Frailty in patients with IDH-mutant gliomas: experience from a high-volume tumor center.

PURPOSE: Gliomas are increasingly diagnosed in an aging population, with treatment outcomes influenced by factors like tumor genetics and patient frailty. This study focused on IDH-mutant gliomas and assessed how frailty affects 30-day readmission and overall survival (OS). We aimed to address a gap in understanding the impact of frailty on this specific glioma subtype. METHODS: 136 patients with an IDH-mutant glioma between 2007 and 2021 were identified at our institution. High frailty was classified by scores ≥ 1 on the 5-factor modified frailty index (mFI-5) and ≥ 3 on the Charlson Comorbidity Index (CCI). Patient and tumor characteristics including age, sex, race, Karnofsky Performance Status (KPS), Body Mass Index (BMI), tumor type and location, type of operation, and therapy course were recorded. Outcomes measured included 30-day readmission and overall survival (OS). Analysis was conducted utilizing logistic regression and Kaplan-Meier curves. RESULTS: Of the 136 patients, 52 (38%) had high frailty: 18 with CCI ≥ 3, 34 with mFI-5 ≥ 1. High frailty correlated with increased BMI (CCI: 30.2, mFI-5: 30.1 kg/m2), more neurological deficits (CCI: 61%, mFI-5: 56%), and older age at surgery (CCI: 63, mFI-5: 48 years). Hospital readmission within 30 days occurred in 8 (5.9%) patients. Logistic regression indicated no significant difference in 30-day readmission rates (CCI: p = 0.30, mFI-5: p = 0.62) or median OS between high and low frailty groups. However, patients treated at our institution with newly diagnosed tumors with high mFI-5 had a 6.79 times higher adjusted death hazard than those with low mFI-5 (p = .049). CONCLUSION: Our analysis revealed that CCI and mFI-5 were not significantly associated with 30-day nor OS. However, in patients with non-recurrent tumors, there was a significant association of mFI-5 with OS. Further study of frailty with larger cohorts is warranted to enhance prognostication of outcome after neurosurgical treatment.

TGF-ß and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma.

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Intramedullary Spinal Cord Tumors: Whole-Genome Sequencing to Assist Management and Prognosis.

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth's penalized likelihood approach was used to account for the low event rates. Fisher's exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors.

Extent of Resection and Outcomes of Patients with Primary Malignant Brain Tumors.

OPINION STATEMENT: We have level II evidence that attempting a gross total resection of newly diagnosed suspected glioblastoma is preferred when a maximally safe resection can be attempted. This recommendation extends to elderly patients and those with butterfly gliomas. However, in cases where patients are poor surgical candidates, or for lesions in eloquent areas, subtotal resection or biopsy may be indicated. Recent studies have discussed "supramaximal surgery," which is defined in different ways by different teams, but there is not enough evidence, yet, to make a consistent recommendation for supramaximal resection for specific patients.

Examining the Effect of ALK and EGFR Mutations on Survival Outcomes in Surgical Lung Brain Metastasis Patients.

In the context of the post-genomic era, where targeted oncological therapies like monoclonal antibodies (mAbs) and tyrosine-kinase inhibitors (TKIs) are gaining prominence, this study investigates whether these therapies can enhance survival for lung carcinoma patients with specific genetic mutations-EGFR-amplified and ALK-rearranged mutations. Prior to this study, no research series had explored how these mutations influence patient survival in cases of surgical lung brain metastases (BMs). Through a multi-site retrospective analysis, the study examined patients who underwent surgical resection for BM arising from primary lung cancer at Emory University Hospital from January 2012 to May 2022. The mutational statuses were determined from brain tissue biopsies, and survival analyses were conducted. Results from 95 patients (average age: 65.8 ± 10.6) showed that while 6.3% had anaplastic lymphoma kinase (ALK)-rearranged mutations and 20.0% had epidermal growth factor receptor (EGFR)-amplified mutations-with 9.5% receiving second-line therapies-these mutations did not significantly correlate with overall survival. Although the sample size of patients receiving targeted therapies was limited, the study highlighted improved overall survival and progression-free survival rates compared to earlier trials, suggesting advancements in systemic lung metastasis treatment. The study suggests that as more targeted therapies emerge, the prospects for increased overall survival and progression-free survival in lung brain metastasis patients will likely improve.

Clinical protocol: Feasibility of evaluating abemaciclib neuropharmacokinetics of diffuse midline glioma using intratumoral microdialysis.

Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.

Promoting diversity in neurosurgery through a virtual symposium.

OBJECTIVE: The rates of women and underrepresented racial and ethnic minority (UREM) students successfully matching into neurosurgical residency are extremely low and do not reflect the makeup of the general population. As of 2019, only 17.5% of neurosurgical residents in the United States were women, 4.95% were Black or African American, and 7.2% were Hispanic or Latinx. Earlier recruitment of UREM students will help to diversify the neurosurgical workforce. Therefore, the authors developed a virtual educational event for undergraduate students entitled "Future Leaders in Neurosurgery Symposium for Underrepresented Students'' (FLNSUS). The primary objectives of the FLNSUS were to expose attendees to 1) neurosurgeons from diverse gender, racial, and ethnic backgrounds; 2) neurosurgical research; 3) opportunities for neurosurgical mentorship; and 4) information about life as a neurosurgeon. The authors hypothesized that the FLNSUS would increase student self-confidence, provide exposure to the specialty, and reduce perceived barriers to a neurosurgical career. METHODS: To measure the change in participant perceptions of neurosurgery, pre- and postsymposium surveys were administered to attendees. Of the 269 participants who completed the presymposium survey, 250 participated in the virtual event and 124 completed the postsymposium survey. Paired pre- and postsurvey responses were used for analysis, yielding a response rate of 46%. To assess the impact of participant perceptions of neurosurgery as a field, pre- and postsurvey responses to questions were compared. The change in response was analyzed, and a nonparametric sign test was performed to check for significant differences. RESULTS: According to the sign test, applicants showed increased familiarity with the field (p < 0.001), increased confidence in their abilities to become neurosurgeons (p = 0.014), and increased exposure to neurosurgeons from diverse gender, racial, and ethnic backgrounds (p < 0.001 for all categories). CONCLUSIONS: These results reflect a significant improvement in student perceptions of neurosurgery and suggest that symposiums like the FLNSUS may promote further diversification of the field. The authors anticipate that events promoting diversity in neurosurgery will lead to a more equitable workforce that will ultimately translate to enhanced research productivity, cultural humility, and patient-centered care in neurosurgery.

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS.

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

Historical determinants of neurosurgical inequities in Africa and the African diaspora: A review and analysis of coloniality.

The movement to decolonize global health challenges clinicians and researchers of sub-disciplines, like global neurosurgery, to redefine their field. As an era of racial reckoning recentres the colonial roots of modern health disparities, reviewing the historical determinants of these disparities can constructively inform decolonization. This article presents a review and analysis of the historical determinants of neurosurgical inequities as understood by a group of scholars who share Sub-Saharan African descent. Vignettes profiling the colonial histories of Cape Verde, Rwanda, Cameroon, Ghana, Brazil, and Haiti illustrate the role of the colonial legacy in the currently unmet need for neurosurgical care in each of these nations. Following this review, a bibliographic lexical analysis of relevant terms then introduces a discussion of converging historical themes, and practical suggestions for transforming global neurosurgery through the decolonial humanism promulgated by anti-racist practices and the dialogic frameworks of conscientization.

A scoping review of pediatric microdialysis: A missed opportunity for microdialysis in the pediatric neuro-oncology setting.

Background: Brain microdialysis is a minimally invasive technique for monitoring analytes, metabolites, drugs, neurotransmitters, and/or cytokines. Studies to date have centered on adults with traumatic brain injury, with a limited number of pediatric studies performed. This scoping review details past use of brain microdialysis in children and identifies potential use for future neuro-oncology trials. Methods: In December 2020, Cochrane Library: CENTRAL, Embase, PubMed, Scopus, and Web of Science: Core Collection were searched. Two reviewers screened all articles by title and abstract review and then full study texts, using microdialysis in patients less than 18 yo. Results: Of the 1171 articles screened, 49 were included. The 49 studies included 472 pediatric patients (age range 0-17 years old), in the brain (21), abdominal (16), and musculoskeletal (12) regions. Intracerebral microdialysis was performed in 64 collective patients, with a median age of 11 years old, and predominance in metabolic evaluations. Conclusion: Historically, pediatric microdialysis was safely performed within the brain in varied neurologic conditions, except neuro-oncology. Adult brain tumor studies using intratumoral/peritumoral microdialysis sampling can inform future pediatric studies to advance diagnosis and treatment options for such aggressive tumors.

Artificial neural networks predict the need for permanent cerebrospinal fluid diversion following posterior fossa tumor resection.

Background: Resection of posterior fossa tumors (PFTs) can result in hydrocephalus that requires permanent cerebrospinal fluid (CSF) diversion. Our goal was to prospectively validate a machine-learning model to predict postoperative hydrocephalus after PFT surgery requiring permanent CSF diversion. Methods: We collected preoperative and postoperative variables on 518 patients that underwent PFT surgery at our center in a retrospective fashion to train several statistical classifiers to predict the need for permanent CSF diversion as a binary class. A total of 62 classifiers relevant to our data structure were surveyed, including regression models, decision trees, Bayesian models, and multilayer perceptron artificial neural networks (ANN). Models were trained using the (N = 518) retrospective data using 10-fold cross-validation to obtain accuracy metrics. Given the low incidence of our positive outcome (12%), we used the positive predictive value along with the area under the receiver operating characteristic curve (AUC) to compare models. The best performing model was then prospectively validated on a set of 90 patients. Results: Twelve percent of patients required permanent CSF diversion after PFT surgery. Of the trained models, 8 classifiers had an AUC greater than 0.5 on prospective testing. ANNs demonstrated the highest AUC of 0.902 with a positive predictive value of 83.3%. Despite comparable AUC, the remaining classifiers had a true positive rate below 35% (compared to ANN, P < .0001). The negative predictive value of the ANN model was 98.8%. Conclusions: ANN-based models can reliably predict the need for ventriculoperitoneal shunt after PFT surgery.

Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

Clinical and radiographic characteristics of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma: a single institution review.

PURPOSE: Genetic analyses of gliomas have identified key molecular features that impact treatment paradigms beyond conventional histomorphology. Despite at-times lower grade histopathologic appearances, IDH-wildtype infiltrating gliomas expressing certain molecular markers behave like higher-grade tumors. For IDH-wildtype infiltrating gliomas lacking traditional features of glioblastoma, these markers form the basis for the novel diagnosis of diffuse astrocytic glioma, IDH-wildtype (wt), with molecular features of glioblastoma (GBM), WHO grade-IV (DAG-G). However, given the novelty of this approach to diagnosis, literature detailing the exact clinical, radiographic, and histopathologic findings associated with these tumors remain in development. METHODS: Data for 25 patients matching the DAG-G diagnosis were obtained from our institution's retrospective database. Information regarding patient demographics, treatment regimens, radiographic imaging, and genetic pathology were analyzed to determine association with clinical outcomes. RESULTS: The initial radiographic findings, histopathology, and symptomatology of patients with DAG-G were similar to lower-grade astrocytomas (WHO grade 2/3). Overall survival (OS) and progression free survival (PFS) associated with our cohort, however, were similar to that of IDH-wt GBM, indicating a more severe clinical course than expected from other associated features (15.1 and 5.39 months respectively). CONCLUSION: Despite multiple features similar to lower-grade gliomas, patients with DAG-G experience clinical courses similar to GBM. Such findings reinforce the need for biopsy and subsequent analysis of molecular features associated with any astrocytoma regardless of presenting characteristics.

Guidelines for optimal utilization of social media for brain tumor stakeholders.

OBJECTIVE: Effective use of social media (SM) by medical professionals is vital for better connections with patients and dissemination of evidence-based information. A study of SM utilization by different stakeholders in the brain tumor community may help determine guidelines for optimal use. METHODS: Facebook, Twitter, and YouTube were searched by using the term "Brain Tumor." Platform-specific metrics were determined, including audience size, as a measure of popularity, and mean annual increase in audience size, as a measure of performance on SM. Accounts were categorized on the basis of apparent ownership and content, with as many as two qualitative themes assigned to each account. Correlations of content themes and posting behavior with popularity and performance metrics were assessed by using the Pearson's test. RESULTS: Facebook (67 pages and 304,581 likes) was predominantly used by organizations (64% of pages). Top themes on Facebook, Twitter, and YouTube were charity and fundraising (67% of pages), education and research (72% of accounts), and experience sharing and support seeking (48% of videos, 60% of views, and 82% of user engagement), respectively. On Facebook, only the presence of other concurrent platforms influenced a page's performance (rho = 0.59) and popularity (rho = 0.61) (p < 0.05). On Twitter, the number of monthly tweets (rho = 0.66) and media utilization (rho = 0.78) were significantly correlated with increased popularity and performance (both p < 0.05). Personal YouTube videos (30% of videos and 61% of views) with the theme of experience sharing and support seeking had the highest level of engagement (60% of views, 70% of comments, and 87% of likes). CONCLUSIONS: Popularity and prevalence of qualitative themes differ among SM platforms. Thus, optimal audience engagement on each platform can be achieved with thematic considerations. Such considerations, along with optimal SM behavior such as media utilization and multiplatform presence, may help increase content popularity and thus increase community access to neurooncology content provided by medical professionals.