A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives.

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.

Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

A Retrospective Cohort Study Evaluating the Comparative Effectiveness of Unilateral Hemilaminectomy and Bilateral Laminectomy in the Resection of Spinal Meningiomas.

BACKGROUND AND OBJECTIVES: The primary treatment modality for spinal meningiomas (SM) is surgical resection. In recent years, minimal invasive spine surgery has gained considerable popularity, attributing its growth to advancements in surgical technologies and improved training of surgeons. Nonetheless, the suitability and effectiveness of minimal invasive spine surgery for intradural spinal tumor resection remain a subject of debate. In this cohort study, we aimed to compare the extent of resection of the unilateral hemilaminectomy approach, a less invasive technique, with the more traditional and invasive bilateral laminectomy. METHODS: We performed a retrospective cohort study including patients with SM who underwent surgery at our department between 1996 and 2020. Cohorts included patients who underwent tumor resection through bilateral laminectomy and patients who underwent a unilateral hemilaminectomy. The primary end point was extent of resection according to the Simpson classification. RESULTS: Of 131 with SM, 36 had a bilateral laminectomy and 95 were operated through a unilateral hemilaminectomy. In both groups, gross total resection, Simpson grades 1 and 2, was achieved in 94.44% and 94.74%, respectively (P = .999). The neurological outcome was also comparable in both cohorts (P = .356). Both length of hospital stay and estimated blood loss were significantly lower in the unilateral cohort (P < .05). CONCLUSION: The results of this study indicate that the unilateral hemilaminectomy yields comparable results in both oncological and neurological outcome when compared with the bilateral laminectomy. Thus, unilateral hemilaminectomy may serve as a viable and safe alternative for the surgical removal of SM.

Does Early Mobilization Following Resection of Spinal Intra-Dural Pathology Increase the Risk of Cerebrospinal Fluid Leaks?-A Dual-Center Comparative Effectiveness Research.

Background and Objectives: Prolonged bed rest after the resection of spinal intradural tumors is postulated to mitigate the development of cerebrospinal fluid leaks (CSFLs), which is one of the feared postoperative complications. Nonetheless, the empirical evidence supporting this conjecture remains limited and requires further investigation. The goal of the study was to investigate whether prolonged bed rest lowers the risk of CSFL after the resection of spinal intradural tumors. The primary outcome was the rate of CSFL in each cohort. Materials and Methods: To validate this hypothesis, we conducted a comparative effectiveness research (CER) study at two distinct academic neurosurgical centers, wherein diverse postoperative treatment protocols were employed. Specifically, one center adopted a prolonged bed rest regimen lasting for three days, while the other implemented early postoperative mobilization. For statistical analysis, case-control matching was performed. Results: Out of an overall 451 cases, we matched 101 patients from each center. We analyzed clinical records and images from each case. In the bed rest center, two patients developed a CSFL (n = 2, 1.98%) compared to four patients (n = 4, 3.96%) in the early mobilization center (p = 0.683). Accordingly, CSFL development was not associated with early mobilization (OR 2.041, 95% CI 0.365-11.403; p = 0.416). Univariate and multivariate analysis identified expansion duraplasty as an independent risk factor for CSFL (OR 60.33, 95% CI: 0.015-0.447; p < 0.001). Conclusions: In this CER, we demonstrate that early mobilization following the resection of spinal intradural tumors does not confer an increased risk of the development of CSFL.

Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Background: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of neoantigens. Results: In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface neoantigens that could be targeted by antibodies and chimeric antigen receptor (CAR)-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas [TCGA]) and 9,166 normal tissue samples (from the Genotype-Tissue Expression project [GTEx]), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN , which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative neoantigens. Conclusions: Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

Mixed Reality as a Teaching Tool for Medical Students in Neurosurgery.

Background and Objectives: Simulation-based learning within neurosurgery provides valuable and realistic educational experiences in a safe environment, enhancing the current teaching model. Mixed reality (MR) simulation can deliver a highly immersive experience through head-mounted displays and has become one of the most promising teaching tools in medical education. We aimed to identify whether an MR neurosurgical simulation module within the setting of an undergraduate neurosurgical hands-on course could improve the satisfaction of medical students. Materials and Methods: The quasi-experimental study with 223 medical students [120 in the conventional group (CG) and 103 in the MR-group (MRG)] was conducted at the University Hospital Münster, Münster, Germany. An MR simulation module was presented to the intervention group during an undergraduate neurosurgical hands-on course. Images of a skull fracture were reconstructed into 3D formats compatible with the MR-Viewer (Brainlab, Munich, Germany). Participants could interact virtually with the model and plan a surgical strategy using Magic Leap goggles. The experience was assessed by rating the course on a visual analog scale ranging from 1 (very poor) to 100 (very good) and an additional Likert-scale questionnaire. Results: The satisfaction score for CG and MRG were 89.3 ± 13.3 and 94.2 ± 7.5, respectively. The Wilcoxon rank-sum test showed that MR users (Mdn = 97.0, IQR = 4, n = 103) were significantly more satisfied than CG users (Mdn = 93.0, IQR = 10, n = 120; ln(W) = 8.99, p < 0.001) with moderate effect size (r^biserial = 0.30, CI95 [0.15, 0.43]), thus indicating that the utilization of MR-simulation is associated with greater satisfaction. Conclusions: This study reports a positive response from medical students towards MR as an educational tool. Feedback from the medical students encourages the adoption of disruptive technologies into medical school curricula.

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens.

T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22 , respectively. TCR-engineered CD8 + T-cells targeting these mutations conferred neoantigen-specific tumor cell eradication. Furthermore, we revealed that cancer-specific dysregulation in splicing factor expression leads to recurrent neojunction expression. Together, these data reveal that a subset of neojunctions are both intratumorally conserved and public, providing the molecular basis for novel T-cell-based immunotherapies that address intratumoral heterogeneity.

Resection of Intramedullary Hemangioblastoma: Timing of Surgery and Its Impact on Neurological Outcome and Quality of Life.

Background and Objectives: Spinal intramedullary hemangioblastomas (SIMH) are benign vascular lesions that are pathological hallmarks of von Hippel-Lindau disease (vHL) and constitute the third most common intramedullary neoplasm in adults. So far, maximal and safe resection is the first choice of treatment. However, as SIMH show no malignant transformation, it remains unclear whether surgical resection is beneficial for all patients. Materials and Methods: We retrospectively analyzed the surgical outcomes of 27 patients who were treated between 2014 and 2022 at our neurosurgical department and investigated potential risk factors that influence the surgical outcome. Pre- and postoperative neurological status were classified according to the McCormick scale. Furthermore, surgical quality indicators, such as length of hospital stay (LOS; days), 90-day readmissions, nosocomial infections, and potential risk factors that might influence the surgical outcome, such as tumor size and surgical approach, have been analyzed. In addition to that, patients were asked to fill out the EQ-5D-3L questionnaire to assess their quality of life after surgery. Results: Surgery on SIMH patients that display no or minor neurological deficits (McCormick scale I or II) is associated with a favorable postoperative outcome and overall higher quality of life compared to those patients that already suffer from severe neurological deficits (McCormick scale III or IV). Conclusion: Early surgical intervention prior to the development of severe neurological deficits may offer a better neurological outcome and quality of life.

Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically "cold" tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG.

Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis.

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [18F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [18F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

The Role of Prolonged Bed Rest in Postoperative Cerebrospinal Fluid Leakage After Surgery of Intradural Pathology-A Retrospective Cohort Study.

BACKGROUND: Postoperative cerebrospinal fluid leakage (CSFL) is a feared complication after surgery on intradural pathologies and may cause postoperative complications and subsequently higher treatment costs. OBJECTIVE: To assess whether prolonged bed rest may lower the risk of CSFL. METHODS: We performed a retrospective cohort study including patients with intradural pathologies who underwent surgery at our department between 2013 and 2021. Cohorts included patients who completed 3 days of postoperative bed rest and patients who were mobilized earlier. The primary end point was the occurrence of clinically proven CSFL. RESULTS: Four hundred and thirty-three patients were included (female [51.7%], male [48.3%]) with a mean age of 48 years (SD ±20). Bed rest was ordered in 315 cases (72.7%). In 7 cases (N = 7/433, 1.6%), we identified a postoperative CSFL. Four of them (N = 4/118) did not preserve bed rest, showing no significant difference to the bed rest cohort (N = 3/315; P = .091). In univariate analysis, laminectomy (N = 4/61; odds ratio [OR] 8.632, 95% CI 1.883-39.573), expansion duraplasty (N = 6/70; OR 33.938, 95% CI 4.019-286.615), and recurrent surgery (N = 5/66; OR 14.959, 95% CI 2.838-78.838) were significant risk factors for developing CSFL. In multivariate analysis, expansion duraplasty was confirmed as independent risk factor (OR 33.937, 95% CI 4.018-286.615, P = .001). In addition, patients with CSFL had significant higher risk for meningitis (N = 3/7; 42.8%, P = .001). CONCLUSION: Prolonged bed rest did not protect patients from developing CSFL after surgery on intradural pathologies. Avoiding laminectomy, large voids, and minimal invasive approaches may play a role in preventing CSFL. Furthermore, special caution is indicated if expansion duraplasty was done.

Idiopathic Ventral Spinal Cord Hernia-A Single-Center Case Series of 11 Patients.

BACKGROUND: Idiopathic spinal cord herniations (ISCH) are rare defects of the ventromedial or mediolateral dura mater with herniation of the spinal cord through the defect with approximately 350 described cases worldwide. Patients usually become symptomatic with motor or sensory neurological deficits and gait disturbances. OBJECTIVE: To describe characteristic symptoms and clinical findings and to evaluate the postoperative course and outcomes of ISCH. METHODS: We present a single-center data analysis of a case series of 11 consecutive patients who were diagnosed with ISCH and underwent surgery in our department between 2009 and 2021. RESULTS: All herniations were located in the thoracic spine between T2 and T9. In most cases, gait ataxia and dysesthesia led to further workup and subsequently to the diagnosis of ISCH. A "far-enough" posterior-lateral surgical approach, hemilaminectomy or laminectomy with a transdural approach, was performed under intraoperative neurophysiological monitoring which was followed by adhesiolysis, repositioning of the spinal cord and sealing using a dura patch. After surgery, clinical symptoms improved in 9 of 11 patients (81.8%), while only 1 patient experienced deterioration of symptoms (9.1%) and 1 patient remained equal (9.1%). The median preoperative McCormick grade was 3 (±0.70), while the median postoperative grade was 2 (±0.98) ( P = .0047). CONCLUSION: In our case series of ISCH, we found that in most patients, neurological deficits improved postoperatively. This indicates that surgery in ISCH should not be delayed in symptomatic patients.

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Postoperative surveillance in cranial and spinal tumor neurosurgery: when is this warranted?

OBJECTIVE: The outbreak of COVID-19 and the sudden increase in the number of patients requiring mechanical ventilation significantly affected the management of neurooncological patients. Hospitals were forced to reallocate already scarce human resources to maximize intensive care unit (ICU) capacities, resulting in a significant postponement of elective procedures for patients with brain and spinal tumors, who traditionally require elective postoperative surveillance on ICU or intermediate care wards. This study aimed to characterize those patients in whom postoperative monitoring is required by analyzing early postoperative complications and associated risk factors. METHODS: All patients included in the analysis experienced benign or malignant cerebral or intradural tumors and underwent surgery between September 2017 and May 2019 at University Hospital Münster, Germany. Patient data were generated from a semiautomatic, prospectively designed database. The occurrence of adverse events within 24 hours and 30 days postoperatively-including unplanned reoperation, postoperative hemorrhage, CSF leakage, and pulmonary embolism-was chosen as the primary outcome measure. Furthermore, reasons and risk factors that led to a prolonged stay on the ICU were investigated. By performing multivariable logistic regression modeling, a risk score for early postoperative adverse events was calculated by assigning points based on beta coefficients. RESULTS: Eight hundred eleven patients were included in the study. Eleven patients (1.4%) had an early adverse event within 24 hours, which was either an unplanned reoperation (0.9%, n = 7) or a pulmonary embolism (0.5%, n = 4) within 24 hours. To predict the incidence of early postoperative complications, a score was developed including the number of secondary diagnoses, BMI, and incision closure time, termed the SOS score. According to this score, 0.3% of the patients were at low risk, 2.5% at intermediate risk, and 12% at high risk (p < 0.001). CONCLUSIONS: Postoperative surveillance in cranial and spinal tumor neurosurgery might only be required in a distinct patient collective. In this study, the authors present a new score allowing efficient prediction of the likelihood of early adverse events in patients undergoing neurooncological procedures, thus helping to stratify the necessity for ICU or intermediate care unit beds. Nevertheless, validation of the score in a multicenter prospective setting is needed.

Correction: Gallus et al. Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma. Cancers 2023, 15, 3726.

It has come to our attention that the previously published manuscript contained an outdated iteration of Table 1 [...].

How Should We Treat Meningeal Melanocytoma? A Retrospective Analysis of Potential Treatment Strategies.

BACKGROUND: Meningeal melanocytomas (MM) are rare primary melanocytic tumors of the leptomeninges with an incidence of 1:10,000,000. Until now, there has been only sparse information about this tumor entity. Here, we provide a meta-analysis of all cases published in the English language since 1972. METHODS: A literature review was performed using PubMed and Web of Science. All published cases were evaluated for location, sex, age, therapeutic approach, and outcome. In total, we included 201 patient cases in our meta-analysis. RESULTS: The majority of MM was diagnosed more frequently in men between the third and fifth decade of life. Surgery is the preferred therapeutic approach, and total resection is associated with the best outcome. Patients with partial resection or tumor recurrence benefit from adjuvant radiotherapy, whereas chemo- or immunotherapies do not improve the disease course. Malignant transformation was described in 18 patients. Of these, 11 patients developed metastasis. CONCLUSIONS: We present the first retrospective meta-analysis of all MM cases published in the English language, including an evaluation of different treatment strategies allowing us to suggest a novel treatment guideline highlighting the importance of total resection for recurrence-free survival and characterizing those cases which benefit from adjuvant radiotherapy.

Minimally Invasive Facetectomy and Fusion for Resection of Extensive Dumbbell Tumors in the Lumbar Spine.

Background and Objectives: Resection of dumbbell tumors can be challenging, and facet joint sparing approaches carry the risk of incomplete resection. In contrast, additional facetectomy may allow better surgical exposure at the cost of spinal stability. The aim of this study is to compare facet-sparing and facetectomy approaches for the treatment of lumbar spine dumbbell tumors. Materials and Methods: In a cohort study setting, we analyzed Eden type 2 and 3 tumors operated in our department. Conventional facet-sparing microsurgical or facetectomy approaches with minimally invasive fusions were performed according to individual surgeons' preference. Primary outcomes were extent of resection and tumor progression over time. Secondary outcomes were perioperative adverse events. Results: Nineteen patients were included. Nine patients were operated on using a facet-sparing technique. Ten patients underwent facetectomy and fusion. While only one patient (11%) in the facet-sparing group experienced gross total resection (GTR), this was achieved for all patients in the facetectomy group (100%). The relative risk (RR) for incomplete resection in the facet-sparing cohort was 18.7 (95% CI 1.23-284.047; p = 0.035). In addition, time to progression was shorter in the facet-sparing cohort (p = 0.022) and all patients with a residual tumor underwent a second resection after a median follow-up time of 42 months (IQR 25-66). Conclusions: Minimally invasive resection of lumbar Eden type 2 and 3 dumbbell tumors including facetectomy in combination with instrumentation appears to be safe and superior to the facet-sparing approach in terms of local tumor control.

Risk Factors for Postoperative Cerebrospinal Fluid Leakage After Intradural Spine Surgery.

OBJECTIVE: Well-defined risk factors for cerebrospinal fluid leakage (CSFL) after intradural spine surgery are scarce in the literature. The aim of the present study was to identify patient- and surgery-related risk factors and the incidence of CSFL. METHODS: For the present retrospective cohort study, we identified consecutive patients who had undergone intradural spine surgery between 2009 and 2021 at our department. The primary endpoint was the incidence of clinically or radiologically proven CSFL. The effects of the clinical and surgical factors on the occurrence of CSFL were analyzed. RESULTS: A total of 375 patients (60.3% women; mean age, 54 ± 16.5 years) were included. Of the 375 patients, 30 (8%) had experienced postoperative CSFL and, thus, a significantly greater risk of wound healing disorders (odds ratio [OR], 24.9; 95% confidence interval [CI], 9.3-66.7) and surgical site infections (OR, 8.4; 95% CI, 2.6-27.7; P < 0.01 for each). No patient-related factors were associated with the development of CSFL. Previous surgery at the index level correlated significantly with the occurrence of postoperative CSFL (OR, 2.76; 95% CI, 1.1-6.8; P = 0.03) on multivariate analysis. Furthermore, patients with intradural tumors tended to have a greater risk of CSFL (OR, 2.3; 95% CI, 0.9-5.8; P = 0.07). Surgery-related factors did not influence the occurrence of CSFL. Surgery on the thoracic spine had resulted in a significantly lower postoperative CSFL rate compared with surgery on the cervical or lumbar spine (OR, -2.5; 95% CI, 1.3-4.9; P = 0.02). CONCLUSIONS: Our study found no modifiable risk factors for preventing CSFL after intradural spine surgery. Patients with previous surgery at the index level had a greater risk of CSFL. The occurrence of CSFL resulted in significantly more wound healing disorders and surgical site infections, necessitating further therapy.

Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis.

OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65114-123 peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long-standing GAD65-LE.