservative therapy in chronic subdural hematoma: a single-center retrospective analysis.

INTRODUCTION: Conservative therapy is a viable option for patients with chronic subdural hematoma (cSDH) who express no, or only mild symptoms. It is not clear which factors are associated with success of conservative therapy. This study aims to determine conservative therapy's success rate and to identify features possibly associated with success. METHODS: A monocenter retrospective cohort study, including cSDH patients treated conservatively (wait-and-watch) from 2012 to 2022, was performed. The primary outcome was success of conservative therapy, defined as 'no crossover to surgery' during the follow-up period. Secondary outcomes were (1) factors associated with success, analyzed with univariate and multivariable logistic regression analyses, (2) 30-day mortality (3) time to crossover and (4) reasons for crossover. RESULTS: We included 159 patients. Conservative therapy was successful in 96 (60%) patients. Hematoma volume (OR 0.79, 95% CI 0.69-0.92) and hypodense hematoma type (OR 3.57, 95% 1.38-9.23) were associated with success. Thirty-day mortality rate was 5% and the median duration between diagnosis and surgery was 19 days (IQR 8-39). Clinical deterioration was the most frequent reason for crossover (in 61/63 patients, 97%) and was accompanied by radiological hematoma progression in 42 patients (67%). CONCLUSION: In this selected group of patients, conservative therapy was successful in 60%. Smaller hematoma volume and hypodense hematoma type were associated with success. As time until crossover was approximately three weeks, deploying conservative therapy as primary treatment seems safe and could be rewarding as surgical complications can be avoided. Improvement in patient selection in future cohorts remains warranted.

Clinical course of patients with conservatively managed cerebral cavernous malformations.

INTRODUCTION: There is uncertainty whether patients with a cerebral cavernous malformation (CCM) should undergo conservative or surgical treatment, resulting in practice variation among hospitals. Our objective was to report clinical outcomes of patients with primarily conservatively managed CCMs. PATIENTS AND METHODS: This single-center cohort study included consecutive adult CCM patients, diagnosed in 2000-2023, who underwent conservative management as primary treatment strategy. Data were extracted from medical records, and we systematically conducted telephone and questionnaire follow-up. Functional status was assessed on the modified Rankin Scale (mRS). RESULTS: Of 345 patients, we included 265 patients with a CCM (median age 46 years; 45% male). At baseline, 131 (49%) patients presented with symptomatic hemorrhage (SH), and 134 (51%) with other symptoms or asymptomatically. During 58 months (IQR 35-94) median follow-up, 51 (19%) patients experienced a SH, 33 (12%) a seizure, and 13 (5%) focal neurological deficits. Fourteen (5%) patients underwent intervention (surgery n = 11, radiosurgery n = 4). Presentation with SH was associated with higher annual bleeding rates (6.0% vs 1.5%, p < 0.001), and higher cumulative 5-/10-year bleeding risks (31%/41% vs 7%, p < 0.001). Brainstem CCM was associated with higher cumulative 5-/10-year bleeding risks (27%/38% vs 17%/21%, p = 0.038). Nineteen (7%) patients died; two (0.8%) directly attributable to CCM. Of 246 surviving patients, 205 (83%) completed the questionnaire. At follow-up, 172/224 (77%) patients were functionally independent (mRS score ⩽2). DISCUSSION AND CONCLUSION: The majority of conservatively managed CCM patients remained free of a SH during follow-up. Few patients required intervention, and death attributable to the CCM was rare. These data may help patient counseling and treatment decisions.

Plasma neurofilament light chain as a biomarker for poor outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurofilament light chain (NfL), a biomarker reflecting neuro-axonal damage, may be useful in improving clinical outcome prediction after aSAH. We explore the robust and additional value of NfL to neurological and radiological grading scales in predicting poor outcome after aSAH. METHODS: In this prospective cohort study conducted in a single tertiary center, blood samples were collected of aSAH patients within 24 hours after ictus and before endovascular/surgical intervention. The primary endpoint was poor outcome at six months' follow-up. Receiver operating curves (ROC), area under the curve (AUC, 95% CI) and model-fit (Nagelkerke R2) were calculated for NfL, neurological grading scale (WFNS), modified Fisher, age and sex. A combined ROC and AUC were calculated for variables with an AUC≥0.70. RESULTS: A total of 66 (42%) had poor outcome. The AUC of NfL for poor outcome was 0.70 (0.62-0.78). Combining NfL and WFNS resulted in a slightly higher model-fit and not-significantly higher AUC for predicting poor outcome (R2 0.51; AUC 0.86, 0.80-0.92) compared to WFNS alone. When patients were stratified according to hemorrhage severity, median NfL [IQR] levels were significantly higher in poor grade (14 [7-32] pg/ml) than good grade patients (7 [5-14] pg/ml). Within poor grade patients, median NfL [IQR] levels were significantly higher in non-survivors (19 [11-36] pg/ml) than survivors (7 [6-13] pg/ml). CONCLUSION: In the entire aSAH cohort, plasma NfL has an acceptable predictive performance but does not improve clinical outcome prediction. However, NfL may have potential value in subgroups based on hemorrhage severity.

The immunological landscape of peripheral blood in glioblastoma patients and immunological consequences of age and dexamethasone treatment.

Background: Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume. Methods: High-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses. Results: Glioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells. Conclusion: High-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment with immunotherapy.

Recurrent Chronic Subdural Hematoma After Burr-Hole Surgery and Postoperative Drainage: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Reported recurrence rates of chronic subdural hematoma treated by burr-hole surgery with postoperative drainage vary considerably in the literature. We performed a systematic review and meta-analysis to define the recurrence rate of burr-hole surgery with postoperative drainage. METHODS: PubMed and EMBASE were searched, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. We used the Newcastle-Ottawa scale and Cochrane risk-of-bias tool for quality assessment of included studies and the random-effects model to calculate pooled incidence rates in R with the metaprop function if appropriate. RESULTS: The search yielded 2969 references; 709 were screened full text, and 189 met the inclusion criteria. In 174 studies (34 393 patients), the number of recurrences was reported as per patient and 15 studies (3078 hematomas) reported the number of recurrences per hematoma, for a pooled incidence of 11.2% (95% CI: 10.3-12.1; I 2 = 87.7%) and 11.0% (95% CI: 8.6-13.4; I 2 = 78.0%), respectively. The pooled incidence of 48 studies (15 298 patients) with the highest quality was 12.8% (95% CI 11.4-14.2; I 2 = 86.1%). Treatment-related mortality (56 patients) has a pooled incidence of 0.7% (95% CI 0.0-1.4; I 2 = 0.0%). CONCLUSION: The recurrence rate of chronic subdural hematoma treated by burr-hole surgery and postoperative drainage is 12.8%.

Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage.

BACKGROUND: The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS: We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS: We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION: Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture.

Prehemorrhage antiplatelet use in aneurysmal subarachnoid hemorrhage and impact on clinical outcome.

BACKGROUND: Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage. AIMS: To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome. METHODS: Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into "antiplatelet-user" and "non-user" according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1-3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion. RESULTS: Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08-3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome. CONCLUSION: In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months.

Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury: a systematic review.

OBJECTIVE: Secondary health conditions (SHCs) are long-term complications that frequently occur due to traumatic spinal cord injury (tSCI) and can negatively affect quality of life in this patient population. This study provides an overview of the associations between the severity and level of injury and the occurrence of SHCs in tSCI. METHODS: A systematic search was conducted in PubMed and Embase that retrieved 44 studies on the influence of severity and/or level of injury on the occurrence of SHCs in the subacute and chronic phase of tSCI (from 3 months after trauma). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: In the majority of studies, patients with motor-complete tSCI (American Spinal Injury Association [ASIA] Impairment Scale [AIS] grade A or B) had a significantly increased occurrence of SHCs in comparison to patients with motor-incomplete tSCI (AIS grade C or D), such as respiratory and urogenital complications, musculoskeletal disorders, pressure ulcers, and autonomic dysreflexia. In contrast, an increased prevalence of pain was seen in patients with motor-incomplete injuries. In addition, higher rates of pulmonary infections, spasticity, and autonomic dysreflexia were observed in patients with tetraplegia. Patients with paraplegia more commonly suffered from hypertension, venous thromboembolism, and pain. CONCLUSIONS: This review suggests that patients with a motor-complete tSCI have an increased risk of developing SHCs during the subacute and chronic stage of tSCI in comparison with patients with motor-incomplete tSCI. Future studies should examine whether systematic monitoring during rehabilitation and the subacute and chronic phase in patients with motor-complete tSCI could lead to early detection and potential prevention of SHCs in this population.

Impact of Surgical Timing on Motor Level Lowering in Motor Complete Traumatic Spinal Cord Injury Patients.

Patients with complete traumatic spinal cord injury (tSCI) have a low potential to recover ambulation. Motor level recovery, adjacent to the level of injury, could influence functional independency. This study addresses whether surgical timing influences motor level recovery in patients with motor complete (American Spinal Injury Association [ASIA] Impairment Scale A [AIS A]) and motor incomplete (AIS B) tSCI. A retrospective cohort study was performed in the Netherlands in patients with AIS A/B tSCI (C2-L2), who consecutively underwent surgery between January 2010 and April 2020. Neurological examination was performed directly at presentation to the emergency room and at discharge from the rehabilitation facility. Motor level lowering, AIS grade, and upper and lower extremity motor score recovery were calculated for patients who underwent early (< 24 h) and late (24 h+) surgery. A total of 96 patients met the inclusion criteria. In the multi-variate analysis, late surgical decompression (24 h+) was negatively associated with ≥1 motor level lowering and ≥2 AIS grade improvement [odds ratio (OR) 0.11 [95% confidence interval (CI): 0.01, 0.67], p = 0.046, and OR 0.06 [95% CI: 0.00, 047], p = 0.030. respectively). The presence of sacral sparing (AIS B) at initial examination, and cervical level of the tSCI were associated with ≥1 motor level lowering. In addition, AO Spine C-type injuries were negatively associated with any type of neurological recovery, except motor level lowering. Although sensorimotor complete injuries as well as thoracolumbar injuries negatively influence neurological recovery, early surgical decompression (< 24 h) appears independently associated with enhanced neurological recovery in patients with traumatic spinal cord injury despite level and severity of injury.

Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury.

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM. PATIENTS AND METHODS: Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. RESULTS: The median tumor sunitinib concentration of 1.9 µmol/L (range 1.0-3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 µmol/L, 3.0-8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. CONCLUSIONS: Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.

Development of the SAFETEA Scores for Predicting Risks of Complications of Preventive Endovascular or Microneurosurgical Intracranial Aneurysm Occlusion.

OBJECTIVE: Preventive unruptured intracranial aneurysm occlusion can reduce the risk of subarachnoid hemorrhage, but both endovascular and microneurosurgical treatment carry a risk of serious complications. To improve individualized management decisions, we developed risk scores for complications of endovascular and microneurosurgical treatment based on easily retrievable patient, aneurysm, and treatment characteristics. METHODS: For this multicenter cohort study, we combined individual patient data from unruptured intracranial aneurysm patients ≥18 years undergoing preventive endovascular treatment (standard, balloon-assisted or stent-assisted coiling, Woven EndoBridge-device, or flow-diverting stent) or microneurosurgical clipping at one of 10 participating centers from three continents between 2000-2018. The primary outcome was death from any cause or clinical deterioration from neurological complications ≤30 days. We selected predictors based on previous knowledge about relevant risk factors and predictor performance and studied the association between predictors and complications with logistic regression. We assessed model performance with calibration plots and concordance (c) statistics. RESULTS: Of 1282 included patients, 94 (7.3%) had neurological symptoms that resolved <30 days, 140 (10.9%) had persisting neurological symptoms, and 6 died (0.5%)). At 30 days, 52 patients (4.1%) were dead or dependent. Predictors of procedural complications were: size of aneurysm, aneurysm location, familial subarachnoid hemorrhage, earlier atherosclerotic disease, treatment volume, endovascular modality (for endovascular treatment) or extra aneurysm configuration factors (for microneurosurgical treatment; branching artery from aneurysm neck or unfavorable dome-to-neck ratio), and age (acronym: SAFETEA). For endovascular treatment (n=752), the c-statistic was 0.72 (95%CI:0.67-0.77) and the absolute complication risk ranged from 3.2% (95%CI:1.6%-14.9%;≤1 point) to 33.1% (95%CI:25.4%-41.5%;≥6 points). For microneurosurgical treatment (n=530), the c-statistic was 0.72 (95%CI:0.67-0.77) and the complication risk ranged from 4.9% (95%CI:1.5%-14.9%;≤1 point) to 49.9% (95%CI:39.4%-60.6%;≥6 points). CONCLUSIONS: The SAFETEA risk scores for endovascular and microneurosurgical treatment are based on seven easily retrievable risk factors to predict the absolute risk of procedural complications in patients with unruptured intracranial aneurysms. The scores need external validation before the predicted risks can be properly used to support decision making in clinical practice.

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial.

BACKGROUND AND OBJECTIVES: The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS: The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS: Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Effect of Steroids as an Adjunct to Surgical Treatment in Patients with Chronic Subdural Hematoma.

The role of steroids as an adjunct to surgery for chronic subdural hematoma (cSDH) remains unclear. We evaluated the effect of steroids as an adjunct to surgery on recurrence rates, complications, and mortality. We retrospectively collected data of 525 patients operated on for cSDH between January 2010 and April 2015 at the Amsterdam University Medical Centers and Erasmus Medical Center Rotterdam. Data from patients with and without steroid use as an adjunct to surgery were obtained from medical records and compared using the chi-square test, independent-samples t-test, and Mann-Whitney U test, where applicable. Associations between adjuvant steroid use and complications were analyzed with univariable (penalized likelihood) logistic regression analysis. Multi-variate logistic regression was performed to analyze the influence of adjuvant steroid use on recurrence. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Two hundred seventy-eight of the 525 patients (53%) were treated with adjuvant steroids. Surgery for recurrences occurred less in patients of the steroid group (9% vs. 14%; odds ratio [OR] 0.57; 95% confidence interval [CI], 0.33-0.99), but the effect was not significant after correction for confounders (adjusted aOR, 0.59; 95% CI, 0.33-1.05). In the steroid group, delirium (10% vs. 3%; OR, 3.99; 95% CI, 1.72-9.29) and dysregulated glucose levels occurred more frequently (2% vs. 0%; OR, 11.81; 95% CI, 1.38-1542.79), but multi-variate analysis was not possible. After propensity-score matching, McNemar's chi-square test showed that adjuvant steroid use was not significantly associated with recurrence rate (p = 0.10). Steroids as an adjunct to surgery in patients with cSDH did not have a favorable effect on the recurrence rate in our data after controlling for confounders.

The added value of cerebrospinal fluid analysis in patients with subarachnoid hemorrhage after negative noncontrast CT.

OBJECTIVE: In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings. METHODS: Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist. RESULTS: Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms). CONCLUSIONS: CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.