Chetan Bettegowda

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1, 2, 3, 4, 5, 6, 7, 8, 9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10, 11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells 13, 14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T …

ObjectiveCareful hematologic management is required in surgical patients with traumatic acute subdural hematoma (aSDH) taking antithrombotic medications. We sought to compare outcomes between patients with aSDH taking antithrombotic medications at admission who received antithrombotic reversal with patients with aSDH not taking antithrombotics.MethodsRetrospective review identified patients with traumatic aSDH requiring surgical evacuation. The cohort was divided based on antithrombotic use and whether pharmacologic reversal agents or platelet transfusions were administered. A 3-way comparison of outcomes was performed between patients taking anticoagulants who received pharmacologic reversal, patients taking antiplatelets who received platelet transfusion, and patients not taking antithrombotics. Multivariable regressions, adjusted for injury severity, further investigated associations with …

PurposeThere is limited literature describing care coordination for patients with glioblastoma (GBM). We aimed to investigate the impact of primary care and electronic health information exchange (HIE) between neurosurgeons, oncologists, and primary care providers (PCP) on GBM treatment patterns, postoperative outcomes, and survival.MethodsWe identified adult GBM patients undergoing primary resection at our institution (2007–2020). HIE was defined as shared electronic medical information between PCPs, oncologists, and neurosurgeons. Multivariate logistic regression analyses were used to determine the effect of PCPs and HIE upon initiation and completion of adjuvant therapy. Kaplan-Meier and multivariate Cox regression models were used to evaluate overall survival (OS).ResultsAmong 374 patients (mean age±SD: 57.7±13.5, 39.0% female), 81.0% had a PCP and 62.4% had electronic HIE. In …

ObjectiveIntramedullary spinal cord (IMSC) subependymomas are rare World Health Organization grade 1 ependymal tumors. The potential presence of functional neural tissue within the tumor and poorly demarcated planes presents a risk to resection. Anticipating a subependymoma on preoperative imaging can inform surgical decision-making and improve patient counseling. Here, we present our experience recognizing IMSC subependymomas on preoperative magnetic resonance imaging (MRI) based on a distinctive characteristic termed the “ribbon sign.”MethodsWe retrospectively reviewed preoperative MRIs of patients presenting with IMSC tumors at a large tertiary academic institution between April 2005 and January 2022. The diagnosis was confirmed histologically. The “ribbon sign” was defined as a ribbon-like structure of T2 isointense spinal cord tissue interwoven between regions of T2 hyperintense …

IntroductionNeurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies.MethodsThe Response Evaluation in Neurofibromatosis and Schwannomatosis biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings.ResultsLiquid biopsy has emerged as a promising assay for neurofibromatosis 1 …

Background The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. Methods The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and CSF-liquid biopsy in central nervous system lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). Results Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, steroids responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments and prediction of outcome. Conclusions Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS …

METHODS:We retrospectively identified 176 adult IDHmAstro patients with available next-generation sequencing (NGS). All tumors were regraded based on the 2021 and 2016 WHO grading schema using relevant histopathological (mitotic rate, microvascular proliferation, necrosis) and molecular (CDKN2A) features. The prognostic ability of each grading schema was evaluated with Kaplan-Meier and multivariate Cox Regression analyses.RESULTS:The cohort consisted of 76 grade 2 (43.2%), 45 grade 3 (25.6%), and 55 grade 4 (31.3%) IDHmAstro cases using the 2021 grading schema. Only four patients (2%) had a grade change from the 2016 WHO grading scheme-one prior 2016 WHO grade II and three grade III tumors, all regraded to Grade 4 based on present CDKN2A homozygous deletion. When assessed based on both classification schemas, WHO Grade 4/IV tumors were associated with lower OS than …

OBJECTIVE Chordomas are locally aggressive neoplasms of the spine or skull base that arise from embryonic remnants of the notochord. Intradural chordomas represent a rare subset of these neoplasms, and few studies have described intradural chordomas in the spine. This review evaluates the presentation, management, and outcomes of intradural spinal chordomas. METHODS A systematic review of PubMed/MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science was performed. Studies describing at least 1 case of intradural chordomas anywhere in the spine were included. Extracted details included presenting symptoms, radiological findings, treatment course, follow-up, and disease progression. RESULTS Thirty-one studies, with a total of 41 patients, were included in this review. Seventy-six percent (31/41) of patients had …

OBJECTIVE Factors that may drive recommendations for operative intervention for patients with intramedullary spinal cord tumors (ISCTs) have yet to be extensively studied. The authors investigated racial and socioeconomic disparities in the management of patients with primary spinal cord ependymomas and nonependymal gliomas, with the aim of determining the associations between socioeconomic patient characteristics, survival, and recommendations for the resection of primary ISCTs. METHODS The Surveillance, Epidemiology, and End Results registry was queried to identify all patients> 18 years of age with ISCTs diagnosed between 2000 and 2019. Univariable and multivariable logistic regression analyses were used to calculate odds ratios for variables associated with receiving a surgical recommendation. Log-rank tests and multivariable Cox proportional hazards models were used to investigate …

METHODS:We analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival, 3 cervical, 2 lumbar, and 14 sacral tumors) through multiplex immunofluorescence. In addition, we investigated the phenotype of tumor-infiltrating and peripheral B cells and myeloid cells from five chordoma patients employing single-cell RNA sequencing.RESULTS:Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of B cells, T cells, and macrophages. Cluster 1 was characterized by moderate immune cell infiltration, cluster 2 was immune-desertic, and cluster 3 was highly infiltrated by B and T cells. Findings from single-cell transcriptomics revealed that regulatory B cells and plasma cells were the most abundant B cell populations infiltrating tumors. In addition, we found the presence of tumor-infiltrating …

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the …

BACKGROUNDSocioeconomic status (SES) is a major determinant of quality of life and outcomes. However, SES remains difficult to measure comprehensively. Distress communities index (DCI), a composite of seven socioeconomic factors, has been increasingly recognized for its correlation with poor outcomes.OBJECTIVETo determine the predictive value of DCI on outcomes following intracranial tumor surgery.METHODSA single institution, retrospective review was conducted to identify adult intracranial tumor patients undergoing resection (2016–2021). Patient ZIP codes were matched to DCI and stratified by DCI quartiles (low:0–24.9, low-intermediate:25–49.9, intermediate-high:50–74.9, high:75–100). Univariate followed by multivariate regressions assessed the effects of DCI on postoperative outcomes. Receiver operating curves (ROC) were generated for significant outcomes.RESULTSA total of 2,389 …

ObjectiveThe Hospital Frailty Risk Score (HFRS) is a tool for quantifying patient frailty using International Classification of Diseases, Tenth Revision codes. This study aimed to determine the utility of the HFRS in predicting surgical outcomes after resection of glioblastoma (GBM) and compare its prognostic ability with other validated indices such as American Society of Anesthesiologists score and Charlson Comorbidity Index.MethodsA retrospective analysis was conducted using a GBM patient database (2017–2019) at a single institution. HFRS was calculated using International Classification of Diseases, Tenth Revision codes. Bivariate logistic regression was used to model prognostic ability of each frailty index, and model discrimination was assessed using area under the receiver operating characteristic curve. Multivariate linear and logistic regression models were used to assess for significant associations …

Deep learning models have demonstrated great potential in medical 3D imaging, but their development is limited by the expensive, large volume of annotated data required. Active learning (AL) addresses this by training a model on a subset of the most informative data samples without compromising performance. We compared different AL strategies and propose a framework that minimizes the amount of data needed for state-of-the-art performance. 638 multi-institutional brain tumor MRI images were used to train a 3D U-net model and compare AL strategies. We investigated uncertainty sampling, annotation redundancy restriction, and initial dataset selection techniques. Uncertainty estimation techniques including Bayesian estimation with dropout, bootstrapping, and margins sampling were compared to random query. Strategies to avoid annotation redundancy by removing similar images within the to-be-annotated subset were considered as well. We determined the minimum amount of data necessary to achieve similar performance to the model trained on the full dataset ({\alpha} = 0.1). A variance-based selection strategy using radiomics to identify the initial training dataset is also proposed. Bayesian approximation with dropout at training and testing showed similar results to that of the full data model with less than 20% of the training data (p=0.293) compared to random query achieving similar performance at 56.5% of the training data (p=0.814). Annotation redundancy restriction techniques achieved state-of-the-art performance at approximately 40%-50% of the training data. Radiomics dataset initialization had higher Dice with initial …

METHODS:We retrospectively reviewed all patients undergoing microvascular decompression at our institution, identifying patients with either sole arterial or venous compression. We dichotomized patients into arterial or venous groups and obtained demographics and postoperative complications for each case. Barrow Neurological Index (BNI) pain scores were collected preoperatively, postoperatively, and at final follow-up, as well as recurrence of pain. Differences were calculated via Chi-squared tests and t-tests. Ordinal regression was used to account for variables known to influence TN pain. Kaplan-Meier analysis was used to determine recurrence-free survival.RESULTS:Of 1044 patients, 642 (61.7%) had either sole arterial or venous compression. 472 of these cases demonstrated arterial compression, and 170 displayed sole venous compression. Patients in the venous compression group were significantly …

Purpose We aimed to develop and validate a deep learning (DL) model to automatically segment posterior fossa ependymoma (PF-EPN) and predict its molecular subtypes [Group A (PFA) and Group B (PFB)] from preoperative MR images. Experimental Design We retrospectively identified 227 PF-EPNs (development and internal test sets) with available preoperative T2-weighted (T2w) MR images and molecular status to develop and test a 3D nnU-Net (referred to as T2-nnU-Net) for tumor segmentation and molecular subtype prediction. The network was externally tested using an external independent set [n = 40; subset-1 (n = 31) and subset-2 (n =9)] and prospectively enrolled cases [prospective validation set (n = 27)]. The Dice similarity coefficient was used to evaluate the segmentation performance. Receiver operating characteristic analysis for molecular subtype …

The current approach to diagnosing and monitoring tumors of the central nervous system relies almost exclusively on radiographic imaging and neurosurgical procedures. Cerebrospinal fluid (CSF) is appealing for diagnosis because it is already part of the standard of care for the diagnosis or management of several types of CNS disease, including cancer, and the tumor DNA is more highly concentrated inside the blood brain barrier than in plasma or other bodily fluids. Even though cytology is widely used, sensitivity remains low ranging from 2% to 50%, depending on cancer type. We report an analytic technique that efficiently introduces identical molecular barcodes to both strands of CSF template DNA molecules for the identification of cancer specific somatic mutations and copy number alterations. We apply this approach to 126 CSF samples obtained from individuals with known primary or metastatic tumors …

METHODS:We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 1995 to 2022. Patients were included if they had no history of surgical intervention, available preoperative MRI imaging, and postoperative follow-up data. Barrow Neurological Institute pain scores were assigned at various time points. We collected baseline patient information, pain characteristics, and perioperative complications for each patient. In addition, we recorded evidence of pain recurrence. Patients were dichotomized into those with evidence of neurovascular compression on preoperative MRI vs those without. The effect of neurovascular compression on pain-free survival was assessed using Kaplan-Meier Cox proportional hazards analyses.RESULTS:Of the 2726 patients reviewed, 298 met our inclusion criteria. Our study comprised 261 patients with no evidence of neurovascular compression …

BackgroundPatient-reported outcome measures (PROMs) are increasingly used to assess patients’ perioperative health. The PROM Information System 29 (PROMIS-29) is a well-validated global health assessment instrument for patient physical health, though its utility in cranial neurosurgery is unclear.ObjectiveTo investigate the utility of preoperative PROMIS-29 physical health (PH) summary scores in predicting postoperative outcomes in brain tumor patients.MethodsAdult brain tumor patients undergoing resection at a single institution (January 2018-December 2021) were identified and prospectively received PROMIS-29 surveys during pre-operative visits. PH summary scores were constructed and optimum prediction thresholds for length of stay (LOS), discharge disposition (DD), and 30-day readmission were approximated by finding the Youden index of the associated receiver operating characteristic curves …

Background and objectivesAcute subdural hematoma (aSDH) after traumatic brain injury frequently requires emergent craniotomy (CO) or decompressive craniectomy (DC). We sought to determine the variables associated with either surgical approach and to compare outcomes between matched patients.MethodsA multi-center retrospective review was used to identify traumatic aSDH patients who underwent CO or DC. Patient variables independently associated with surgical approach were used for coarsened exact matching. Multivariate logistic regression and multivariate Cox proportional-hazards regression were conducted on matched patients to determine independent predictors of mortality.ResultsSeventy-six patients underwent CO and sixty-two underwent DC for aSDH evacuation. DC patients were 21.4 years younger (P < 0.001), more likely to be male (80.6 % vs 60.5 %, P = 0.011), and present with GCS …