An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.

Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP:

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Practice-Pattern Variation in Sedation of Neurotrauma Patients in the Intensive Care Unit: An International Survey.

Background: Analgo-sedation plays an important role during intensive care management of traumatic brain injury (TBI) patients, however, limited evidence is available to guide practice. We sought to quantify practice-pattern variation in neurotrauma sedation management, surveying an international sample of providers. Methods: An electronic survey consisting of 56 questions was distributed internationally to neurocritical care providers utilizing the Research Electronic Data Capture platform. Descriptive statistics were used to quantitatively describe and summarize the responses. Results: Ninety-five providers from 37 countries responded. 56.8% were attending physicians with primary medical training most commonly in intensive care medicine (68.4%) and anesthesiology (26.3%). Institutional sedation guidelines for TBI patients were available in 43.2%. Most common sedative agents for induction and maintenance, respectively, were propofol (87.5% and 88.4%), opioids (60.2% and 70.5%), and benzodiazepines (53.4% and 68.4%). Induction and maintenance sedatives, respectively, are mostly chosen according to provider preference (68.2% and 58.9%) rather than institutional guidelines (26.1% and 35.8%). Sedation duration for patients with intracranial hypertension ranged from 24 h to 14 days. Neurological wake-up testing (NWT) was routinely performed in 70.5%. The most common NWT frequency was every 24 h (47.8%), although 20.8% performed NWT at least every 2 h. Richmond Agitation and Sedation Scale targets varied from deep sedation (34.7%) to alert and calm (17.9%). Conclusions: Among critically ill TBI patients, sedation management follows provider preference rather than institutional sedation guidelines. Wide practice-pattern variation exists for the type, duration, and target of sedative management and NWT performance. Future comparative effectiveness research investigating these differences may help optimize sedation strategies to promote recovery.

County-level disparities in care for patients with glioblastoma.

OBJECTIVE: Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities in glioblastoma (GBM) care in the United States, focusing on access to surgery and the use of adjuvant temozolomide chemotherapy and radiation therapy. METHODS: Using repeated cross-sectional data from the Surveillance, Epidemiology, and End Results 17 database; the Area Health Resources File; and the American Community Survey, from 2010 to 2019, the authors performed multivariate regression analyses to understand the associations between county-level racial and socioeconomic characteristics, as well as the rates of surgery performed, delays in surgery, and use of adjuvant chemotherapy and radiation therapy for newly diagnosed GBM. RESULTS: In total, 29,609 GBM patients from 602 different US counties over a decade were included in this study. Counties with lower rates of surgery for GBM were associated with a higher percentage of Black residents (coefficient [CE] -0.001, 95% CI -0.002 to 0; p < 0.05) and being located in the Midwest (CE -0.132, 95% CI -0.195 to -0.069; p < 0.001) or West (CE -0.127, 95% CI -0.189 to -0.065; p < 0.001) relative to the Northeast. Counties with delayed surgical treatment were more likely to lack neurosurgeons (adjusted OR [aOR] 2.52, 95% CI 1.77-3.60; p < 0.001), have a higher percentage of Black residents (aOR 1.011, 95% CI 1.00-1.02; p < 0.05), and be located in the Midwest (aOR 3.042, 95% CI 1.12-8.24; p < 0.05) or West (aOR 3.175, 95% CI 1.12-8.97 p < 0.05). Counties with high rates of adjuvant radiation therapy were less likely to have higher percentages of Black residents (aOR 0.987, 95% CI 0.980-0.995; p < 0.01) and uninsured individuals (aOR 0.962, 95% CI 0.937-0.987; p < 0.01). CONCLUSIONS: Counties without neurosurgeons and those with a higher percentage of Black patients have delays in surgical care and demonstrate lower overall rates of surgery and adjuvant therapy for GBM. This study underscores the need for targeted interventions and policies that address structural barriers in healthcare access, improve equitable distribution of the neurosurgery workforce, and ensure timely and comprehensive GBM care to all populations.

Decision making and surgical modality selection in glioblastoma patients: an international multicenter survey.

PURPOSE: Due to the lack of consensus on the management of glioblastoma patients, there exists variability amongst surgeons and centers regarding treatment decisions. Though, objective data about the extent of this heterogeneity is still lacking. We aim to evaluate and analyze the similarities and differences in neurosurgical practice patterns. METHODS: The survey was distributed to members of the neurosurgical societies of the Netherlands (NVVN), Europe (EANS), the United Kingdom (SBNS) and the United States (CNS) between January and March 2021 with questions about the selection of surgical modality and decision making in glioblastoma patients. RESULTS: Survey respondents (224 neurosurgeons) were from 41 countries. Overall, the most notable differences observed were the presence and timing of a multidisciplinary tumor board; the importance and role of various perioperative factors in the decision-making process, and the preferred treatment in various glioblastoma cases and case variants. Tumor boards were more common at academic centers. The intended extent of resection for glioblastoma resections in eloquent areas was limited more often in European neurosurgeons. We found a strong relationship between the surgeon's theoretical survey answers and their actual approach in presented patient cases. In general, the factors which were found to be theoretically the most important in surgical decision making were confirmed to influence the respondents' decisions to the greatest extent in practice as well. DISCUSSION: This survey illustrates the theoretical and practical heterogeneity among surgeons and centers in their decision making and treatment selection for glioblastoma patients. These data invite further evaluations to identify key variables that can be optimized and may therefore benefit from consensus.

Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.

Microscale Physiological Events on the Human Cortical Surface.

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.

Guidelines in the management of CNS tumors.

INTRODUCTION: Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS). METHODS: The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice. CONCLUSION: This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults.

QUESTION: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. QUESTION: Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?). TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. QUESTION: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. QUESTION: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.

Virtual education in neurosurgery during the COVID-19 pandemic.

OBJECTIVE: Neurosurgical education in the US has changed significantly as a consequence of the novel coronavirus (COVID-19) pandemic. Institutional social distancing requirements have resulted in many neurosurgical programs utilizing video conferencing for educational activities. However, it is unclear how or if these practices should continue after the pandemic. The objective of this study was to characterize virtual education in neurosurgery and understand how it should be utilized after COVID-19. METHODS: A 24-question, 3-part online survey was administered anonymously to all 117 US neurosurgical residency programs from May 15, 2020, to June 15, 2020. Questions pertained to the current use of virtual conferencing, preferences over traditional conferences, and future inclinations. The Likert scale (1 = strongly disagree, 3 = neutral, 5 = strongly agree) was used. Comparisons were calculated using the Mann-Whitney U-test. Statistical significance was set at 0.05. RESULTS: One-hundred eight responses were recorded. Overall, 38 respondents (35.2%) were attendings and 70 (64.8%) were trainees. Forty-one respondents (38.0%) indicated attending 5-6 conferences per week and 70 (64.8%) attend national virtual conferences. When considering different conference types, there was no overall preference (scores < 3) for virtual conferences over traditional conferences. In regard to future use, respondents strongly agreed that they would continue the practice at some capacity after the pandemic (median score 5). Overall, respondents agreed that virtual conferences would partially replace traditional conferences (median score 4), whereas they strongly disagreed with the complete replacement of traditional conferences (median score 1). The most common choices for the partial replacement of tradition conferences were case conferences (59/108, 55%) and board preparation (64/108, 59%). Lastly, there was a significant difference in scores for continued use of virtual conferencing in those who attend nationally sponsored conferences (median score 5, n = 70) and those who do not (median score 4, n = 38; U = 1762.50, z = 2.97, r = 0.29, p = 0.003). CONCLUSIONS: Virtual conferences will likely remain an integral part of neurosurgical education after the COVID-19 pandemic has abated. Across the country, residents and faculty report a preference for continued use of virtual conferencing, especially virtual case conferences and board preparation. Some traditional conferences may even be replaced with virtual conferences, in particular those that are more didactic. Furthermore, nationally sponsored virtual conferences have a positive effect on the preferences for continued use of virtual conferences.

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

BACKGROUND: Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS: In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS: We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION: Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE: Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.

Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide.

Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings.

The role of surgery in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: Surgical resection is recommended over observation to improve overall survival for patients with diffuse low-grade glioma (Level III) although observation has no negative impact on cognitive performance and quality of life (Level II). QUESTION: What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: IMPACT OF EXTENT OF RESECTION ON PFS: LEVEL II: It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rate of progression after GTR is fairly high. LEVEL III: Greater extent of resection can improve OS in LGG patients. QUESTION: What tools are available to increase extent of resection in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: INTRAOPERATIVE MRI DURING SURGERY: LEVEL III: The use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs. QUESTION: What is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: SURGICAL RESECTION AND SEIZURE CONTROL: LEVEL III: After taking into account the patient's clinical status and tumor location, gross total resection is recommended for patients with diffuse LGG as a way to achieve more favorable seizure control. LEVEL III: Taking into account the patient's clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis. QUESTION: What tools can improve the safety of surgery for LGGs in eloquent locations? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: PREOPERATIVE IMAGING: LEVEL III: It is recommended that preoperative functional MRI and diffusion tensor imaging be utilized in the appropriate clinical setting to improve functional outcome after surgery for LGG. LEVEL III: Intraoperative mapping is recommended for patients with diffuse LGGs in eloquent locations compared to patients with non-eloquently located diffuse LGGs as a way of preserving function.

The role of neuropathology in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma. QUESTION: What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult? RECOMMENDATION: LEVEL I: Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma. LEVEL III: Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method? LEVEL II: IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse glioma, and is recommended as an additional test for classification and prognosis. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method? LEVEL III: 1p/19q loss-of-heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method? RECOMMENDATION: There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results? LEVEL III: Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). QUESTION: Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? RECOMMENDATIONS: IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations. QUESTION: What role does chemotherapy have in LGG recurrence? RECOMMENDATIONS: TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. QUESTION: What role does radiation have in LGG recurrence? RECOMMENDATIONS: RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. SURGERY AT RECURRENCE: There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.

The Absence of Fever or Leukocytosis Does Not Exclude Infection Following Cranioplasty.

BACKGROUND: Cranioplasty encompasses various cranial reconstruction techniques that are used following craniectomy due to stroke or trauma. Despite classical infectious signs, symptoms, and radiologic findings, however, the diagnosis of infection following cranioplasty can be elusive, with the potential to result in definitive treatment delay. We sought to determine if fever or leukocytosis at presentation were indicative of infection, as well as to identify any factors that may limit its applicability. METHODS: Following institutional review board approval, a retrospective cohort of 239 patients who underwent cranioplasty following craniectomy for stroke or trauma was established from 2001-2011 at a single center (Massachusetts General Hospital). Analysis was then focused on those who developed a surgical site infection, as defined by either frank intra-operative purulence or positive intra-operative cultures, and subsequently underwent operative management. RESULTS: In 27 total cases of surgical site infection, only two had a fever and four had leukocytosis at presentation. This yielded a false-negative rate for fever of 92.6% and for leukocytosis of 85.2%. In regard to infectious etiology, 22 (81.5%) cases generated positive intra-operative cultures, with Propionibacterium acnes being the most common organism isolated. Median interval to infection was 99 days from initial cranioplasty to time of infectious presentation, and average follow-up was 3.4 years. CONCLUSIONS: The utilization of fever and elevated white blood cell count in the diagnosis of post-cranioplasty infection is associated with a high false-negative rate, making the absence of these features insufficient to exclude the diagnosis of infection.

Low-grade gliomas.

Low-grade gliomas (LGGs) are a diverse group of primary brain tumors that often arise in young, otherwise healthy patients and generally have an indolent course with longer-term survival in comparison with high-grade gliomas. Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment-related risks. We review in this article current management strategies for LGG, including surgery, radiotherapy, and chemotherapy. In addition, the importance of profiling the genetic and molecular properties of LGGs in the development of targeted anticancer therapies is also reviewed. Finally, given the prevalence of these tumors in otherwise healthy young patients, the impact of treatment on neurocognitive function and quality of life is also evaluated.

Fluorescence and immune-cell infiltration of nonneoplastic, postbrachytherapy brain tissue in 5-ALA-guided resection of recurrent anaplastic meningioma: illustrative case.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is a well-established technique for resecting high-grade gliomas. However, its application in meningiomas, especially those previously treated with radiation therapy, remains under investigation. OBSERVATIONS: A 48-year-old female with recurrent anaplastic meningioma, World Health Organization grade 3, underwent a right-sided craniotomy using off-label 5-ALA as a surgical adjunct. The patient had previously undergone brachytherapy seed implantation (20 × cesium 131) for tumor management. During the surgery, a large fluorescent tumor mass adjacent to the brachytherapy-treated area was resected, and the prior brachytherapy seeds were removed. Interestingly, the surrounding brain tissue in the irradiated area showed robust 5-ALA fluorescence. Pathological examination confirmed that the fluorescent brain tissue was nonneoplastic and associated with lymphocyte and macrophage infiltration. LESSONS: This case report presents unique 5-ALA fluorescence in nonneoplastic tissue following brachytherapy, which was found during the resection of recurrent anaplastic meningioma. This phenomenon may reflect an intricate interplay among radiation therapy, immune cells, the tumor microenvironment, and 5-ALA metabolism. Given that false-positive findings in fluorescence-guided surgery can lead to unnecessary tissue resection and increased surgical morbidity, further research is warranted to elucidate the mechanisms underlying this phenomenon and its implications for meningioma surgery.

Neurological Surgery Residency Programs in the United States: A National Cross-Sectional Survey.

BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education has approved 117 neurological surgery residency programs which develop and educate neurosurgical trainees. We present the current landscape of neurosurgical training in the United States by examining multiple aspects of neurological surgery residencies in the 2022-2023 academic year and investigate the impact of program structure on resident academic productivity. METHODS: Demographic data were collected from publicly available websites and reports from the National Resident Match Program. A 34-question survey was circulated by e-mail to program directors to assess multiple features of neurological surgery residency programs, including curricular structure, fellowship availability, recent program changes, graduation requirements, and resources supporting career development. Mean resident productivity by program was collected from the literature. RESULTS: Across all 117 programs, there was a median of 2.0 (range 1.0-4.0) resident positions per year and 1.0 (range 0.0-2.0) research/elective years. Programs offered a median of 1.0 (range 0.0-7.0) Committee on Advanced Subspecialty Training-accredited fellowships, with endovascular fellowships being most frequently offered (53.8%). The survey response rate was 75/117 (64.1%). Of survey respondents, the median number of clinical sites was 3.0 (range 1.0-6.0). Almost half of programs surveyed (46.7%) reported funding mechanisms for residents, including R25, T32, and other in-house grants. Residents received a median academic stipend of $1000 (range $0-$10 000) per year. Nearly all programs (93.3%) supported wellness activities for residents, which most frequently occurred quarterly (46.7%). Annual academic stipend size was the only significant predictor of resident academic productivity (R 2 = 0.17, P = .002). CONCLUSION: Neurological surgery residency programs successfully train the next generation of neurosurgeons focusing on education, clinical training, case numbers, and milestones. These programs offer trainees the chance to tailor their career trajectories within residency, creating a rewarding and personalized experience that aligns with their career aspirations.