Nonenhancing Gliomas Research Articles

INDIGO: A global, randomized, double-blind, phase III study of vorasidenib (VOR; AG-881) vs placebo in patients (pts) with residual or recurrent grade II glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation.

TPS2574 Background: Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options consist of surgery followed by observation (“watch and wait”) for pts with lower risk for disease progression or post-operative chemo-radiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (m IDH1/2) occur in approximately 70% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate (2-HG). VOR, an oral, potent, reversible, brain-penetrant inhibitor of mIDH1/2, was evaluated in 76 pts with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at doses of < 100 mg daily. Preliminary clinical activity was observed in non-enhancing glioma pts in both studies, most recently with an objective response rate (ORR) of 30.8% at 50 mg QD in the perioperative study and > 90% 2-HG suppression at this dose level relative to untreated control samples (Mellinghoff et al., J Clin Oncol 2019). Methods: Approximately 366 pts will be randomized 1:1 to VOR (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria include: age ≥12 years; grade 2 oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed m IDH1/2 status; ≥1 prior surgery for glioma within the previous 5 years but no other anticancer therapy; Karnofsky performance status ≥80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the VOR arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint is progression-free survival assessed by independent review. Secondary endpoints include safety and tolerability, tumor growth rate assessed by volume, time to next intervention, ORR, overall survival, quality of life assessed by the Functional Assessment of Cancer Therapy–Brain questionnaire, and plasma pharmacokinetics. Exploratory endpoints include seizure activity and neuro-cognitive function. Clinical data will be reviewed regularly throughout the study by an independent data monitoring committee. The study is currently enrolling pts in the US, with additional countries planned (NCT04164901). Clinical trial information: NCT04164901 .

Incidence of high grade gliomas presenting as radiographically non-enhancing lesions: experience in 111 surgically treated non-enhancing gliomas with tissue diagnosis.

Although non-enhancing lesions suspicious for glioma are usually assumed to be low grade glioma (LGG), some high grade glioma (HGG) do not enhance, which may lead to a delay in biopsy and/or resection, diagnosis, and treatment initiation. Thus, there is a clear need for a large-sample study that quantifies the rate of malignant, non-enhancing gliomas. We retrospectively reviewed our series of 561 consecutive surgically treated gliomas with tissue diagnosis, 111 of which were non-enhancing, to determine the prevalence of high-grade histology in radiographically presumed LGG. Relative expression of tumor markers were also reported for non-enhancing lesions to investigate genetic correlates. We identified 561 surgically treated gliomas with tissue diagnosis from August 2012 to July 2018 and found that 111 patients (19.8%) demonstrated non-enhancing lesions suspicious for glioma on preoperative MRI. Thirty-one (27.9%) of the non-enhancing lesions were classified as HGGs (WHO Grade III or IV). Non-enhancing lesions were four times more likely to be HGG in patients older than 60years than patients younger than 35years (41.2% vs. 11.4%, Pearson Chi2 p < 0.001). Binomial logistic regression showed a significant inverse effect of age on the presence of IDH mutation in non-enhancing HGGs (p = 0.007). A clinically significant proportion (27.9%) of non-enhancing lesions were found to be HGG on final pathologic diagnosis. Thus, in patients with good functional and health status, especially those older than 60years, we recommend obtaining tissue diagnosis of all lesions suspected to be glioma, even those that are non-enhancing, to guide diagnosis as well as early initiation of chemotherapy and radiation therapy.

ACT-14 A FIRST-IN-HUMAN STUDY OF MUTANT IDH1 INHIBITOR DS-1001B IN PATIENTS WITH RECURRENT GLIOMAS

BACKGROUNDWHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in intratumoral accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier.METHODSIn this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and D-2-HG levels.RESULTSBetween Jan 2017 and May 2019, DS-1001b (125–1400 mg bid) had administered for 47 pts, and 15 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1–2. Gr 3 AEs were observed in 40% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Of 35 evaluable pts with contrast enhancing gliomas, one, five and 11 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable 12 pts with contrast non-enhancing gliomas, four achieved minor response and eight achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently.CONCLUSIONSDS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. The latest data will be updated. Funding source: This study was funded by Daiichi Sankyo Co., Ltd.

The correlation of fractional anisotropy parameters with Ki-67 index, and the clinical implication in grading of non-enhancing gliomas and neuronal-glial tumors

PurposeTo investigate the correlation between the FA parameters and Ki-67 labeling index, and their diagnostic performance in grading supratentorial non-enhancing gliomas and neuronal-glial tumors (GNGT). MethodsThis institutional review board-approved, Health Insurance Portability and Accountability (HIPAA) compliant retrospective study enrolled 35 patients, including 19 with low grade GNGT and 16 with high grade GNGT. The mean FA, maximal FA and mean maximal FA values derived from diffusion tensor imaging were measured. The correlation between the FA parameters and the Ki-67 labeling index was assessed by Spearman rank test. The receiver operating characteristic curve analysis and multivariate logistic regression analysis were performed to detect the optimal imaging parameters in grading GNGT. ResultsThe three FA parameters of low grade GNGT were significantly lower than the high grade GNGT (p < 0.001). The mean FA, maximal FA and mean maximal FA had significant positive correlation with Ki-67 labeling index (p = 0.001, p < 0.001, p < 0.001 respectively). The maximal FA showed a higher sensitivity and specificity in grading of non-enhancing GNGT with specificity of 78.9%, sensitivity of 100.0%, respectively. ConclusionsThe FA parameters correlated with Ki-67 labeling index, and were useful surrogates in preoperative grading supratentorial non-enhancing GNGT.

Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study.

BackgroundSurgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)–weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration.MethodsWe included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis.ResultsA total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79‒0.99) detected tumor better than T1G MRI (0.56, 0.39‒0.72; P < 0.001) and [18F]FET PET (0.76, 0.66‒0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65–0.98) compared with 0.69 (0.56–0.81; P = 0.019) for [18F]FET PET.ConclusionCombining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.

P04.11 Voxelwise correlation between vascular MRI parameters obtained with ASL and DSC is decreased in IDH-wt non-enhancing glioma

Abstract BACKGROUND Comparative studies of dynamic susceptibility contrast (DSC) based measurement of cerebral blood volume (CBV) or cerebral blood flow (CBF) and arterial spin labelling (ASL) based measurement of CBF have previously shown good correlation of these parameters in human glioma. However, these studies were mostly done before inclusion of the mutation status of the isocitrate dehydrogenase (IDH) encoding gene in brain tumour classification. In light of the call for gadolinium-free imaging, here we investigate the effect of IDH-mutation status on the correlation between ASL and DSC-based perfusion measurements in non-enhancing glioma. MATERIAL AND METHODS Twenty-two patients with non-enhancing glioma and confirmed IDH-mutation status (next generation sequencing, 6 IDH-wildtype and 16 IDH-mutated) underwent 3T MRI scanning (GE, Milwaukee, WI, USA). Image acquisition included a 3D spiral pseudocontinuous ASL with time-encoded labelling (7 effective label delays from 0.8 to 2 s, reconstruction matrix 128x128x42, resolution 1.9x1.9x3.5 mm3), and 2D DSC imaging (122 TRs, TR/TE 1500m/18.6ms, 15 slices, voxel size: 1.88x1.88x4 mm3) in which a bolus of 7.5ml of gadolinium-based contrast agent (Gadovist, Bayer, Leverkussen, GE) was injected. A pre-load bolus of equal size was given 5 minutes prior to DSC imaging. DSC and ASL images were motion corrected and linearly registered to high resolution FLAIR images (FSL, version 5.0.9, Oxford, UK). DSC-relative CBV (rCBV), DSC-relative CBF (rCBF), and ASL-CBF maps were calculated via previously described methods. The glioma region of interest (ROI) was determined via manual segmentation on the FLAIR images. Voxel-wise Pearson’s linear correlation coefficients (ρ) within this ROI were calculated between ASL-CBF and DSC-rCBV, and between ASL-CBF and DSC-rCBF. RESULTS Normalised histograms indicate that IDH-wt glioma has higher values for ASL-CBF, DSC-rCBV, and DSC-rCBF than IDH-mutated glioma. IDH-wildtype glioma has a significantly lower ρ ASL-CBF vs DSC-rCBV and ρ ASL-CBF vs DSC-rCBF than IDH-mutated glioma (two-sample t-tests p &lt; 0.05). CONCLUSION IDH-mutation status of non-enhancing glioma potentially affects the correlation between ASL-CBF and DSC-rCBF/rCBV and should be taken into account when moving towards ASL-only imaging. The decreased correlation between ASL and DSC-based vascular parameters in IDH-wt gliomas may be due to more aggressive vasculature in subtypes of IDH-wt tumours. Future work includes expansion of the current patient cohort (part of the ongoing iGENE study).

Preoperative Resectability Estimates of Nonenhancing Glioma by Neurosurgeons and a Resection Probability Map.

Preoperative interpretation of resectability of diffuse nonenhancing glioma is primarily based on individual surgical expertise. To compare the accuracy and precision between observed resections and preoperative estimates of neurosurgeons and a resection probability map (RPM). We hypothesize that the RPM estimates is as good as senior neurosurgeons. A total of 234 consecutive patients were included from 2 centers, who had resective surgery with functional mapping between 2006 and 2012 for a supra-tentorial nonenhancing glioma. Extent of resection (EOR) and residual tumor volume (RTV) were segmented and an RPM was constructed in standard brain space. Three junior and three senior neurosurgeons estimated EOR and RTV, blinded for postoperative results. We determined the agreement between the estimates and calculated the diagnostic accuracy of the neurosurgeons and the RPM to predict the observed resections. Preoperative estimates of resection results by junior and senior neurosurgeons were significantly biased towards overestimation of EOR (4.2% and 11.2%) and underestimation of RTV (4.3 and 9.0 mL), whereas estimates of the RPM were unbiased (-2.6% and -.2 mL, respectively). The limits of agreement were wide for neurosurgeons and for the RPM. The RPM was significantly more accurate in identifying patients in whom an EOR >40% was observed than neurosurgeons. Neurosurgeons estimate preoperative resectability before surgery of a nonenhancing glioma rather accurate-with a small bias-and imprecise-with wide limits of agreement. An RPM provides unbiased resectability estimates, which can be useful for surgical decision-making, planning, and education.

Can Virtual Contrast Enhancement in Brain MRI Replace Gadolinium?: A Feasibility Study.

Gadolinium-based contrast agents (GBCAs) have become an integral part in daily clinical decision making in the last 3 decades. However, there is a broad consensus that GBCAs should be exclusively used if no contrast-free magnetic resonance imaging (MRI) technique is available to reduce the amount of applied GBCAs in patients. In the current study, we investigate the possibility of predicting contrast enhancement from noncontrast multiparametric brain MRI scans using a deep-learning (DL) architecture. A Bayesian DL architecture for the prediction of virtual contrast enhancement was developed using 10-channel multiparametric MRI data acquired before GBCA application. The model was quantitatively and qualitatively evaluated on 116 data sets from glioma patients and healthy subjects by comparing the virtual contrast enhancement maps to the ground truth contrast-enhanced T1-weighted imaging. Subjects were split in 3 different groups: enhancing tumors (n = 47), nonenhancing tumors (n = 39), and patients without pathologic changes (n = 30). The tumor regions were segmented for a detailed analysis of subregions. The influence of the different MRI sequences was determined. Quantitative results of the virtual contrast enhancement yielded a sensitivity of 91.8% and a specificity of 91.2%. T2-weighted imaging, followed by diffusion-weighted imaging, was the most influential sequence for the prediction of virtual contrast enhancement. Analysis of the whole brain showed a mean area under the curve of 0.969 ± 0.019, a peak signal-to-noise ratio of 22.967 ± 1.162 dB, and a structural similarity index of 0.872 ± 0.031. Enhancing and nonenhancing tumor subregions performed worse (except for the peak signal-to-noise ratio of the nonenhancing tumors). The qualitative evaluation by 2 raters using a 4-point Likert scale showed good to excellent (3-4) results for 91.5% of the enhancing and 92.3% of the nonenhancing gliomas. However, despite the good scores and ratings, there were visual deviations between the virtual contrast maps and the ground truth, including a more blurry, less nodular-like ring enhancement, few low-contrast false-positive enhancements of nonenhancing gliomas, and a tendency to omit smaller vessels. These "features" were also exploited by 2 trained radiologists when performing a Turing test, allowing them to discriminate between real and virtual contrast-enhanced images in 80% and 90% of the cases, respectively. The introduced model for virtual gadolinium enhancement demonstrates a very good quantitative and qualitative performance. Future systematic studies in larger patient collectives with varying neurological disorders need to evaluate if the introduced virtual contrast enhancement might reduce GBCA exposure in clinical practice.

Phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001b in patients with recurrent or progressive IDH1 mutant gliomas.

2004 Background: WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 ( IDH1) mutations, resulting in intratumoral accumulation of oncometabolite 2-hydroxyglutarate (2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier. Methods: In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and 2-HG levels. Results: Between Jan 2017 and Oct 2018, DS-1001b (125-1400 mg bid) had administered for 45 pts (median age 44 yrs, prior radiation therapy 100%, prior chemotherapy 82%), and 17 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1-2. Gr 3 AEs were observed in 42.2% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Common AEs ( &gt; 20%) were skin hyperpigmentation, diarrhea, pruritus, nausea, rash, and headache. Of 29 evaluable pts with contrast enhancing gliomas, one, three and 10 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable nine pts with contrast non-enhancing gliomas, two achieved minor response and seven achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently. The brain/plasma ratio of free form of DS-1001b ranged 0.19‒0.77 in 3 pts. Conclusions: DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. Clinical trial information: NCT03030066.

First-line Chemotherapy With Temozolomide Alone for Non-enhancing Adult Brainstem Gliomas, With a Diffuse Subtype and Showing Clinical and/or Radiological Infiltrative Pattern of Progression

First-line Chemotherapy With Temozolomide Alone for Non-enhancing Adult Brainstem Gliomas, With a Diffuse Subtype and Showing Clinical and/or Radiological Infiltrative Pattern of Progression

ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents

PurposeTo quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used.MethodsA total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed.ResultsSeven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001).ConclusionGadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.

The Relationship Between IDH1 Mutation Status and Metabolic Imaging in Nonenhancing Supratentorial Diffuse Gliomas: A 11C-MET PET Study

Purpose:We evaluated the relationship between isocitrate dehydrogenase 1 (IDH1) mutation status and metabolic imaging in patients with nonenhancing supratentorial diffuse gliomas using 11C-methionine positron emission tomography (11C-MET PET).Materials and Methods:Between June 2012 and November 2017, we enrolled 86 (38 women and 48 men; mean age, 41.9 ± 13.1 years [range, 8-67 years]) patients with newly diagnosed supratentorial diffuse gliomas. All patients underwent preoperative 11C-MET PET. Tumor samples were obtained and immunohistochemically analyzed for IDH1 mutation status.Results:The mutant and wild-type IDH1 diffuse gliomas had significantly different mean maximum standardized uptake value values (2.73 [95% confidence interval, CI: 2.32-3.16] vs 3.85 [95% CI: 3.22-4.51], respectively; P = .004) and mean tumor-to-background ratio (1.90 [95% CI: 1.65-2.16] vs 2.59 [95% CI: 2.17-3.04], respectively; P = .007).Conclusions: 11C-methionine PET can noninvasively evaluate the IDH1 mutation status of patients with nonenhancing supratentorial diffuse gliomas.

P01.133 Preoperative predictors of malignancy in non-enhancing glioma in the era of molecular classification

P01.133 Preoperative predictors of malignancy in non-enhancing glioma in the era of molecular classification

Non-enhancing gliomas: does intraoperative ultrasonography improve resections?

PurposeNon-enhancing diffuse gliomas are a challenging surgical proposition. Delineation of tumor extent on preoperative imaging and intraoperative visualization are often difficult. MethodsWe retrospectively analyzed all cases of non-enhancing gliomas that were operated on using navigated 3-dimensional ultrasonography (US). tumor delineation (good, moderate, or poor) on preoperative magnetic resonance imaging (MRI) and intraoperative US was compared. Post-resection US findings with respect to residual tumor status were compared to the postoperative imaging findings. The extent of resection was calculated and recorded.ResultsThere were 55 gliomas (43 high-grade, 12 low-grade). Forty were close to eloquent areas. The pre-resection concordance of MRI with US was 56%, with US defining more tumors as well-delineated (n=26) than MRI (n=13). US was used for resection control in 50 cases. Gross tumor resection was achieved in 24 cases (51%). US correctly predicted the residual tumor status in 78% of cases. The use of US led to radical resections even in some tumors preoperatively deemed to be unresectable. However, eloquent location was the only independent predictor of the extent of resection.ConclusionIntraoperative US is a useful tool for guiding resection of non-enhancing gliomas. It may be better than MRI for delineating these tumors, and may thereby facilitate improved resection of these otherwise poorly delineated tumors. However, functional boundaries remain the main limiting factor for achieving complete resection of non-enhancing gliomas.

Application of MRS- and ASL-guided navigation for biopsy of intracranial tumors.

The diagnosis of a tumor depends on accurate identification of the target area for biopsy. However, tumor heterogeneity and the inability of conventional structural data for identifying the most malignant areas can reduce this accuracy. To evaluate the feasibility and practicality of magnetic resonance spectroscopy (MRS)- and arterial spin labeling (ASL)-guided MRI navigation for needle biopsy of intracranial tumors. Thirty patients with intracranial tumors who underwent intraoperative stereotactic biopsy were retrospectively analyzed. Contrast-enhanced 3D-BRAVO or 3D-T2FLAIR structural data, combined with MRS and ASL data, were used to identify the target area for biopsy. High-choline or high-perfusion sites were chosen preferentially, and then the puncture trajectory was optimized to obtain specimens for histopathologic examination. Twenty-two specimens were collected from 20 glioma patients (two specimens each were collected from two patients) and ten specimens were collected from ten lymphoma patients. The diagnosis rate after the biopsy was 93.3% (28/30). Two gliomas were initially diagnosed as gliosis and subsequently diagnosed correctly after the collection of a second biopsy specimen. Combined MRS and ASL helped target selection in 23 cases (76.7%), including three cases each of low-enhancing and non-enhancing gliomas. In two cases, the target selection decision was changed because the areas initially chosen on the basis of positron emission tomography data did not match the high-perfusion areas identified with ASL. Compared with conventional MRI, combined MRS and ASL improved the accuracy of target selection for the stereotactic biopsy of intracranial tumors.

Endoscopy in Temporal Lobe Glioma and Metastasis Resection: Is There a Role?

Surgical access to the temporal lobe is complex with many eloquent white fiber tracts, requiring careful preoperative surgical planning. Many microsurgical approaches to the temporal lobes are described, each with their own disadvantages. The adoption of the endoscope in neurosurgery has increased the options available when treating these difficult access tumors. We present our experience of a novel, minimally invasive, endoscopic approach to resect temporal lobe tumors. All patients undergoing endoscopic temporal lobe tumor resection between December 1, 2011 and December 1, 2017, with a single surgeon, were included. Tumors were resected through a minicraniotomy using a high-definition rigid endoscope with a 0- and 30-degree viewing angle. Bimanual resection was performed using standard microsurgical technique. There were 45 patients (22 men and 23 women) with a mean age of 53 years. There were 23 (51%) glioblastoma multiforme, 11 (24%) metastases, 7 (16%) astrocytoma, 3 (7%) anaplastic astrocytoma, and 1 (2%) World Health Organization grade I glioneuronal tumor. In 82.2% of cases (37/45), >95% resection was achieved and 42.2% (19/45) of patients achieving gross total resection. The endoscope has a role in temporallobe intraparenchymal tumor surgery, especiallyin3illustrative scenarios: 1) medial temporal, parahippocampal-gyruslow-grade nonenhancing gliomas, 2) subcortical high-gradeglioma and metastases medial to the sagittal stratum, and 3) recurrent gliomas with cystic resection cavity. The endoscope offers a safe and useful adjunct to the surgeons' armamentarium in brain tumor surgery. A minimally invasive approach also reduces surgical morbidity and length of stay.

Stereotactic image-based histological analysis reveals a correlation between 11C-methionine uptake and MGMT promoter methylation in non-enhancing gliomas.

Gliomas are genetically and histopathologically heterogeneous. Intratumoral heterogeneity in the MGMT promoter methylation status is an important clinical biomarker of glioblastoma. A higher uptake of 11C-methionine in positron-emission tomography (PET) reportedly reflects increased MGMT promoter methylation; however, non-stereotactic comparison of MGMT methylation and 11C-methionine PET images may not be accurate. The present study examined the correlation between 11C-methionine uptake and MGMT promoter methylation in non-enhancing gliomas using stereotactic image-based histological analysis. Data were collected from 9 patients with newly diagnosed non-enhancing glioma who underwent magnetic resonance imaging and 11C-methionine PET during pre-surgical examination. Clinical data were also collected from 3 patients during repeat surgery. The correlation between 11C-methionine uptake and MGMT methylation or cell density was analyzed using histological specimens obtained by multiple stereotactic sampling and an exact local comparison of 11C-methionine PET images and histological specimens was made. A total of 31 stereotactic sample sites were identified. In newly diagnosed cases, the tumor to normal uptake (T/N) ratio revealed a significant positive correlation with MGMT methylation (R=0.54, P=0.009) and a marginal correlation with cell density (R=0.42, P=0.05). In recurrent cases, the T/N ratio demonstrated no correlation with MGMT methylation (R=0.01, P=0.97) or cell density (R=0.15, P=0.70). An increased uptake of 11C-methionine in PET may reflect increased MGMT promoter methylation according to stereotactic image-based histological analysis. 11C-methionine PET could therefore be a useful tool for detecting regional MGMT promoter methylation in non-enhancing primary glioma.

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

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. To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy. Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection. 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). Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.

Influence of region-of-interest designs on quantitative measurement of multimodal imaging of MR non-enhancing gliomas.

A number of studies have revealed the usefulness of multimodal imaging in gliomas. Although the results have been heavily affected by the method used for region of interest (ROI) design, the most discriminatory method for setting the ROI remains unclear. The aim of the present study was to determine the most suitable ROI design for 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) positron emission tomography (PET), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) obtained by diffusion tensor imaging (DTI) from the viewpoint of grades of non-enhancing gliomas. A total of 31 consecutive patients with newly diagnosed, histologically confirmed magnetic resonance (MR) non-enhancing gliomas who underwent FDG-PET, MET-PET and DTI were retrospectively investigated. Quantitative measurements were performed using four different ROIs; hotspot/tumor center and whole tumor, constructed in either two-dimensional (2D) or three-dimensional (3D). Histopathological grading of the tumor was considered as empirical truth and the quantitative measurements obtained from each ROI was correlated with the grade of the tumor. The most discriminating ROI for non-enhancing glioma grading was different according to the different imaging modalities. 2D-hotspot/center ROI was most discriminating for FDG-PET (P=0.087), ADC map (P=0.0083), and FA map (P=0.25), whereas 3D-whole tumor ROI was best for MET-PET (P=0.0050). In the majority of scenarios, 2D-ROIs performed better than 3D-ROIs. Results from the image analysis using FDG-PET, MET-PET, ADC and FA may be affected by ROI design and the most discriminating ROI for non-enhancing glioma grading was different according to the imaging modality.