Carter, Bob S.

Abstract High-grade gliomas (HGGs) are aggressive, infiltrative brain tumors with poor survival outcomes and limited therapeutic options. Their spatial and molecular heterogeneity necessitates large, well-curated datasets integrating imaging, clinical, and genomic information to enable precision medicine and drive novel treatment development. Using the Medtronic StealthStation neuronavigation system, we collected over 1,000 spatially localized intraoperative biopsy samples from more than 250 patients undergoing resection for glioma at Mayo Clinic and partnering sites. Each biopsy site was recorded with 3D coordinates, labeled in real time, flash-frozen, and annotated with metadata including collection time, anatomical location, and surgical plan. Samples were processed and entered into a secure database along with the corresponding sampling coordinates, frozen pathology, whole-exome and RNA sequencing data, 5-ALA fluorescence status, patient demographics, and T1, T1Gd, T2, and T2-FLAIR MRI. This multimodal dataset supports radiogenomic research by enabling precise mapping of imaging features to molecular characteristics. A subset of this data, including 268 biopsies from 52 patients (25 male, 27 female) with reported intraoperative 5-ALA fluorescence, was used to develop a radiomics model predicting locoregional patterns of 5-ALA positivity based on preoperative MRI. Image features were extracted from the biopsy sample coordinates across multiple MRI sequences and paired with corresponding 5-ALA fluorescence status to train the model for regional fluorescence prediction. The final model achieved 83% accuracy on the training set and 86% on the validation set using a 70-15-15 data split; this included 208 samples for training and 42 for validation, stratified by patient to ensure no overlap of samples from the same individual across sets. These findings demonstrate the feasibility of predicting 5-ALA fluorescence using radiomic features from standard preoperative MRI, offering a promising noninvasive strategy for improving intraoperative decision-making and enabling more precise, personalized resections in patients with high-grade gliomas.

This combined American Neurotology Society, American Otological Society, and American Academy of Otolaryngology – Head and Neck Surgery Foundation document aims to provide guidance during the coronavirus disease of 2019 (COVID-19) on 1) “priority” of care for otologic and neurotologic patients in the office and operating room, and 2) optimal utilization of personal protective equipment. Given the paucity of evidence to inform otologic and neurotologic best practices during COVID-19, the recommendations herein are based on relevant peer-reviewed articles, the Centers for Disease Control and Prevention COVID-19 guidelines, United States and international hospital policies, and expert opinion. The suggestions presented here are not meant to be definitive, and best practices will undoubtedly change with increasing knowledge and high-quality data related to COVID-19. Interpretation of this guidance document is dependent on local factors including prevalence of COVID-19 in the surgeons’ local community. This is not intended to set a standard of care, and should not supersede the clinician's best judgement when managing specific clinical concerns and/or regional conditions. Access to otologic and neurotologic care during and after the COVID-19 pandemic is dependent upon adequate protection of physicians, audiologists, and ancillary support staff. Otolaryngologists and associated staff are at high risk for COVID-19 disease transmission based on close contact with mucosal surfaces of the upper aerodigestive tract during diagnostic evaluation and therapeutic procedures. While many otologic and neurotologic conditions are not imminently life threatening, they have a major impact on communication, daily functioning, and quality of life. In addition, progression of disease and delay in treatment can result in cranial nerve deficits, intracranial and life-threatening complications, and/or irreversible consequences. In this regard, many otologic and neurotologic conditions should rightfully be considered “urgent,” and almost all require timely attention to permit optimal outcomes. It is reasonable to proceed with otologic and neurotologic clinic visits and operative cases based on input from expert opinion of otologic care providers, clinic/hospital administration, infection prevention and control specialists, and local and state public health leaders. Significant regional variations in COVID-19 prevalence exist; therefore, physicians working with local municipalities are best suited to make determinations on the appropriateness and timing of otologic and neurotologic care.

Abstract When unrepaired, alkylated DNA can induce cell death or trigger mutagenesis. Cellular capacity for repair of these lesions by O6-methylguanine methyltransferase (MGMT) dictates the equilibrium between cell viability and genetic diversity. Treatment of glioblastoma cells with temozolomide (TMZ) induced ATM- and Rad3-related (ATR) kinase dependent polyribonucleotide nucleotidyltransferase 1 (PNPT1) degradation of miR-181d. miR-181d suppresses MGMT expression; its degradation increases the mean MGMT expression of the cell population. miR-181d degradation also magnifies the cell-to-cell variability in MGMT expression, expanding the genetic heterogeneity of the population. This expanded heterogeneity enhances the “fitness” of the population and constitutes a novel form of chemotherapeutic resistance. These effects can be suppressed by overexpression of miR-181d, suggesting miRNA delivery as a strategy for glioblastoma therapy. To characterize the mechanism of acquired resistance, we profiled the expression of 2400 miRNAs before and after TMZ treatment. In independent patient-derived neurosphere lines, the majority of miRNAs remained unchanged after treatment. However, miR-181d was consistently suppressed after TMZ treatment. Our previous work demonstrated miR-181d as the master regulator of MGMT. We confirmed TMZ-induced suppression of miR-181d using independent in vitro and in vivo models as well as matched pre- and post-TMZ treated clinical specimens. TMZ-induced miR-181d suppression persisted after transcriptional inhibition, suggesting degradation as the primary mechanism. We performed an siRNA screen and identified polyribonucleotide nucleotidyltransferase 1 (PNPT1) as the gene responsible for miR-181d degradation. CRISPR inactivation of PNPT1 eliminated TMZ-induced suppression of miR-181d; this was rescued by wild-type PNPT1 but not by PNPT1 harboring RNAse-inactivating mutations. TMZ-induced degradation of miR-181d requires ATR kinase. Silencing or inhibition of ATR eliminated binding of PNPT1 to miR-181d and prevented degradation of miR-181d. TMZ-sensitizing effects of ATR inhibition were reversed by anti-miR-181d, suggesting miR-181d is essential in this process. In addition to elevating the mean MGMT expression of the population, single-cell analysis revealed that miR-181d degradation broadened the cell-to-cell variability in MGMT expression in vitro. In matched clinical pre- and post-TMZ treated specimens, variability in MGMT expression was significantly elevated in post-TMZ samples. This was recapitulated using The Cancer Genome Atlas (TCGA) database. We propose that miR-181d degradation-mediated expansion of genetic heterogeneity enhances the “fitness” of the population, constituting a novel form of chemotherapeutic resistance. These effects are suppressed by miR-181d overexpression, suggesting miRNA delivery as a strategy for glioblastoma therapy. Citation Format: Valya Ramakrishnan, Johnny Akers, Thien Nguyen, Aaron Wang, Bandita Adhikari, Brian Hirshman, Jie Li, Jann Sarkaria, Wei Hua, Mao Ying, Masayuki Nitta, Tao Jiang, Bob Carter, Clark C. Chen. miR-181d degradation mediated genetic heterogeneity and acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1956.

OBJECTIVEThe subspecialization of neurosurgical practice is an ongoing trend in modern neurosurgery. However, it remains unclear whether the degree of surgeon specialization is associated with improved patient outcomes. The authors hypothesized that a trend toward increased neurosurgeon specialization was associated with improved patient morbidity and mortality rates.METHODSThe Nationwide Inpatient Sample (NIS) was used (1998–2009). Patients were included in a spinal analysis cohort for instrumented spine surgery involving the cervical spine (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 81.31–81.33, 81.01–81.03, 84.61–84.62, and 84.66) or lumbar spine (codes 81.04–81.08, 81.34–81.38, 84.64–84.65, and 84.68). A cranial analysis cohort consisted of patients receiving a parenchymal excision or lobectomy operation (codes 01.53 and 01.59). Surgeon specialization was measured using unique surgeon identifiers in the NIS and defined as the proportion of a surgeon’s total practice dedicated to cranial or spinal cases.RESULTSA total of 46,029 and 231,875 patients were identified in the cranial and spinal analysis cohorts, respectively. On multivariate analysis in the cranial analysis cohort (after controlling for overall surgeon volume, patient demographic data/comorbidities, hospital characteristics, and admitting source), each percentage-point increase in a surgeon’s cranial specialization (that is, the proportion of cranial cases) was associated with a 0.0060 reduction in the log odds of patient mortality (95% CI 0.0034–0.0086) and a 0.0042 reduction in the log odds of morbidity (95% CI 0.0032–0.0052). This resulted in a 15% difference in the predicted probability of mortality for neurosurgeons at the 75th versus the 25th percentile of cranial specialization. In the spinal analysis cohort, each percentage-point increase in a surgeon’s spinal specialization was associated with a 0.0122 reduction in the log odds of mortality (95% CI 0.0074–0.0170) and a 0.0058 reduction in the log odds of morbidity (95% CI 0.0049–0.0067). This resulted in a 26.8% difference in the predicted probability of mortality for neurosurgeons at the 75th versus the 25th percentile of spinal specialization.CONCLUSIONSFor both spinal and cranial surgery patient cohorts derived from the NIS database, increased surgeon specialization was significantly and independently associated with improved mortality and morbidity rates, even after controlling for overall case volume.

Abstract BACKGROUND Cerebrospinal fluid (CSF) leak is a well-recognized complication after surgical resection of vestibular schwannomas and is associated with a number of secondary complications, including readmission and meningitis. OBJECTIVE To identify risk factors for and timing of 30-d readmission with CSF leak. METHODS Patients who had undergone surgical resection of a vestibular schwannoma from 1995 to 2010 were identified in the California Office of Statewide Health Planning and Development database. The most common admission diagnoses were identified by International Classification of Disease, ninth Revision, diagnosis codes, and predictors of readmission with CSF leak were determined using logistic regression. RESULTS A total of 6820 patients were identified. CSF leak, though a relatively uncommon cause of admission after discharge (3.52% of all patients), was implicated in nearly half of 490 readmissions (48.98%). Significant independent predictors of readmission with CSF leak were male sex (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.32-2.25), first admission at a teaching hospital (OR 3.32, 95% CI 1.06-10.39), CSF leak during first admission (OR 1.84, 95% CI 1.33-2.55), obesity during first admission (OR 2.10, 95% CI 1.20-3.66), and case volume of first admission hospital (OR of log case volume 0.82, 95% CI 0.70-0.95). Median time to readmission was 6 d from hospital discharge. CONCLUSION This study has quantified CSF leak as an important contributor to nearly half of all readmissions following vestibular schwannoma surgery. We propose that surgeons should focus on technical factors that may reduce CSF leakage and take advantage of potential screening strategies for the detection of CSF leakage prior to first admission discharge.

It is well established that traumatic brain injury (TBI) is associated with the development of psychiatric disorders. However, the impact of psychiatric disorders on TBI outcome is less well understood. We examined the outcomes of patients who experienced a traumatic subdural hemorrhage and whether a comorbid psychiatric disorder was associated with a change in outcome. A retrospective observational study was performed in the California Office of Statewide Health Planning and Development (OSHPD) and the Nationwide Inpatient Sample (NIS). Patients hospitalized for acute subdural hemorrhage were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Patients with coexisting psychiatric diagnoses were identified. Outcomes studied included mortality and adverse discharge disposition. In OSPHD, diagnoses of depression (OR = 0.64, p < 0.001), bipolar disorder (OR = 0.45, p < 0.05), and anxiety (OR = 0.37, p < 0.001) were associated with reduced mortality during hospitalization for TBI, with a trend toward psychosis (OR = 0.56, p = 0.08). Schizophrenia had no effect. Diagnoses of psychosis (OR = 2.12, p < 0.001) and schizophrenia (OR = 2.60, p < 0.001) were associated with increased adverse discharge. Depression and bipolar disorder had no effect, and anxiety was associated with reduced adverse discharge (OR = 0.73, p = 0.01). Results were confirmed using the NIS. Analysis revealed novel associations between coexisting psychiatric diagnoses and TBI outcomes, with some subgroups having decreased mortality and increased adverse discharge. Potential mechanisms include pharmacological effects of frequently prescribed psychiatric medications, the pathophysiology of individual psychiatric disorders, or under-coding of psychiatric illness in the most severely injured patients. Because pharmacological mechanisms, if validated, might lead to improved outcome in TBI patients, further studies may provide significant public health benefit.

Abstract BACKGROUND Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS Neurosurgeons’ individual surgical goals varied significantly ( P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor ( R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes ( P < .01) and nonresectable residual ( P < .01), but not resectable residual. CONCLUSION In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.