Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.

PURPOSE: Glioblastoma (GBM) patient outcomes remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: Here, we report the findings of four subjects enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells (PBMCs) pre- and post-NeoVax for subjects 1-3 using IFNg-ELISPOT assay. A statistically significant increase in IFNg producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from subject 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest NeoVax did stimulate expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in GBM patients.

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies.

The human cerebrovascular system is responsible for maintaining neural function through oxygenation, nutrient supply, filtration of toxins, and additional specialized tasks. While the cerebrovascular system has resilience imparted by elaborate redundant collateral circulation from supportive tertiary structures, it is not infallible, and is susceptible to developing structural vascular abnormalities. The causes of this class of structural cerebrovascular diseases can be broadly categorized as 1) intrinsic developmental diseases resulting from genetic or other underlying aberrations (arteriovenous malformations and cavernous malformations) or 2) extrinsic acquired diseases that cause compensatory mechanisms to drive vascular remodeling (aneurysms and arteriovenous fistulae). Cerebrovascular diseases of both types pose significant risks to patients, in some cases leading to death or disability. The drivers of such diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.

Natural history and growth rate of intracranial aneurysms in Loeys-Dietz syndrome: implications for treatment.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a heritable aortopathy associated with craniofacial abnormalities and dilatation and dissection of the aorta and its branches, as well as increased risk for intracranial aneurysms (ICAs). Given the rarity of the disease, the authors aimed to better define the natural history and role for the treatment for ICAs in these patients. METHODS: The medical records of 83 patients with LDS were retrospectively reviewed to obtain clinical and genetic history and vascular imaging of the aorta, aortic branches, and intracranial vessels. Serial radiology reports and cervical and intracranial vascular images were reviewed to determine presence, location, and size of ICAs. RESULTS: In total, 55 patients (66.3%) had at least two screening intracranial vascular examinations, and 19 (22.9%) had at least 1 ICA detected. Aneurysms were typically small (mean ± SD 3.2 ± 1.8 mm). ICAs were most often located in the cavernous carotid, followed by the ophthalmic and anterior cerebral artery vessels. The rate of ICA growth was 0.43 ± 0.53 mm/year, similar to that of the general population. Three patients underwent intervention for an ICA, with 1 procedure complicated by stroke and resulting in transient hemiparesis. Several illustrative cases detail the authors' experience with ICA growth, de novo aneurysm formation, and ICA intervention in this rare patient population. CONCLUSIONS: ICAs in patients with LDS are common, are frequently small, and have a growth rate similar to that of unruptured ICAs in the general population. More aggressive or earlier intervention for asymptomatic ICAs identified in LDS patients compared with the general population is likely unwarranted based on the authors' experience at their institution.

A Low Subfrontal Dural Opening for Operative Management of Anterior Skull Base Lesions.

Introduction A low subfrontal dural opening technique that limits brain manipulation was assessed in patients who underwent frontotemporal approaches for anterior fossa lesions. Methods A retrospective review was performed for cases using a low subfrontal dural opening including characterization of demographics, lesion size and location, neurological and ophthalmological assessments, clinical course, and imaging findings. Results A low subfrontal dural opening was performed in 23 patients (17F, 6M), median age of 53 years (range 23-81) with a median follow-up duration of 21.9 months (range 6.2-67.1). Lesions included 22 meningiomas (nine anterior clinoid, 12 tuberculum sellae, and one sphenoid wing), one unruptured internal carotid artery aneurysm clipped during a meningioma resection, and one optic nerve cavernous malformation. Maximal possible resection was achieved in all cases including gross total resection in 16/22 (72.7%), near total in 1/22 (4.5%), and subtotal in 5/22 (22.7%) in which tumor involvement of critical structures limited complete resection. Eighteen patients presented with vision loss; 11 (61%) improved postoperatively, three (17%) were stable, and four (22%) worsened. The mean ICU stay and time to discharge were 1.3 days (range 0-3) and 3.8 days (range 2-8). Conclusion A low sub-frontal dural opening for approaches to the anterior fossa can be performed with minimal brain exposure, early visualization of the optico-carotid cistern for cerebrospinal fluid release, minimizing need for fixed brain retraction, and Sylvian fissure dissection. This technique can potentially reduce surgical risk and provide excellent exposure for anterior skull base lesions with favorable extent of resection, visual recovery, and complication rates.

A challenging case of recurrent and progressive fusiform anterior circulation intracranial aneurysms: illustrative case.

BACKGROUND: Intracranial fusiform aneurysms are circumferential dilations of cerebral arteries that can lead to complications including ischemic stroke due to vessel occlusion, subarachnoid hemorrhage, or intracerebral hemorrhage. Treatment options for fusiform aneurysms have expanded significantly in recent years. Microsurgical treatment options include proximal and distal surgical occlusion and microsurgical trapping of the aneurysm, usually in association with high-flow bypass procedures. Endovascular treatment options include the placement of coils and/or flow diverters. OBSERVATIONS: Here the authors report a case of aggressive surveillance and treatment of a man with multiple progressive, recurrent, and de novo fusiform aneurysms of the left anterior cerebral circulation over 16 years. Because the long-term course of his treatment coincided with the recent expansion of endovascular treatment options, he underwent every type of treatment listed above. LESSONS: This case demonstrates the wide range of therapeutic options for fusiform aneurysms and how the treatment model for these lesions has evolved.

Relationship between phenotypic features in Loeys-Dietz syndrome and the presence of intracranial aneurysms.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant condition characterized by aneurysms of the aorta, aortic branches, and intracranial arteries; skeletal and cutaneous abnormalities; and craniofacial malformations. Previous authors have reported that higher craniofacial severity index (CFI) scores, which indicate more severe craniofacial abnormalities, correlate with the severity of aortic aneurysm pathology. However, the association between syndromic features and the formation of intracranial aneurysms in LDS patients has yet to be determined. In this study, the authors evaluate the incidence of phenotypic abnormalities, craniofacial features, and Chiari malformation type I (CM-I) in a large LDS cohort and explore possible risk factors for the development of intracranial aneurysms. METHODS: This was a retrospective cohort study of all patients with LDS who had been seen at the Marfan Syndrome and Aortopathy Center at Washington University School of Medicine in St. Louis in 2010-2022. Medical records were reviewed to obtain demographic, clinical, and radiographic data. The prevalence of craniofacial, skeletal, and cutaneous pathologies was determined. Bivariate logistic regression was performed to identify possible risk factors for the formation of an intracranial aneurysm. RESULTS: Eighty-one patients with complete medical records and intracranial vascular imaging were included in the analysis, and 18 patients (22.2%) had at least 1 intracranial aneurysm. Patients frequently demonstrated the thin or translucent skin, doughy skin texture, hypertelorism, uvular abnormalities, and joint hypermobility typical of LDS. CM-I was common, occurring in 7.4% of the patients. Importantly, the patients with intracranial aneurysms were more likely to have CM-I (22.2%) than those without intracranial aneurysms (3.2%). The mean CFI score in the cohort with available data was 1.81, with higher means in the patients with the TGFBR1 or TGFBR2 disease-causing variants (2.05 and 3.30, respectively) and lower in the patients with the SMAD3, TGFB2, or TGFB3 pathogenic variants (CFI < 1). No significant CFI difference was observed in patients with or without intracranial aneurysms (2.06 vs 1.74, p = 0.61). CONCLUSIONS: CM-I, and not the CFI, is significantly associated with the presence of intracranial aneurysms in patients with LDS. Surveillance for intracranial aneurysms is essential in all patients with LDS and should not be limited to those with severe phenotypes. Long-term monitoring studies will be necessary to determine whether a correlation between craniofacial abnormalities and adverse outcomes from intracranial aneurysms (growth, intervention, or rupture) exists.

Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm.

OBJECTIVE: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.

Survival After Resection of Newly-Diagnosed Intracranial Grade II Ependymomas: An Initial Multicenter Analysis and the Logistics of Intraoperative Magnetic Resonance Imaging.

OBJECTIVE: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions. METHODS: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined. RESULTS: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan-Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72). CONCLUSIONS: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI.

Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response.

BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.

Surgical management of colloid cysts of the third ventricle: a single-institution comparison of endoscopic and microsurgical resection.

OBJECTIVE: Colloid cysts of the third ventricle are histologically benign lesions that can cause obstructive hydrocephalus and death. Historically, colloid cysts have been removed by open microsurgical approaches. More recently, minimally invasive endoscopic and port-based techniques have offered decreased complications and length of stay, with improved patient satisfaction. METHODS: A single-center retrospective analysis of patients with colloid cysts who underwent surgery at a large tertiary care hospital was performed. The cohort was assessed based on the surgical approach, comparing endoscopic resection to open microsurgical resection. The primary endpoint was rate of perioperative complications. Univariate analysis was used to assess several procedure-related variables and the cost of treatment. Multivariate analysis was used to assess predictors of perioperative complications. Total inpatient cost for each case was extracted from the health system financial database. RESULTS: The study included 78 patients with colloid cysts who underwent resection either via an endoscopic approach (n = 33) or through a craniotomy (n = 45) with an interhemispheric-transcallosal or transcortical-transventricular approach. Nearly all patients were symptomatic, and half had obstructive hydrocephalus. Endoscopic resection was associated with reduced operative time (3.2 vs 4.9 hours, p < 0.001); lower complication rate (6.1% vs 33.1%, p = 0.009); reduced length of stay (4.1 vs 8.9 days, p < 0.001); and improved discharge to home (100% vs 75.6%, p = 0.008) compared to microsurgical resection. Coagulated residual cyst wall remnants were more common after endoscopic resection (63.6% vs 19.0%, p < 0.001) although this was not associated with a significantly increased rate of reoperation for recurrence. The mean follow-up was longer in the microsurgical resection group (3.1 vs 4.9 years, p = 0.016). The total inpatient cost of endoscopic resection was, on average, one-half (47%) that of microsurgical resection. When complications were encountered, the total inpatient cost of microsurgical resection was 4 times greater than that of endoscopic resection where no major complications were observed. The increased cost-effectiveness of endoscopic resection remained during reoperation. CONCLUSIONS: Endoscopic resection of colloid cysts of the third ventricle offers a significant reduction in perioperative complications when compared to microsurgical resection. Endoscopic resection optimizes nearly all procedure-related variables compared to microsurgical resection, and reduces total inpatient cost by > 50%. However, endoscopic resection is associated with a significantly increased likelihood of residual coagulated cyst wall remnants that could increase the rate of reoperation for recurrence. Taken together, endoscopic resection represents a safe and effective minimally invasive approach for removal of colloid cysts.

Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis.

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies.This article is highlighted in the In This Issue feature, p. 1.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators.

Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM.

Intraoperative MRI for newly diagnosed supratentorial glioblastoma: a multicenter-registry comparative study to conventional surgery.

OBJECTIVE: Intraoperative MRI (iMRI) is used in the surgical treatment of glioblastoma, with uncertain effects on outcomes. The authors evaluated the impact of iMRI on extent of resection (EOR) and overall survival (OS) while controlling for other known and suspected predictors. METHODS: A multicenter retrospective cohort of 640 adult patients with newly diagnosed supratentorial glioblastoma who underwent resection was evaluated. iMRI was performed in 332/640 cases (51.9%). Reviews of MRI features and tumor volumetric analysis were performed on a subsample of cases (n = 286; 110 non-iMRI, 176 iMRI) from a single institution. RESULTS: The median age was 60.0 years (mean 58.5 years, range 20.5-86.3 years). The median OS was 17.0 months (95% CI 15.6-18.4 months). Gross-total resection (GTR) was achieved in 403/640 cases (63.0%). Kaplan-Meier analysis of 286 cases with volumetric analysis for EOR (grouped into 100%, 95%-99%, 80%-94%, and 50%-79%) showed longer OS for 100% EOR compared to all other groups (p < 0.01). Additional resection after iMRI was performed in 104/122 cases (85.2%) with initial subtotal resection (STR), leading to a 6.3% mean increase in EOR and a 2.2-cm3 mean decrease in tumor volume. For iMRI cases with volumetric analysis, the GTR rate increased from 54/176 (30.7%) on iMRI to 126/176 (71.5%) postoperatively. The EOR was significantly higher in the iMRI group for intended GTR and STR groups (p = 0.02 and p < 0.01, respectively). Predictors of GTR on multivariate logistic regression included iMRI use and intended GTR. Predictors of shorter OS on multivariate Cox regression included older age, STR, isocitrate dehydrogenase 1 (IDH1) wild type, no O6-methylguanine DNA methyltransferase (MGMT) methylation, and no Stupp therapy. iMRI was a significant predictor of OS on univariate (HR 0.82, 95% CI 0.69-0.98; p = 0.03) but not multivariate analyses. Use of iMRI was not associated with an increased rate of new permanent neurological deficits. CONCLUSIONS: GTR increased OS for patients with newly diagnosed glioblastoma after adjusting for other prognostic factors. iMRI increased EOR and GTR rate and was a significant predictor of GTR on multivariate analysis; however, iMRI was not an independent predictor of OS. Additional supporting evidence is needed to determine the clinical benefit of iMRI in the management of glioblastoma.

A tribute to the late Professor Donald Simpson, Australian neurosurgeon and namesake of the Simpson grading system for meningioma extent of resection.

Donald Simpson (1927-2018) was a neurosurgeon from Adelaide, Australia, who is often cited for the 1957 publication he wrote as a trainee on the relationship between extent of resection and outcomes for meningiomas. That paper summarized a series of over 300 patients operated on in England by well-known neurosurgeons Sir Hugh Cairns and Joseph Buford Pennybacker. Simpson was also known later in his career, when he was at the University of Adelaide in South Australia, for his contributions to the areas of hydrocephalus, spina bifida, craniofacial anomalies, head injury, brain abscesses, and neurosurgical history, and he published extensively on these topics. In addition to his work in clinical neurosurgery, Simpson made humanitarian contributions studying kuru in New Guinea and aiding refugees during the Vietnam War. Simpson was an active member and leader of many Australian surgical organizations and was an officer of the Order of Australia. Donald Simpson's legacy as an adult and pediatric neurosurgeon, an academician, a leader, and a humanitarian is extensive and will prove long lasting. Professor Simpson's life serves as an example from which all neurosurgeons may learn.

Using Histopathology to Assess the Reliability of Intraoperative Magnetic Resonance Imaging in Guiding Additional Brain Tumor Resection: A Multicenter Study.

BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) is a powerful tool for guiding brain tumor resections, provided that it accurately discerns residual tumor. OBJECTIVE: To use histopathology to assess how reliably iMRI may discern additional tumor for a variety of tumor types, independent of the indications for iMRI. METHODS: A multicenter database was used to calculate the odds of additional resection during the same surgical session for grade I to IV gliomas and pituitary adenomas. The reliability of iMRI for identifying residual tumor was assessed using histopathology of tissue resected after iMRI. RESULTS: Gliomas (904/1517 cases, 59.6%) were more likely than pituitary adenomas (176/515, 34.2%) to receive additional resection after iMRI (P < .001), but these tumors were equally likely to have additional tissue sent for histopathology (398/904, 44.4% vs 66/176, 37.5%; P = .11). Tissue samples were available for resections after iMRI for 464 cases, with 415 (89.4%) positive for tumor. Additional resections after iMRI for gliomas (361/398, 90.7%) were more likely to yield additional tumor compared to pituitary adenomas (54/66, 81.8%) (P = .03). There were no significant differences in resection after iMRI yielding histopathologically positive tumor between grade I (58/65 cases, 89.2%; referent), grade II (82/92, 89.1%) (P = .98), grade III (72/81, 88.9%) (P = .95), or grade IV gliomas (149/160, 93.1%) (P = .33). Additional resection for previously resected tumors (122/135 cases, 90.4%) was equally likely to yield histopathologically confirmed tumor compared to newly-diagnosed tumors (293/329, 89.0%) (P = .83). CONCLUSION: Histopathological analysis of tissue resected after use of iMRI for grade I to IV gliomas and pituitary adenomas demonstrates that iMRI is highly reliable for identifying residual tumor.

Impact of Intraoperative Magnetic Resonance Imaging and Other Factors on Surgical Outcomes for Newly Diagnosed Grade II Astrocytomas and Oligodendrogliomas: A Multicenter Study.

BACKGROUND: Few studies use large, multi-institutional patient cohorts to examine the role of intraoperative magnetic resonance imaging (iMRI) in the resection of grade II gliomas. OBJECTIVE: To assess the impact of iMRI and other factors on overall survival (OS) and progression-free survival (PFS) for newly diagnosed grade II astrocytomas and oligodendrogliomas. METHODS: Retrospective analyses of a multicenter database assessed the impact of patient-, treatment-, and tumor-related factors on OS and PFS. RESULTS: A total of 232 resections (112 astrocytomas and 120 oligodendrogliomas) were analyzed. Oligodendrogliomas had longer OS (P < .001) and PFS (P = .01) than astrocytomas. Multivariate analyses demonstrated improved OS for gross total resection (GTR) vs subtotal resection (STR; P = .006, hazard ratio [HR]: .23) and near total resection (NTR; P = .02, HR: .64). GTR vs STR (P = .02, HR: .54), GTR vs NTR (P = .04, HR: .49), and iMRI use (P = .02, HR: .54) were associated with longer PFS. Frontal (P = .048, HR: 2.11) and occipital/parietal (P = .003, HR: 3.59) locations were associated with shorter PFS (vs temporal). Kaplan-Meier analyses showed longer OS with increasing extent of surgical resection (EOR) (P = .03) and 1p/19q gene deletions (P = .02). PFS improved with increasing EOR (P = .01), GTR vs NTR (P = .02), and resections above STR (P = .04). Factors influencing adjuvant treatment (35.3% of patients) included age (P = .002, odds ratio [OR]: 1.04) and EOR (P = .003, OR: .39) but not glioma subtype or location. Additional tumor resection after iMRI was performed in 105/159 (66%) iMRI cases, yielding GTR in 54.5% of these instances. CONCLUSION: EOR is a major determinant of OS and PFS for patients with grade II astrocytomas and oligodendrogliomas. Intraoperative MRI may improve EOR and was associated with increased PFS.

Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery.

PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.