Obesity and meningioma: a US population-based study paired with analysis of a multi-institutional cohort.

OBJECTIVE: Whether obesity is associated with meningioma and the impact of obesity by gender has been debated. The primary objective of this study was to investigate differences in BMI between male and female patients undergoing craniotomy for meningioma and compare those with patients undergoing craniotomy for other intracranial tumors. The secondary objective was to compare meningioma location and progression-free survival (PFS) between obese and nonobese patients in a multi-institutional cohort. METHODS: National data were obtained from the National Surgical Quality Improvement Program (NSQIP) database. Male and female patients were analyzed separately. Patients undergoing craniotomies for meningioma were compared with patients of the same sex undergoing craniotomies for other intracranial tumors. Institutional data from two academic centers were collected for all male and an equivalent number of female meningioma patients undergoing meningioma resection. Multivariate regression controlling for age was used to determine differences in meningioma location. Kaplan-Meier curves and log-rank tests were computed to investigate differences in PFS. RESULTS: From NSQIP, 4163 male meningioma patients were compared with 24,266 controls, and 9372 female meningioma patients were compared with 21,538 controls. Male and female patients undergoing meningioma resection were more likely to be overweight or obese compared with patients undergoing craniotomy for other tumors, with the odds ratio increasing with increasing weight class (all p < 0.0001). In the multi-institutional cohort, meningiomas were more common along the skull base in male patients (p = 0.0123), but not in female patients (p = 0.1246). There was no difference in PFS between obese and nonobese male (p = 0.4104) or female (p = 0.5504) patients. Obesity was associated with increased risk of pulmonary embolism in both male and female patients undergoing meningioma resection (p = 0.0043). CONCLUSIONS: Male and female patients undergoing meningioma resection are more likely to be obese than patients undergoing craniotomy for other intracranial tumors. Obese males are more likely to have meningiomas in the skull base compared with other locations, but this association was not found in females. There was no significant difference in PFS among obese patients. The mechanism by which obesity increases meningioma incidence remains to be determined.

On-Call Workload Differences in Neurosurgery: Resident Call "Weather" and a Departure from Colored Cloud Labels.

BACKGROUND AND OBJECTIVES: Labeling residents as "black" or "white" clouds based on perceived or presumed workloads is a timeworn custom across medical training and practice. Previous studies examining whether such perceptions align with objective workload patterns have offered conflicting results. We assessed whether such peer-assigned labels were associated with between-resident differences in objective, on-call workload metrics in three classes of neurosurgery junior residents. In doing so, we introduce more inclusive terminology for perceived differences in workload metrics. METHODS: Residents were instructed to complete surveys to identify "sunny", "neutral", and "stormy" residents, reflecting least to greatest perceived workloads, of their respective classes. We retrospectively reviewed department and electronic medical records to record volume of on-call work over the first 4 months of each resident's 2nd postgraduate academic year. Inter-rater agreement of survey responses was measured using Fleiss' kappa. All statistical analyses were performed with a significance threshold of P < .05. RESULTS: Across all classes, there was strong inter-rater agreement in the identification of stormy and sunny residents (Kappa = 1.000, P = .003). While differences in on-call workload measures existed within each class, "weather" designations did not consistently reflect these differences. There were significant intraclass differences in per shift consult volume in two classes ( P = .035 and P = .009); however, consult volume corresponded to a resident's weather designations in only one class. Stormy residents generally saw more emergencies and, in 2 classes, performed more bedside procedures than their peers. CONCLUSION: Significant differences in objective on-call experience exist between junior neurosurgery residents. Self- and peer-assigned weather labels did not consistently align with a pattern of these differences, suggesting that other factors contribute to such labels.

Rapid Passive Gamma Mapping as an Adjunct to Electrical Stimulation Mapping for Functional Localization in Resection of Primary Brain Neoplasms.

OBJECTIVE: We examined the utility of passive high gamma mapping (HGM) as an adjunct to conventional awake brain mapping during glioma resection. We compared functional and survival outcomes before and after implementing intraoperative HGM. METHODS: This was a retrospective cohort study of 75 patients who underwent a first-time, awake craniotomy for glioma resection. Patients were stratified by whether their operation occurred before or after the implementation of a U.S. Food and Drug Administration-approved high-gamma mapping tool in July 2017. RESULTS: The preimplementation and postimplementation cohorts included 28 and 47 patients, respectively. Median intraoperative time (261 vs. 261 minutes, P = 0.250) and extent of resection (97.14% vs. 98.19%, P = 0.481) were comparable between cohorts. Median Karnofsky performance status at initial follow-up was similar between cohorts (P = 0.650). Multivariable Cox regression models demonstrated an adjusted hazard ratio for overall survival of 0.10 (95% confidence interval: 0.02-0.43, P = 0.002) for the postimplementation cohort relative to the preimplementation cohort. Progression-free survival adjusted for insular involvement showed an adjusted hazard ratio of 1.00 (95% confidence interval: 0.49-2.06, P = 0.999) following HGM implementation. Falling short of statistical significance, prevalence of intraoperative seizures and/or afterdischarges decreased after HGM implementation as well (12.7% vs. 25%, P = 0.150). CONCLUSIONS: Our results tentatively indicate that passive HGM is a safe and potentially useful adjunct to electrical stimulation mapping for awake cortical mapping, conferring at least comparable functional and survival outcomes with a nonsignificant lower rate of intraoperative epileptiform events. Considering the limitations of our study design and patient cohort, further investigation is needed to better identify optimal use cases for HGM.

Milestones for neurosurgery sub-interns: a novel evaluation tool to quantitatively differentiate residency applicants.

OBJECTIVE: The study objective was to create a novel milestones evaluation form for neurosurgery sub-interns and assess its potential as a quantitative and standardized performance assessment to compare potential residency applicants. In this pilot study, the authors aimed to determine the form's interrater reliability, relationship to percentile assignments in the neurosurgery standardized letter of recommendation (SLOR), ability to quantitatively differentiate tiers of students, and ease of use. METHODS: Medical student milestones were either adapted from the resident Neurological Surgery Milestones or created de novo to evaluate a student's medical knowledge, procedural aptitude, professionalism, interpersonal and communication skills, and evidence-based practice and improvement. Four milestone levels were defined, corresponding to estimated 3rd-year medical student through 2nd-year resident levels. Faculty and resident evaluations as well as student self-evaluations were completed for 35 sub-interns across 8 programs. A cumulative milestone score (CMS) was computed for each student. Student CMSs were compared both within and between programs. Interrater reliability was determined with Kendall's coefficient of concordance (Kendall's W). Student CMSs were compared against their percentile assignments in the SLOR using analysis of variance with post hoc testing. CMS-derived percentile rankings were assigned to quantitatively distinguish tiers of students. Students and faculty were surveyed on the form's usefulness. RESULTS: The average faculty rating overall was 3.20, similar to the estimated competency level of an intern. Student and faculty ratings were similar, whereas resident ratings were lower (p < 0.001). Students were rated most highly in coachability and feedback (3.49 and 3.67, respectively) and lowest in bedside procedural aptitude (2.90 and 2.85, respectively) in both faculty and self-evaluations. The median CMS was 26.5 (IQR 21.75-29.75, range 14-32) with only 2 students (5.7%) achieving the highest rating of 32. Programs that evaluated the most students differentiated the highest-performing students from the lowest by at least 13 points. A program with 3 faculty raters demonstrated scoring agreement across 5 students (p = 0.024). The CMS differed significantly between SLOR percentile assignments, despite 25% of students being assigned to the top fifth percentile. CMS-driven percentile assignment significantly differentiated the bottom, middle, and top third of students (p < 0.001). Faculty and students strongly endorsed the milestones form. CONCLUSIONS: The medical student milestones form was well received and differentiated neurosurgery sub-interns both within and across programs. This form has potential as a replacement for numerical Step 1 scoring as a standardized, quantitative performance assessment for neurosurgery residency applicants.

Mismatch repair-deficient glioma with spatially distinct IDH-mutant and IDH-wild type components arising in the setting of Lynch syndrome.

Pathogenic mutations in MLH1, MSH2, PMS2, and MSH6 compromise DNA mismatch repair mechanisms and in the heterozygous state result in Lynch syndrome, which is typified by a predisposition to endometrial, ovarian, colorectal, gastric, breast, hematologic, and soft tissue cancers. Rarely, germline pathogenic aberrations in these genes are associated with the development of primary central nervous system tumors. We present a report of an adult female with no prior cancer history who presented with a multicentric, infiltrative supratentorial glioma involving both the left anterior temporal horn and left precentral gyrus. Surgical treatment and neuropathological/molecular evaluation of these lesions revealed discordant isocitrate dehydrogenase (IDH) status and histologic grade at these spatially distinct disease sites. A frameshift alteration within the MLH1 gene (p.R217fs*12, c.648delT) was identified in both lesions and subsequently identified in germline testing of a blood sample, consistent with Lynch syndrome. Despite distinct histopathologic features and divergent IDH status of the patient's tumors, the molecular findings suggest that both sites of intracranial neoplasia may have developed as a consequence of underlying monoallelic germline mismatch repair deficiency. This case illustrates the importance of characterizing the genetic profile of multicentric gliomas and highlights the oncogenic potential of germline mismatch repair gene pathogenic alterations within central nervous system gliomas.

Response to Preoperative Dexamethasone Predicts Postoperative Neurological Improvement of Focal Neurological Deficits in Patients With Brain Metastases.

BACKGROUND: Steroids are used ubiquitously in the preoperative management of patients with brain tumor. The rate of improvement in focal deficits with steroids and the prognostic value of such a response are not known. OBJECTIVE: To determine the rate at which focal neurological deficits respond to preoperative corticosteroids in patients with brain metastases and whether such an improvement could predict long-term recovery of neurological function after surgery. METHODS: Patients with brain metastases and related deficits in language, visual field, or motor domains who received corticosteroids before surgery were identified. Characteristics between steroid responders and nonresponders were compared. RESULTS: Ninety six patients demonstrated a visual field (13 patients), language (19), or motor (64) deficit and received dexamethasone in the week before surgery (average cumulative dose 43 mg; average duration 2.7 days). 38.5% of patients' deficits improved with steroids before surgery, while 82.3% of patients improved by follow-up. Motor deficits were more likely to improve both preoperatively ( P = .014) and postoperatively ( P = .010). All 37 responders remained improved at follow-up whereas 42 of 59 (71%) of nonresponders ultimately improved ( P < .001). All other clinical characteristics, including dose and duration, were similar between groups. CONCLUSION: A response to steroids before surgery is highly predictive of long-term improvement postoperatively in brain metastasis patients with focal neurological deficits. Lack of a response portends a somewhat less favorable prognosis. Duration and intensity of therapy do not seem to affect the likelihood of response.

Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer.

Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive "liquid" biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.

Effects of 24-hour versus night-float call schedules on the clinical and operative experiences of postgraduate year 2 and 3 neurosurgical residents.

OBJECTIVE: To comply with the removal of the 88-hour week exemption and to support additional operative experience during junior residency, Oregon Health & Science University (OHSU) switched from a night-float call schedule to a modified 24-hour call schedule on July 1, 2019. This study compared the volumes of clinical, procedural, and operative cases experienced by postgraduate year 2 (PGY-2) and PGY-3 residents under these systems. METHODS: The authors retrospectively studied billing and related clinical records, call schedules, and Accreditation Council for Graduate Medical Education case logs for PGY-2 and PGY-3 residents at OHSU, a tertiary academic health center, for the first 4 months of the academic years from 2017 to 2020. The authors analyzed the volumes of new patient consultations, bedside procedures, and operative procedures performed by each PGY-2 and PGY-3 resident during these years, comparing the volumes experienced under each call system. RESULTS: Changing from a PGY-2 resident-focused night-float call system to a 24-hour call system that was more evenly distributed between PGY-2 and PGY-3 residents resulted in decreased volume of new patient consultations, increased volume of operative procedures, and no change in volume of bedside procedures for PGY-2 residents. PGY-3 residents experienced a decrease in operative procedure volume under the 24-hour call system. CONCLUSIONS: Transition from a night-float system to a 24-hour call system altered the distribution of clinical and procedural experiences between PGY-2 and PGY-3 residents. Further research is necessary to understand the impact of these changes on educational outcomes, quality and safety of patient care, and resident satisfaction.

Optimal timing of radiotherapy following brain metastases surgery.

Background: There is growing evidence supporting the need for a short time delay before starting radiotherapy (RT) treatment postsurgery for most optimal responses. The timing of RT initiation and effects on outcomes have been evaluated in a variety of malignancies, but the relationship remains to be well established for brain metastasis. Methods: Retrospective study of 176 patients (aged 18-89 years) with brain metastases at a single institution (March 2009 to August 2018) who received RT following surgical resection. Time interval (≤22 and >22 days) from surgical resection to initiation of RT and any potential impact on patient outcomes were assessed. Results: Patients who underwent RT >22 days after surgical resection had a decreased risk for all-cause mortality of 47.2% (95% CI: 8.60, 69.5%). Additionally, waiting >40 days for RT after surgical resection more than doubled the risk of tumor progression; adjusted hazard ratio 2.02 (95% CI: 1.12, 3.64). Conclusions: Findings indicate that a short interval delay (>22 days) following surgical resection is required before RT initiation for optimal treatment effects in brain metastasis. Our timing of RT postsurgical resection data adds definition to current heterogeneity in RT timing, which is especially important for standardized clinical trial design and patient outcomes.

Regression of Multiple Meningiomas after Discontinuation of Chronic Hormone Therapy: A Case Report.

Introduction Meningiomas are more common in females and frequently express progesterone and estrogen receptors. Recent studies have revealed a high incidence of meningiomas in situations in which estrogen/progesterone levels are increased such as pregnancy, gender reassignment therapy, and fertility treatment. While the relationship remains unclear and controversial, these findings suggest exposure to high levels of endogenous or exogenous hormones may increase the risk of developing a meningioma. Patients and Methods A 40-year-old female with a history of endometriosis treated with chronic progesterone therapy presented with a visual deficit and was found to have multiple meningiomas, which regressed after cessation of exogenous progesterone. Conclusion A history of chronic hormone therapy should be included when evaluating patients diagnosed with meningiomas, particularly at a younger age and with multiple meningiomas. Cessation of exogenous progesterone resulting in regression of meningiomas suggests a direct action of progesterone on growth. Future studies are warranted to better elucidate this relationship.

Standardizing postoperative care for pediatric intradural Chiari decompressions to decrease length of stay.

OBJECTIVE: Amid national and local budget crises, cutting costs while maintaining quality care is a top priority. Chiari malformation is a relatively common pediatric neurosurgical pathology, and postoperative care varies widely. The postoperative course can be complicated by pain and nausea, which can extend the hospital stay. In this study, the authors aimed to examine whether instituting a standardized postoperative care protocol would decrease overall patient hospital length of stay (LOS) as well as cost to families and the hospital system. METHODS: A retrospective study of pediatric patients who underwent an intradural Chiari decompression with expansile duraplasty at a single institution from January 2016 to September 2019 was performed. A standardized postoperative care protocol was instituted on May 17, 2018. Pre- and postprotocol groups were primarily analyzed for demographics, LOS, and the estimated financial expense of the hospital stay. Secondary analysis included readmissions, opioid consumption, and follow-up. RESULTS: The analysis included 132 pediatric patients who underwent an intradural Chiari decompression with expansile duraplasty. The preprotocol group included 97 patients and the postprotocol group included 35 patients. Patient age ranged from 0.5 to 26 years (mean 9.5 years). The mean LOS preprotocol was 55.48 hours (range 25.90-127.77 hours), and the mean postprotocol LOS was 46.39 hours (range 27.58-77.38 hours). The comparison between means showed a statistically significant decrease following protocol initiation (95% CI 1.87-16.31 hours, p = 0.014). In the preprotocol group, 21 of 97 patients (22%) were discharged the first day after surgery compared with 14 of 35 patients (40%) in the postprotocol group (p = 0.045). The estimated cost of one night on the pediatric neurosurgical intermediate ward was approximately $4500, which gives overall cost estimates for 100 theoretical cases of $927,800 for the preprotocol group and $732,900 for the postprotocol group. CONCLUSIONS: By instituting a Chiari protocol, postoperative LOS was significantly decreased, which resulted in decreased healthcare costs while maintaining high-quality and safe care.

Changing Hands: A Rising Role of the Tumor Surgeon in Teaching Sylvian Fissure Dissection.

OBJECTIVE: The landscape of microneurosurgery has changed considerably over the past 2 decades, with a decline in indications for open surgery on cerebrovascular pathology and ever-increasing indications for open resection of brain tumors. This study investigated how these trends in case volume affected residents' training experiences in microsurgery and, specifically, Sylvian fissure dissection. METHODS: Resident case logs were reviewed, identifying open cerebrovascular operations and craniotomies for tumor. Operations involving Sylvian fissure dissection were identified through operative reports. Changes in case number by resident were plotted over time, and linear regression was applied. RESULTS: Among 23 chief residents, 3045 operations were identified, 1071 of which were for cerebrovascular pathology and 1974 for tumor. Open cerebrovascular experience decreased (P < 0.0001) while tumor volume remained unchanged (P = 0.221). The number of Sylvian fissure dissections per resident did not change over time overall (P = 0.583) or within cerebrovascular operations (P = 0.071). The number of Sylvian fissure dissections in tumor operations increased (P = 0.004). This effect was predominated by an increase in intraaxial tumors approached via Sylvian fissure dissection (P = 0.003). The proportion of Sylvian fissure dissections in tumor surgery increased from 15% in 2009 to 34% by 2019 (P = 0.003). CONCLUSIONS: Residents are seeing an increasing proportion of their Sylvian fissure dissection experience during tumor operations. The distribution of this experience will continue to evolve as surgical indications change but suggests a growing role for tumor surgeons in resident training in microsurgery.

The clinical heterogeneity of entirely nonenhancing CNS lymphoma: a case series.

CNS lymphoma often presents with atypical imaging characteristics leading to delay in diagnosis and initiation of treatment. Among the most rarely reported of these is entirely nonenhancing CNS lymphoma, which is estimated at an incidence of about 1%. Here, we present three cases of nonenhancing CNS lymphoma in immune competent patients at both initial presentation and recurrence and in primary as well as secondary CNS lymphoma. Diffusion- and perfusion-weighted imaging was found helpful in diagnosis in some cases.

The Evolving Role of the Oncologic Neurosurgeon: Looking Beyond Extent of Resection in the Modern Era.

Neurosurgeons have played an essential role in glioma management and research for over a century. While the past twenty years have played witness to many exciting developments in glioma biology, diagnosis, and classification, relatively few novel, effective treatment strategies have been introduced. The role of neurosurgery in glioma management has been clarified, with a large body of evidence in support of maximal safe resection. However, neurosurgeons have also played a critical role in translational research during this period. The development of new MRI technologies has benefited greatly from validation with stereotactically-targeted human tissue. Careful banking of surgically acquired tissue was key to the development of a new classification scheme for glioma. Similarly, we have garnered a considerably deeper understanding of molecular and genetic properties of glioma through analysis of large surgical specimens. As our classification schemes become more sophisticated, incorporating targeted tissue sampling into the development of novel treatment strategies becomes essential. Such ex vivo analysis could be instrumental in determining mechanisms of treatment failure or success. Modern tumor neurosurgeons should consider themselves surgical neuro-oncologists, with engagement in translational research essential to furthering the field and improving outlooks for our patients.

Extent of BOLD Vascular Dysregulation Is Greater in Diffuse Gliomas without Isocitrate Dehydrogenase 1 R132H Mutation.

Purpose To determine the effect that R132H mutation status of diffuse glioma has on extent of vascular dysregulation and extent of residual blood oxygen level-dependent (BOLD) abnormality after surgical resection. Materials and Methods This study was an institutional review board-approved retrospective analysis of an institutional database of patients, and informed consent was waived. From 2010 to 2017, 39 treatment-naïve patients with diffuse glioma underwent preoperative echo-planar imaging and BOLD functional magnetic resonance imaging. BOLD vascular dysregulation maps were made by identifying voxels with time series similar to tumor and dissimilar to healthy brain. The spatial overlap between tumor and vascular dysregulation was characterized by using the Dice coefficient, and areas of BOLD abnormality outside the tumor margins were quantified as BOLD-only fraction (BOF). Linear regression was used to assess effects of R132H status on the Dice coefficient, BOF, and residual BOLD abnormality after surgical resection. Results When compared with R132H wild-type (R132H-) gliomas, R132H-mutated (R132H+) gliomas showed greater spatial overlap between BOLD abnormality and tumor (mean Dice coefficient, 0.659 ± 0.02 [standard error] for R132H+ and 0.327 ± 0.04 for R132H-; P < .001), less BOLD abnormality beyond the tumor margin (mean BOF, 0.255 ± 0.03 for R132H+ and 0.728 ± 0.04 for R132H-; P < .001), and less postoperative BOLD abnormality (residual fraction, 0.046 ± 0.0047 for R132H+ and 0.397 ± 0.045 for R132H-; P < .001). Receiver operating characteristic curve analysis showed high sensitivity and specificity in the discrimination of R132H+ tumors from R132H- tumors with calculation of both Dice coefficient and BOF (area under the receiver operating characteristic curve, 0.967 and 0.977, respectively). Conclusion R132H mutation status is an important variable affecting the extent of tumor-associated vascular dysregulation and the residual vascular dysregulation after surgical resection. © RSNA, 2018 Online supplemental material is available for this article.

Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue in Nonenhancing Gliomas.

BACKGROUND: Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined. OBJECTIVE: To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy. METHODS: Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection. RESULTS: Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05). CONCLUSION: Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.

Aggressive resection at the infiltrative margins of glioblastoma facilitated by intraoperative fluorescein guidance.

OBJECTIVE Extent of resection is an important prognostic factor in patients undergoing surgery for glioblastoma (GBM). Recent evidence suggests that intravenously administered fluorescein sodium associates with tumor tissue, facilitating safe maximal resection of GBM. In this study, the authors evaluate the safety and utility of intraoperative fluorescein guidance for the prediction of histopathological alteration both in the contrast-enhancing (CE) regions, where this relationship has been established, and into the non-CE (NCE), diffusely infiltrated margins. METHODS Thirty-two patients received fluorescein sodium (3 mg/kg) intravenously prior to resection. Fluorescence was intraoperatively visualized using a Zeiss Pentero surgical microscope equipped with a YELLOW 560 filter. Stereotactically localized biopsy specimens were acquired from CE and NCE regions based on preoperative MRI in conjunction with neuronavigation. The fluorescence intensity of these specimens was subjectively classified in real time with subsequent quantitative image analysis, histopathological evaluation of localized biopsy specimens, and radiological volumetric assessment of the extent of resection. RESULTS Bright fluorescence was observed in all GBMs and localized to the CE regions and portions of the NCE margins of the tumors, thus serving as a visual guide during resection. Gross-total resection (GTR) was achieved in 84% of the patients with an average resected volume of 95%, and this rate was higher among patients for whom GTR was the surgical goal (GTR achieved in 93.1% of patients, average resected volume of 99.7%). Intraoperative fluorescein staining correlated with histopathological alteration in both CE and NCE regions, with positive predictive values by subjective fluorescence evaluation greater than 96% in NCE regions. CONCLUSIONS Intraoperative administration of fluorescein provides an easily visualized marker for glioma pathology in both CE and NCE regions of GBM. These findings support the use of fluorescein as a microsurgical adjunct for guiding GBM resection to facilitate safe maximal removal.