Case fatality and functional outcome after spontaneous subarachnoid haemorrhage: A systematic review and meta-analysis of time trends and regional variations in population-based studies.

INTRODUCTION: A previous systematic review of population-based studies from 1973 to 2002 found a decrease in case fatality for spontaneous subarachnoid haemorrhage, but could not find a sufficient number of studies to assess changes in functional outcome. Since then, treatment has advanced distinctly. We assessed whether case fatality has decreased further and whether functional outcome has improved. PATIENTS AND METHODS: We searched PubMed and Web of Science for new population-based studies using the same criteria as in our previous systematic review. We assessed changes in case fatality and functional outcome over time using linear regression. RESULTS: We included 24 new studies with 827 patients and analysed 9542 patients described in 62 study periods between 1973 and 2017. Case fatality decreased by 0.3% (95% CI: -0.7 to 0.1) per year. In a sensitivity analysis excluding studies that did not provide 1-month outcome and outliers, the age and sex-adjusted decrease was 0.1% per year (95% CI: -0.9 to 0.6). The mean case fatality rate decreased from 47% (95% CI: 31-63) in the 1970s to 35% (95% CI: 30-39) in the 1990s, and remained stable in the 2000s (34%; 95% CI: 27-41) and 2010s (38%; 95% CI: 15-60). In 15 studies, the mean proportion of patients living independently increased by 0.2% per year (95%CI: -0.7 to 1.1) and the mean was 45% (95% CI: 39-50) in six studies that reported outcome after 12 months. DISCUSSION AND CONCLUSION: From 1973 to 2017, the case-fatality rate of spontaneous subarachnoid haemorrhage declined overall by 13.5%, but remained stable over the last two decades. The data on time trends in functional outcome were inconclusive.

Outcomes After Decompressive Surgery for Severe Cerebral Venous Sinus Thrombosis Associated or Not Associated with Vaccine-Induced Immune Thrombosis with Thrombocytopenia: A Multicenter Cohort Study.

BACKGROUND: Clinical observations indicated that vaccine-induced immune thrombosis with thrombocytopenia (VITT)-associated cerebral venous sinus thrombosis (CVST) often has a space-occupying effect and thus necessitates decompressive surgery (DS). While comparing with non-VITT CVST, this study explored whether VITT-associated CVST exhibits a more fulminant clinical course, different perioperative and intensive care unit management, and worse long-term outcome. METHODS: This multicenter, retrospective cohort study collected patient data from 12 tertiary centers to address priorly formulated hypotheses concerning the clinical course, the perioperative management with related complications, extracerebral complications, and the functional outcome (modified Rankin Scale) in patients with VITT-associated and non-VITT CVST, both with DS. RESULTS: Both groups, each with 16 patients, were balanced regarding demographics, kind of clinical symptoms, and radiological findings at hospital admission. Severity of neurological symptoms, assessed with the National Institute of Health Stroke Scale, was similar between groups at admission and before surgery, whereas more patients with VITT-associated CVST showed a relevant midline shift (≥ 4 mm) before surgery (100% vs. 68.8%, p = 0.043). Patients with VITT-associated CVST tended to undergo DS early, i.e., ≤ 24 h after hospital admission (p = 0.077). Patients with VITT-associated CVST more frequently received platelet transfusion, tranexamic acid, and fibrinogen perioperatively. The postoperative management was comparable, and complications were evenly distributed. More patients with VITT-associated CVST achieved a favorable outcome (modified Rankin Scale ≤ 3) at 3 months (p = 0.043). CONCLUSIONS: Although the prediction of individual courses remains challenging, DS should be considered early in VITT-associated CVST because an overall favorable outcome appears achievable in these patients.

Analysis of aneurysmal subarachnoid hemorrhage as a multistep process.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (ASAH) is a complex disease with higher incidence in women compared to men and in Japan compared to other countries. It was hypothesized that ASAH is consistent with a multistep model of disease. The following assessments were made: (1) the number of steps needed for the disease to occur and (2) whether this number may be different in female versus male and in Japanese versus non-Japanese patients. METHODS: Incidence data were generated from a meta-analysis on ASAH incidence until 2017, which was supplemented with a literature search from 2017 to April 2023. Age- and sex-adjusted incidences per 10-year age groups were calculated and the logarithm of age-specific incidence against the logarithm of age was regressed with least-squares regression. RESULTS: In 2317 ASAH patients a linear relationship between logarithm of incidence and logarithm of age was found with a slope estimate of 3.13 (95% confidence interval 2.60-3.65), consistent with a four-step process. Similar estimates were found for female, male, Japanese and non-Japanese patients. CONCLUSIONS: Our results suggest that ASAH is a four-step process, also in subgroups with higher ASAH incidence. Elucidation of the exact nature of these steps can provide important clues for identification of disease mechanisms underlying ASAH.

Diagnosis of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage and Triggers for Intervention.

INTRODUCTION: Delayed cerebral ischemia (DCI) is a major determinant for poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). Detection and treatment of DCI is a key component in the neurocritical care of patients with aSAH after initial aneurysm repair. METHODS: Narrative review of the literature. RESULTS: Over the past 2 decades, there has been a paradigm shift away from macrovascular (angiographic) vasospasm as a main diagnostic and therapeutic target. Instead, the pathophysiology of DCI is hypothesized to derive from several proischemic pathomechanisms. Clinical examination remains the most reliable means for monitoring and treatment of DCI, but its value is limited in comatose patients. In such patients, monitoring of DCI is usually based on numerous neurophysiological and/or radiological diagnostic modalities. Catheter angiography remains the gold standard for the detection of macrovascular spasm. Computed tomography (CT) angiography is increasingly used instead of catheter angiography because it is less invasive and may be combined with CT perfusion imaging. CT perfusion permits semiquantitative cerebral blood flow measurements, including the evaluation of the microcirculation. It may be used for prediction, early detection, and diagnosis of DCI, with yet-to-prove benefit on clinical outcome when used as a screening modality. Transcranial Doppler may be considered as an additional noninvasive screening tool for flow velocities in the middle cerebral artery, with limited accuracy in other cerebral arteries. Continuous electroencephalography enables detection of early signs of ischemia at a reversible stage prior to clinical manifestation. However, its widespread use is still limited because of the required infrastructure and expertise in data interpretation. Near-infrared spectroscopy, a noninvasive and continuous modality for evaluation of cerebral blood flow dynamics, has shown conflicting results and needs further validation. Monitoring techniques beyond neurological examinations may help in the detection of DCI, especially in comatose patients. However, these techniques are limited because of their invasive nature and/or restriction of measurements to focal brain areas. CONCLUSION: The current literature review underscores the need for incorporating existing modalities and developing new methods to evaluate brain perfusion, brain metabolism, and overall brain function more accurately and more globally.

Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.

BACKGROUND: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations. METHODS: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks. Glioblastoma cells expressed fluorescent markers that permitted the identification of their mitotic history or their cycling versus non-cycling cell state. RESULTS: Live reporter systems were established that allowed us to dynamically determine the invasive behavior, and previous or actual proliferation of distinct glioblastoma cells, in different tumor regions and disease stages over time. Particularly invasive tumor cells that migrated far away from the main tumor mass, when followed over weeks, had a history of marked proliferation and maintained their proliferative capacity during brain colonization. Infiltrating cells showed fewer connections to the multicellular tumor cell network, a typical feature of gliomas. Once tumor cells colonized a new brain region, their phenotype progressively transitioned into tumor microtube-rich, interconnected, slower-cycling glioblastoma cells. Analysis of resected human glioblastomas confirmed a higher proliferative potential of tumor cells from the invasion zone. CONCLUSIONS: The detection of glioblastoma cells that harbor both particularly high proliferative and invasive capabilities during brain tumor progression provides valuable insights into the interrelatedness of proliferation and migration-2 central traits of malignancy in glioma. This contributes to our understanding of how the brain is efficiently colonized in this disease.

Scalp Reconstruction Using the Latissimus Dorsi Free Flap: A 12-Year Experience.

BACKGROUND: Complex scalp defects are regularly reconstructed using microvascular tissue transfer. The latissimus dorsi free flap is one of the workhorse flaps used in scalp reconstruction. These cases necessitate, particularly in the elderly, a close cooperation between plastic surgeons and neurosurgeons. The purpose of this study was to evaluate the suitability of the latissimus dorsi free flap for complex scalp reconstructions and to analyze potential risk factors. METHODS: A retrospective study identified 43 patients undergoing complex scalp reconstruction using a latissimus dorsi free flap at our department between 2010 and 2022. RESULTS: The mean patient age was 61 ± 18 years. Defects were mostly caused by oncologic tumor resections (n = 23; 55%), exposure to a cranioplasty (n = 10; 23%) or infection (n = 4; 9%). The most frequent recipient vessels were the superficial temporal artery (n = 28; 65%), external carotid artery (n = 12; 28%) and the venae comitantes (n = 28; 65%), external jugular vein (n = 6; 14%). The reconstructive success rate was 97.7%. There was one total flap loss (2%). Partial flap loss occurred in five cases (12%). Follow-up was 8 ± 12 months. Major complications were seen in 13 cases, resulting in a revision rate of 26%. Multivariate logistic regression identified active tobacco use as the only risk factor for major complications (odds ratio 8.9; p = 0.04). CONCLUSION: Reconstruction of complex scalp defects using the latissimus dorsi free flap yielded high success rates. Among the potential risk factors, active tobacco use seems to affect the outcome of complex scalp reconstructions.

Validation of the German version of the subarachnoid haemorrhage outcome tool (SAHOT).

Objective: The subarachnoid haemorrhage (SAH) outcome tool (SAHOT) is the first SAH-specific patient reported outcome measure, and was developed in the UK. We aimed to validate the SAHOT outside the UK, and therefore endeavored to adapt the SAHOT into German and to test its psychometric properties. Methods: We adapted and pilot tested the German version. We applied the SAHOT, Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, and EuroQol questionnaires in a cohort of 89 patients with spontaneous SAH after discharge. We assessed internal consistency by Cronbach's α, test-retest reliability by intraclass correlation, and validity by Pearson correlations with established measures. Sensitivity to change was evaluated following neurorehabilitation by effect sizes. Results: The translation of SAHOT resulted in a German version that is semantically and conceptually equivalent to the English version. Internal consistency was good regarding the physical domain (α = 0.83) and excellent for the other domains (α = 0.92-0.93). Test-retest reliability indicated a high level of stability with an intraclass correlation of 0.85 (95% CI: 0.83-0.86). All domains correlated moderately or strongly with established measures (r = 0.41-0.74; p < 0.01). SAHOT total scores showed moderate sensitivity to change (Cohen's d = -0.68), while mRS and GOSE showed no significant sensitivity to change. Conclusion: The SAHOT can be adapted to other health care systems and societies than the UK. The German version of the SAHOT is a reliable and valid instrument, and can be used in future clinical studies and individual assessment after spontaneous SAH.

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.

Associations Between Drug Treatments and the Risk of Aneurysmal Subarachnoid Hemorrhage: a Systematic Review and Meta-analysis.

There is increasing interest in drug therapy for preventing aneurysmal subarachnoid hemorrhage (aSAH). We aimed to comprehensively evaluate the association between drug use and the risk of aSAH. We searched PubMed and Scopus from the databases' inception until December 2021. Observational studies reporting the association between any drug therapy and aSAH were included. The odds ratios (ORs) for each drug used in aSAH were meta-analyzed with a random-effect model. According to the systematic review, 25 observational studies were eligible for the present study. Four therapeutic purpose-based classes (e.g., lipid-lowering agents) and 14 mechanism-based classes (e.g., statins) were meta-analyzed. Anti-hypertensive agents (OR, 0.50; 95% confidence interval [95% CI], 0.33-0.74), statins (OR, 0.55; 95% CI, 0.35-0.85), biguanides (OR, 0.57; 95% CI, 0.34-0.96), and acetylsalicylic acid (ASA) (OR, 0.62; 95% CI, 0.41-0.94) were inversely associated with the risk of aSAH. Non-ASA non-steroidal anti-inflammatory drugs (OR, 1.73; 95% CI, 1.07-2.79), selective cyclooxygenase-2 inhibitors (OR, 2.04; 95% CI, 1.24-3.35), vitamin K antagonists (OR, 1.50; 95% CI, 1.18-1.91), and dipyridamole (OR, 1.77; 95% CI, 1.23-2.54) were positively associated with the incidence of aSAH. There was also a trend toward a positive association between glucocorticoids (OR, 1.38; 95% CI, 0.97-1.94) and aSAH. The present study suggests that anti-hypertensive agents, statins, biguanides, and ASA are candidate drugs for preventing aSAH. By contrast, several drugs (e.g., anti-thrombotic drugs) may increase the risk of aSAH. Thus, the indications of these drugs in patients with intracranial aneurysms should be carefully determined.

Lumbar Spondylodiscitis Mimicking Cholecystitis: A Case Report and Review of Literature.

BACKGROUND: Lower back pain is a frequent cause of emergency department visits and one of the leading causes of the disease burden worldwide. The purpose of this case report and literature review was to discuss atypical abdominal entities mimicking spinal diseases typically presenting with lower back pain. METHODS: A 79-year-old man presented with lower back pain and urinary incontinence after receiving a non-image-guided lumbar infiltration treatment 4 weeks prior to admission. The magnetic resonance imaging (MRI) highlighted multisegmental hyperintensities in the intervertebral disk spaces of the lumbar spine indicative for spondylodiscitis. Antibiotic treatment over a week did not lead to significant clinical improvement. Blood cultures, cardiologic, otorhinolaryngologic, and dental examinations turned out negative for a focus of infection. A computed tomography (CT) guided biopsy was indicated after discontinuation of antibiotic treatment for less than 24 hours. Rapid clinical deterioration with concomitant onset of abdominal pain resulted in the diagnosis of cholecystitis, which required cholecystectomy. We performed a systematic literature review using the Pubmed database for the keywords "spondylodiscitis," "spine," "abdominal," and "cholecystitis," to identify abdominal diseases that mimic spine pathologies and spinal diseases that mimic abdominal pathologies. RESULTS: No other report in English literature of cholecystitis associated with initial onset of lower back pain was identified. Eighteen reports referred to abdominal conditions that mimic spinal diseases, among them a patient with cyclic lumbar back pain who received a lumbar spinal fusion who, after persisting symptoms led to further diagnostic procedures, was ultimately diagnosed with endometriosis. Spinal symptoms included paraplegia and urinary incontinence as results of acute aortic pathologies. Eleven reports presented spinal pain mimicking abdominal conditions including abdominal pain and diarrhea as well as have had surgical procedures such as an appendectomy before the spinal condition was discovered. CONCLUSION: Clinical symptoms of the spine such as lower back pain can be unspecific and lead to false conclusions in the presence of concomitant pathologies in MRI. Only clinical deterioration in our case patient prompted correction of the diagnosis on day 7. Initial workup for alternative common infectious foci such as lung and urinary tract was performed, but further abdominal workup despite the absence of abdominal symptoms may have led to an earlier diagnosis. Our literature review found several cases of misdiagnosed spinal and abdominal conditions. Some had undergone unnecessary surgical procedures before the right diagnosis was made. Because of the high incidence of symptoms such as lumbar back pain and abdominal pain, considering optimal patient care as well as economic aspects, it would be essential to conduct an interdisciplinary clinical management to avoid errors in the early stage of diagnostics.

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.

European Stroke Organisation (ESO) guidelines on management of unruptured intracranial aneurysms.

Unruptured intracranial aneurysms (UIA) occur in around 3% of the population. Important management questions concern if and how to perform preventive UIA occlusion; if, how and when to perform follow up imaging and non-interventional means to reduce the risk of rupture. Using the Standard Operational Procedure of ESO we prepared guidelines according to GRADE methodology. Since no completed randomised trials exist, we used interim analyses of trials, and meta-analyses of observational and case-control studies to provide recommendations to guide UIA management. All recommendations were based on very low evidence. We suggest preventive occlusion if the estimated 5-year rupture risk exceeds the risk of preventive treatment. In general, we cannot recommend endovascular over microsurgical treatment, but suggest flow diverting stents as option only when there are no other low-risk options for UIA repair. To detect UIA recurrence we suggest radiological follow up after occlusion. In patients who are initially observed, we suggest radiological monitoring to detect future UIA growth, smoking cessation, treatment of hypertension, but not treatment with statins or acetylsalicylic acid with the indication to reduce the risk of aneurysm rupture. Additionally, we formulated 15 expert-consensus statements. All experts suggest to assess UIA patients within a multidisciplinary setting (neurosurgery, neuroradiology and neurology) at centres consulting >100 UIA patients per year, to use a shared decision-making process based on the team recommendation and patient preferences, and to repair UIA only in centres performing the proposed treatment in >30 patients with (ruptured or unruptured) aneurysms per year per neurosurgeon or neurointerventionalist. These UIA guidelines provide contemporary recommendations and consensus statement on important aspects of UIA management until more robust data come available.

Multidisciplinary and standardized management of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The appropriate management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We aimed to evaluate the effect of implementing a standardized protocol for detection and management of DCI after aSAH on cerebral infarction and functional outcome. METHODS: We studied two cohorts of aSAH patients, one before (pre-implementation cohort: January 2012 to August 2014) and one after (post-implementation cohort: January 2016 to July 2018) implementation of a multidisciplinary approach, with standardized neurological and radiological assessment and risk-based medical treatment of DCI. We assessed the presence of new hypodensities on CT within 6 weeks after aSAH and categorized cerebral infarction into overall and DCI-related infarctions (hypodensities not within 48 h after IA repair and not attributable to aneurysm occlusion or intraparenchymal hematoma). Functional outcome was assessed at 3 months using the extended Glasgow outcome scale (eGOS), dichotomized into unfavorable (eGOS: 1-5) and favorable (eGOS: 6-8). We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI's), and adjusted for age, WFNS grade, Fisher score, and treatment modality (aOR). RESULTS: In the post-implementation (n = 158) versus the pre-implementation (n = 143) cohort the rates for overall cerebral infarction were 29.1% vs 46.9% (aOR: 0.41 [0.24-0.69]), for DCI-related cerebral infarction 17.7% vs. 31.5% (aOR: 0.41 [0.23-0.76]), and for unfavorable functional outcome at 3 months 37.3% vs. 53.8% (aOR: 0.30 [0.17-0.54]). For patients with DCI, the rates for unfavorable functional outcomes at 3 months in the post-implementation versus the pre-implementation cohort were 42.3% vs. 77.8% (aOR: 0.1 [0.03-0.27]). CONCLUSIONS: A multidisciplinary approach with more frequent and standardized neurological assessment, standardized CT and CT perfusion monitoring, as well as tailored application of induced hypertension and invasive rescue therapy strategies, is associated with a significant reduction of cerebral infarction and unfavorable functional outcome after aneurysmal aSAH.

Comparative Analyses of the Impact of Different Criteria for Sepsis Diagnosis on Outcome in Patients with Spontaneous Subarachnoid Hemorrhage.

Data on sepsis in patients with a subarachnoid hemorrhage (SAH) are scarce. We assessed the impact of different sepsis criteria on the outcome in an SAH cohort. Adult patients admitted to our ICU with a spontaneous SAH between 11/2014 and 11/2018 were retrospectively included. In patients developing an infection, different criteria for sepsis diagnosis (Sepsis-1, Sepsis-3_original, Sepsis-3_modified accounting for SAH-specific therapy, alternative sepsis criteria compiled of consensus conferences) were applied and their impact on functional outcome using the modified Rankin Scale (mRS) on hospital discharge and in-hospital mortality was evaluated. Of 270 SAH patients, 129 (48%) developed an infection. Depending on the underlying criteria, the incidence of sepsis and septic shock ranged between 21-46% and 9-39%. In multivariate logistic regression, the Sepsis-1 criteria were not associated with the outcome. The Sepsis-3 criteria were not associated with the functional outcome, but in shock with mortality. Alternative sepsis criteria were associated with mortality for sepsis and in shock with mortality and the functional outcome. While Sepsis-1 criteria were irrelevant for the outcome in SAH patients, septic shock, according to the Sepsis-3 criteria, adversely impacted survival. This impact was higher for the modified Sepsis-3 criteria, accounting for SAH-specific treatment. Modified Sepsis-3 and alternative sepsis criteria diagnosed septic conditions of a higher relevance for outcomes in patients with an SAH.

Progression Patterns in Non-Contrast-Enhancing Gliomas Support Brain Tumor Responsiveness to Surgical Lesions.

Purpose: The overall benefit of surgical treatments for patients with glioma is undisputed. We have shown preclinically that brain tumor cells form a network that is capable of detecting damage to the tumor, and repair itself. The aim of this study was to determine whether a similar mechanism might contribute to local recurrence in the clinical setting. Methods: We evaluated tumor progression patterns of 24 initially non-contrast-enhancing gliomas that were partially resected or biopsied. We measured the distance between the new contrast enhancement developing over time, and prior surgical lesioning, and evaluated tumor network changes in response to sequential resections by quantifying tumor cells and tumor networks with specific stainings against IDH1-R132H. Results: We found that new contrast enhancement appeared within the residual, non-enhancing tumor mass in 21/24 patients (87.5%). The location of new contrast enhancement within the residual tumor region was non-random; it occurred adjacent to the wall of the resection cavity in 12/21 patients (57.1%). Interestingly, the density of the glioma cell network increased in all patient tumors between initial resection or biopsy and recurrence. In line with the histological and radiological malignization, Ki67 expression increased from initial to final resections in 14/17 cases. Conclusion: The non-random distribution of glioma malignization in patients and unidirectional increase of anatomical tumor networks after surgical procedures provides evidence that surgical lesions, in the presence of residual tumor cells, can stimulate local tumor progression and tumor cell network formation. This argues for the development of intraoperative treatments increasing the benefits from surgical resection by specifically disrupting the mechanisms of local recurrence, particularly tumor cell network functionality.

Patient-Derived Tumor Organoids for Guidance of Personalized Drug Therapies in Recurrent Glioblastoma.

An obstacle to effective uniform treatment of glioblastoma, especially at recurrence, is genetic and cellular intertumoral heterogeneity. Hence, personalized strategies are necessary, as are means to stratify potential targeted therapies in a clinically relevant timeframe. Functional profiling of drug candidates against patient-derived glioblastoma organoids (PD-GBO) holds promise as an empirical method to preclinically discover potentially effective treatments of individual tumors. Here, we describe our establishment of a PD-GBO-based functional profiling platform and the results of its application to four patient tumors. We show that our PD-GBO model system preserves key features of individual patient glioblastomas in vivo. As proof of concept, we tested a panel of 41 FDA-approved drugs and were able to identify potential treatment options for three out of four patients; the turnaround from tumor resection to discovery of treatment option was 13, 14, and 15 days, respectively. These results demonstrate that this approach is a complement and, potentially, an alternative to current molecular profiling efforts in the pursuit of effective personalized treatment discovery in a clinically relevant time period. Furthermore, these results warrant the use of PD-GBO platforms for preclinical identification of new drugs against defined morphological glioblastoma features.

HIP1R and vimentin immunohistochemistry predict 1p/19q status in IDH-mutant glioma.

BACKGROUND: IDH-mutant gliomas are separate based on the codeletion of the chromosomal arms 1p and 19q into oligodendrogliomas IDH-mutant 1p/19q-codeleted and astrocytomas IDH-mutant. While nuclear loss of ATRX expression excludes 1p/19q codeletion, its limited sensitivity prohibits to conclude on 1p/19q status in tumors with retained nuclear ATRX expression. METHODS: Employing mass spectrometry based proteomic analysis in a discovery series containing 35 fresh frozen and 72 formalin fixed and paraffin embedded tumors with established IDH and 1p/19q status, potential biomarkers were discovered. Subsequent validation immunohistochemistry was conducted on two independent series (together 77 oligodendrogliomas IDH-mutant 1p/19q-codeleted and 92 astrocytomas IDH-mutant). RESULTS: We detected highly specific protein patterns distinguishing oligodendroglioma and astrocytoma. In these patterns, high HIP1R and low vimentin levels were observed in oligodendroglioma while low HIP1R and high vimentin levels occurred in astrocytoma. Immunohistochemistry for HIP1R and vimentin expression in 35 cases from the FFPE discovery series confirmed these findings. Blinded evaluation of the validation cohorts predicted the 1p/19q status with a positive and negative predictive value as well as an accuracy of 100% in the first cohort and with a positive predictive value of 83%; negative predictive value of 100% and an accuracy of 92% in the second cohort. Nuclear ATRX loss as marker for astrocytoma increased the sensitivity to 96% and the specificity to 100%. CONCLUSIONS: We demonstrate that immunohistochemistry for HIP1R, vimentin, and ATRX predict 1p/19q status with 100% specificity and 95% sensitivity and therefore, constitutes a simple and inexpensive approach to the classification of IDH-mutant glioma.