Search

Background: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of postsurgical progressive events are failures within 2 cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown., Methods: We developed a predictive model to identify which IDH wild-type GBMs are amenable to radiographic gross-total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation., Results: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an area under the curve of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found that 89% of patients were correctly predicted to achieve a residual volume (RV) < 4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a GTR (RV < 1cc). In these 5 patients at 30 months follow-up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (P = .02)., Conclusions: These findings identify a subset of patients with GBM that may derive local control benefits from radical resection to undetectable molecular margins., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer's disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aβ + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer's disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape., Methods: Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors., Results: Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures ( P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts ( P < .05)., Conclusions: We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity., Methods: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses., Results: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05)., Conclusions: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is a need to establish biomarkers that distinguish between pseudoprogression (PsP) and true tumor progression in patients with glioblastoma (GBM) treated with chemoradiation., Methods: We analyzed magnetic resonance spectroscopic imaging (MRSI) and dynamic susceptibility contrast (DSC) MR perfusion data in patients with GBM with PsP or disease progression after chemoradiation. MRSI metabolites of interest included intratumoral choline (Cho), myo-inositol (mI), glutamate + glutamine (Glx), lactate (Lac), and creatine on the contralateral hemisphere (c-Cr). Student T -tests and area under the ROC curve analyses were used to detect group differences in metabolic ratios and their ability to predict clinical status, respectively., Results: 28 subjects (63 ± 9 years, 19 men) were evaluated. Subjects with true progression ( n = 20) had decreased enhancing region mI/c-Cr ( P = .011), a marker for more aggressive tumors, compared to those with PsP, which predicted tumor progression (AUC: 0.84 [0.76, 0.92]). Those with true progression had elevated Lac/Glx ( P = .0009), a proxy of the Warburg effect, compared to those with PsP which predicted tumor progression (AUC: 0.84 [0.75, 0.92]). Cho/c-Cr did not distinguish between PsP and true tumor progression. Despite rCBV (AUC: 0.70 [0.60, 0.80]) and rCBF (AUC: 0.75 [0.65, 0.84]) being individually predictive of tumor response, they added no additional predictive value when combined with MRSI metabolic markers., Conclusions: Incorporating enhancing lesion MRSI measures of mI/c-Cr and Lac/Glx into brain tumor imaging protocols can distinguish between PsP and true progression and inform patient management decisions., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: In nongastric gastrointestinal (GI) cancers, HER2-positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2-targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially., Materials and Methods: We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty-four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH., Results: A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017)., Conclusion: In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue., Implications for Practice: HER2 amplification is a well-known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2-directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Glioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination., Methods: GL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)-expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes., Results: Combination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3)., Conclusions: Anti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making., Methods: To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas., Results: The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome., Conclusion: We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R)., Methods: We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months)., Results: Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting which patients will suffer P/R after initial treatment. Stratification of patients into 3 risk groups based on non-Simpson grade I resection and low ADC as risk factors correlated with the likelihood of P/R (P < .001). The high-risk group (2 risk factors; n = 39) had a 45% cumulative incidence of P/R, whereas the low-risk group (0 risk factors; n = 31) had no P/R events at 5 years after treatment. Independent of histopathological grade, high-risk patients who received adjuvant radiotherapy had a lower 5-year crude rate of P/R than those without (17% vs 59%; P = .04)., Conclusions: Patients with non-Simpson grade I resection and low ADC meningiomas are at significantly increased risk of P/R and may benefit from adjuvant radiotherapy and/or additional surgery., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Checkpoint inhibitors manipulate the co-stimulatory response between antigen-presenting cells and immune cells-or between the tumor and immune cells-to elicit an antitumor immune response that would have otherwise been suppressed. Checkpoint inhibitors have shown great promise in the clinics, and some inhibitors such as anti-CTLA-4 antibodies and anti-PD-1 antibodies have gained FDA approval for certain tumors. Here we will discuss the current state of checkpoint inhibitors, biomarker strategies, and management of associated toxicities in glioblastoma., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The clinicopathological heterogeneity of glioblastoma (GBM) and the various genetic and phenotypic subtypes in GBM stem cells (GSCs) are well described. However, the relationship between GSCs and the corresponding primary tumor from which they were isolated is poorly understood. We have established GSC-enriched neurosphere cultures from 15 newly diagnosed GBM specimens and examined the relationship between the histopathological and genomic features of GSC-derived orthotopic xenografts and those of the respective patient tumors. GSC-initiated xenografts recapitulate the distinctive cytological hallmarks and diverse histological variants associated with the corresponding patient GBM, including giant cell and gemistocytic GBM, and primitive neuroectodermal tumor (PNET)-like components. This indicates that GSCs generate tumors that preserve patient-specific disease phenotypes. The majority of GSC-derived intracerebral xenografts (11 of 15) demonstrated a highly invasive behavior crossing the midline, whereas the remainder formed discrete nodular and vascular masses. In some cases, GSC invasiveness correlated with preoperative MRI, but not with the status of PI3-kinase/Akt pathways or O(6)-methylguanine methyltransferase expression. Genome-wide screening by array comparative genomic hybridization and fluorescence in situ hybridization revealed that GSCs harbor unique genetic copy number aberrations. GSCs acquiring amplifications of the myc family genes represent only a minority of tumor cells within the original patient tumors. Thus, GSCs are a genetically distinct subpopulation of neoplastic cells within a GBM. These studies highlight the value of GSCs for preclinical modeling of clinically relevant, patient-specific GBM and, thus, pave the way for testing novel anti-GSC/GBM agents for personalized therapy.

Contemporary reports of patient outcomes after biopsy or resection of primary brain tumors typically reflect results at specialized centers. Such reports may not be representative of practices in nonspecialized settings. This analysis uses a nationwide hospital discharge database to examine trends in mortality and outcome at hospital discharge in 38,028 admissions for biopsy or resection of supratentorial primary brain tumors in adults between 1988 and 2000, particularly in relation to provider caseload. Multivariate analyses showed that large-volume centers had lower in-hospital postoperative mortality rates than centers with lighter caseloads, both for craniotomies (odds ratio [OR] 0.75 for a tenfold larger caseload) and for needle (closed) biopsies (OR 0.54). Adverse discharge disposition was also less likely at high-volume hospitals, both for craniotomies (OR 0.77) and for needle biopsies (OR 0.67). The annual number of surgical admissions increased by 53% during the 12-year study period, and in-hospital mortality rates decreased during this period, from 4.8% to 1.8%. Mortality rates decreased over time, both for craniotomies and for needle biopsies. Subgroup analyses showed larger relative mortality rate reductions at large-volume centers than at small-volume centers (73% vs. 43%, respectively). The number of US hospitals performing one or more craniotomies annually for primary brain tumors decreased slightly, and the number performing needle biopsies increased. There was little change in median hospital annual craniotomy caseloads, but the largest centers had disproportionate growth in volume. The 100 highest-caseload US hospitals accounted for an estimated 30% of the total US surgical primary brain tumor caseload in 1988 and 41% in 2000. Our findings do not establish minimum volume thresholds for acceptable surgical care of primary brain tumors. However, they do suggest a trend toward progressive centralization of craniotomies for primary brain tumor toward large-volume US centers during this interval.