2-Hydroxyglutarate magnetic resonance spectroscopy in adult brainstem glioma.

OBJECTIVE: Adult brainstem gliomas (BSGs) are rare tumors of the CNS that are poorly understood. Upregulation of the oncometabolite 2-hydroxyglutarate (2HG) in the tumor indicates the mutation of isocitrate dehydrogenase (IDH), which can be detected by magnetic resonance spectroscopy (MRS). Although histological examination is required for the definitive diagnosis of BSG, 2HG-optimized MRS (2HG-MRS) may be useful, considering the difficult nature of brainstem lesion biopsy. The aim of this study was to evaluate the utility of 2HG-MRS for diagnosing IDH-mutant adult BSG. METHODS: Patients with a radiographically confirmed brainstem tumor underwent 3T MRS. A single voxel was set in the lesion with reference to the T2 or fluid-attenuated inversion recovery image and analyzed according to the 2HG-tailored MRS protocol (point-resolved spectroscopic sequence; echo time 35 msec). All patients underwent intraoperative navigation-guided or CT-guided stereotactic biopsy for histopathological diagnosis. The status of IDH and H3K27M mutations was confirmed by immunohistochemistry and direct DNA sequencing. In addition, the authors examined the relationship between patients' 2HG concentrations and survival time. RESULTS: Ten patients (7 men, 3 women; median age 33.5 years) underwent 2HG-MRS and biopsy. Four patients had an H3K27M mutation and 4 had an IDH1 mutation (1 R132H canonical IDH mutation, 2 R132S and 1 R132G noncanonical IDH mutations). Two had neither H3K27M nor IDH mutations. The H3K27M and IDH mutations were mutually exclusive. Most tumors were located in the pons. There was no significant radiological difference between mutant H3K27M and IDH on a conventional MRI sequence. A 2HG concentration ≥ 1.8 mM on MRS demonstrated 100% (95% CI 28%-100%) sensitivity and 100% (95% CI 42%-100%) specificity for IDH-mutant BSG (p = 0.0048). The median overall survival was 10 months in IDH-wild-type BSG patients (n = 6) and could not be estimated in IDH-mutant BSG patients (n = 4) due to the small number of deaths (p = 0.008). CONCLUSIONS: 2HG-MRS demonstrated high sensitivity and specificity for the prediction of IDH-mutant BSG. In addition, 2HG-MRS may be useful for predicting the prognosis of adult BSG patients.

Glutamic Acid and Total Creatine as Predictive Markers for Epilepsy in Glioblastoma by Using Magnetic Resonance Spectroscopy Before Surgery.

OBJECTIVE: Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. METHODS: Fifty-one patients with glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Single-voxel (1.5 cm3) MRS, in an enhanced lesion, was acquired using a double-echo point-resolved spectroscopic sequence with chemical-shift selective water suppression. MRS data were quantified with linear combination model (LC-Model) software. We compared the MRS data between groups with and without epilepsy during the postoperative course (EP). RESULTS: The ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (Glu/tCr and Glx/tCr) in the tumor were associated with epilepsy history. The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of EP (area under curve: 0.82). In the analysis excluding patients with preoperative epilepsy, a Glu/tCr value of 1.81 was 75% sensitive and 88% specific for the prediction (area under curve: 0.87). CONCLUSIONS: Intratumoral metabolite concentrations measured using pretreatment 3.0-T MRI/1H-MRS changed characteristically in the group with EP. Our study suggests that the Glu/tCr ratio in tumors has adequate reliability in predicting EP. Pretreatment MRS is a minimally invasive and simple procedure that can provide useful information on glioblastoma patients.

Hyperintense signal on diffusion-weighted imaging for monitoring the acute response and local recurrence after photodynamic therapy in malignant gliomas.

PURPOSE: Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel localized treatment for malignant glioma that provides effective local control. The acute response of malignant glioma to PDT can be detected as linear transient hyperintense signal on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient values without symptoms. However, their long-term clinical significance has not yet been examined. The aim of this study was to clarify the link between hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. METHODS: Thirty patients (16 men; median age, 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed the signal changes on DWI after PDT and the relationship between these findings and the recurrence pattern. RESULTS: All patients showed linear hyperintense signal on DWI at the surface of the resected cavity from day 1 after PDT. These changes disappeared in about 30 days without any neurological deterioration. During a mean post-PDT follow-up of 14.3 months, 19 patients (63%) exhibited recurrence: 10 local, 1 distant, and 8 disseminated. All of the local recurrences arose from areas that did not show hyperintense signal on DWI obtained on day 1 after PDT. CONCLUSIONS: The local recurrence in malignant glioma after PDT occurs in an area without hyperintense signal on DWI as an acute response to PDT. This characteristic finding could aid in the monitoring of local recurrence after PDT.

The Histopathologic and Radiologic Features of T2-FLAIR Mismatch Sign in IDH-Mutant 1p/19q Non-codeleted Astrocytomas.

OBJECTIVE: The T2-FLAIR mismatch sign is a useful imaging sign in clinical magnetic resonance imaging studies for detecting isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted astrocytomas. However, the association between the mismatch sign and pathologic findings is poorly understood. Therefore, the aim of this study was to elucidate the relationship of histopathologic and radiologic features with the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. METHODS: We divided 17 IDH-mutant 1p/19q non-codeleted patients into 2 groups according to mismatch sign presence (WITH, n = 9; WITHOUT, n = 8) and retrospectively analyzed their pathologic findings and apparent diffusion coefficient (ADC) values. We also compared these findings between the tumor Core (central area) and Rim (marginal area). RESULTS: In the pathologic analysis, Core of the WITH group contained numerous microcysts whereas Rim had abundant neuroglial fibrils and cellularity. In contrast, Core of the WITHOUT group had highly concentrated neuroglial fibrils. In ADC analysis, Core of the WITH group had significantly higher ADC values compared with Rim (P < 0.001). However, there was no significant difference between Core and Rim in the WITHOUT group (P = 0.12). The WITH group had a significantly higher Core/Rim ratio of ADC values compared with the WITHOUT group (P < 0.001). CONCLUSIONS: This study provides evidence that a region-dependent microstructural difference could reflect the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. Core of the mismatch sign characteristically had microcystic changes accompanied by higher ADC values, whereas Rim had abundant neuroglial fibrils and cellularity accompanied by lower ADC values.

Glioma cells require one-carbon metabolism to survive glutamine starvation.

Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around "pseudopalisading necrosis." Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results highlight a critical role for serine-dependent one-carbon metabolism in surviving glutamine starvation and suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

Metabolic changes and anti-tumor effects of a ketogenic diet combined with anti-angiogenic therapy in a glioblastoma mouse model.

The ketogenic diet (KD) is a high fat and low carbohydrate diet that produces ketone bodies through imitation of starvation. The combination of KD and Bevacizumab (Bev), a VEGF inhibitor, is considered to further reduce the supply of glucose to the tumor. The metabolite changes in U87 glioblastoma mouse models treated with KD and/or Bev were examined using gas chromatography-mass spectrometry. The combination therapy of KD and Bev showed a decrease in the rate of tumor growth and an increase in the survival time of mice, although KD alone did not have survival benefit. In the metabolome analysis, the pattern of changes for most amino acids are similar between tumor and brain tissues, however, some amino acids such as aspartic acid and glutamic acid were different between tumors and brain tissues. The KD enhanced the anti-tumor efficacy of Bev in a glioblastoma intracranial implantation mouse model, based on lowest levels of microvascular density (CD31) and cellular proliferation markers (Ki-67 and CCND1) in KD + Bev tumors compared to the other groups. These results suggested that KD combined with Bev may be a useful treatment strategy for patients with GBM.

Intraoperative 3-T Magnetic Resonance Spectroscopy for Detection of Proliferative Remnants of Glioma.

BACKGROUND: Few studies have examined the usefulness of intraoperative magnetic resonance spectroscopy (iMRS) for identifying abnormal signals at the resection margin during glioma surgery. The aim of this study was to assess the value of iMRS for detecting proliferative remnants of glioma at the resection margin. METHODS: Fifteen patients with newly diagnosed glioma underwent single-voxel 3-T iMRS concurrently with intraoperative magnetic resonance imaging-assisted surgery. Volumes of interest (VOIs) were placed at T2-hyperintense or contrast-enhancing lesions at the resection margin. In addition to technical verification, the correlation between the MIB-1 labeling index (a pathologic feature) and metabolites measured using iMRS (N-acetyl-L-aspartate [NAA], choline [Cho], and Cho/NAA ratio) was analyzed. RESULTS: iMRS was performed for 20 VOIs in 15 patients. Fourteen (70%) of these VOIs were confirmed to be MIB-1-positive. There was a significant positive correlation between the Cho/NAA ratio and MIB-1 index (r = 0.46, P = 0.04). Cho level (P = 0.003) and Cho/NAA ratio (P = 0.002) were significantly higher in VOIs that were MIB-1-positive than in those that were MIB-1-negative. Detection of a Cho level >1.074 mM and a Cho/NAA ratio >0.48 using iMRS resulted in high diagnostic accuracy for MIB-1-positive remnants (Cho level: sensitivity 86%, specificity 100%; Cho/NAA ratio: sensitivity 79%, specificity 100%). CONCLUSIONS: This study provides evidence that 3-T iMRS can detect proliferative remnants of glioma at the resection margin using the Cho level and Cho/NAA ratio, suggesting that intraoperative magnetic resonance imaging-assisted surgery with iMRS would be practicable in glioma.

Intractable Hiccups After Coil Embolization of Partially Thrombosed Posterior Inferior Cerebellar Artery Aneurysm.

BACKGROUND: Hiccups are defined as sudden-onset involuntary contractions of the diaphragm followed by immediate inspiration and laryngeal closure, and they are considered intractable if prolonged beyond 1 month. A reflux arc involving phrenic, vagal, and central midbrain modulation is likely responsible for hiccups. We herein report a case of intractable hiccups caused by compression of the dorsal aspect of the medulla oblongata after treatment of a partially thrombosed distal posterior inferior cerebellar artery (PICA) aneurysm. CASE DESCRIPTION: A 51-year-old man presented with severe headache and was diagnosed with subarachnoid hemorrhage. Magnetic resonance imaging and cerebral angiography showed a partially thrombosed distal PICA aneurysm associated with a fusiform aneurysm in the ipsilateral vertebral artery. Based on the limited distribution of the clot, we performed endovascular coil occlusion of the aneurysm lumen followed by parent vessel occlusion for the distal PICA aneurysm. After the procedure, the patient presented with hiccups that could not be controlled by any medications. Magnetic resonance imaging showed an area of hyperintensity at the bilateral dorsal part of the medulla adjacent to the embolized aneurysm. The hiccups spontaneously disappeared 1 month after the procedure, and the abnormal signal findings also disappeared within the same period. The hiccups did not recur for 30 months postoperatively. CONCLUSIONS: In this case, the precise location of the culprit lesion causing the patient's hiccups was the dorsal medulla oblongata. Clinicians should be aware of the possibility of structural or functional disorders of the reflux arc in patients with intractable hiccups.