Predicting Isocitrate Dehydrogenase Status in Non-Contrast-Enhanced Adult-Type Astrocytic Tumors Using Diffusion Tensor Imaging and 11C-Methionine, 11C-Choline, and 18F-Fluorodeoxyglucose PET.

We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between May 2012 and December 2022. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) values using diffusion tensor imaging. We evaluated the tumor/normal brain uptake (T/N) ratios using 11C-methionine, 11C-choline, and 18F-fluorodeoxyglucose PET; extracted the parameters with significant differences in distinguishing the IDH status; and verified their diagnostic accuracy. Patients with astrocytomas were significantly younger than those with glioblastomas. The following MRI findings were significant predictors of IDH-wt instead of IDH-mut: thalamus invasion, contralateral cerebral hemisphere invasion, location adjacent to the ventricular walls, higher FA value, and lower MD value. The T/N ratio for all tracers was significantly higher for IDH-wt than for IDH-mut. In a composite diagnosis based on nine parameters, including age, 84.4% of cases with 0-4 points were of IDH-mut; conversely, 100% of cases with 6-9 points were of IDH-wt. Composite diagnosis using all parameters, including MRI and PET findings with significant differences, may help guide treatment decisions for early-stage gliomas.

Posttraumatic epilepsy in chronic disorders of consciousness due to severe traumatic brain injury after traffic accidents.

PURPOSE: To evaluate the clinical state of posttraumatic epilepsy (PTE) in patients with chronic disorders of consciousness (CDC) due to severe traumatic brain injury (STBI) after traffic accidents and clarify the risk factors for seizure occurrence in such patients. METHODS: Two hundred ninety-three patients with CDC due to STBI (mean age at admission [±standard deviation]: 36.4 ± 17.9 years; men: 71.7 %; mean duration of injury to admission: 416 ± 732 days; mean hospitalization time: 899 ± 319 days) were enrolled in this study. We retrospectively investigated the relationship between seizure conditions (type and frequency) and clinical data, including age, sex, pathological types of brain injury, with/without surgical intervention, degree of CDC, and administration of antiseizure medications (ASMs). RESULTS: Overall, 52.9 % (n = 155/293) and 64.2 % of the patients (n = 183/of 285 patients surviving at discharge) were administered ASMs at admission and discharge, respectively. One hundred thirty-two patients (45.1 %) experienced epileptic seizures during hospitalization, and the mean seizure frequency was 4.0 ± 0.4 times per year. In multivariate analysis, significant and independent risk factors of seizure occurrence were revealed to be male sex, high National Agency for Automotive Safety and Victims' Aid score, hypoxic encephalopathy, and history of the neurosurgical operations. CONCLUSION: The high prevalence of PTE in patients with CDC due to STBI, and the significant and independent risk factors for seizure occurrence in the chronic clinical phase were revealed. We expect that this study will aid toward improving clinical assessment and management of epileptic seizures in the population.

Resection of positive tissue on methionine-PET is associated with improved survival in glioblastomas.

BACKGROUND AND PURPOSE: The volume of excised tumor in contrast-enhanced areas evaluated via magnetic resonance imaging is known to have a strong influence on the survival of patients with glioblastoma (GBM). In this study, we investigated the effect of tumor resection on the survival of patients with GBM in the 11 C-methionine (MET) accumulation area using MET-positron emission tomography (MET-PET). METHODS: A total of 26 patients (median age, 69 years; 15 males) who had undergone tumor resection and MET-PET before and after surgery, after being newly diagnosed with GBM, were included in the study. MET-PET before and after tumor resection were compared. The association between the decrease in the maximum standardized uptake value (SUV) of the tumor divided by the normal cortical mean SUV (%; ΔT/N), the MET extent of resection (MET-EOR) from the % reduction in the MET accumulation area (%), and residual MET accumulation area (in cm3 ; MET-residual tumor volume [RTV]), as well as the survival time of patients with GBM, were evaluated via univariate analysis. RESULTS: ΔT/N were positively associated with survival (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.97-0.99], p = .02). MET-RTV revealed a negative association with survival (HR, 1.02 [95% CI, 1.01-1.04], p = .04). Additionally, MET-EOR showed a strong trend with survival (HR, 0.99 [95% CI, 0.97-1.01], p = .06). CONCLUSIONS: Surgical resection of MET-accumulated areas in GBM significantly prolongs the survival of patients with GBM. However, a prospective large-scale multicenter study is needed to confirm our findings.

Combining methionine-PET and MRI fluid-attenuated inversion-recovery mismatch to determine glioma molecular subtype.

BACKGROUND AND PURPOSE: 11 C-methionine (MET)-PET is a useful tool in neuro-oncology. The T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign on MRI is a characteristic finding in lower grade gliomas with isocitrate dehydrogenase (IDH) mutations and the absence of the 1p/19q codeletion; however, the T2-FLAIR mismatch sign has low sensitivity in differentiating gliomas and does not aid in identifying glioblastomas with IDH mutations. We therefore investigated the efficacy of the combination of the T2-FLAIR mismatch sign and MET-PET for accurately determining the molecular subtype of gliomas of all grades. METHODS: The present study comprised 208 adult patients diagnosed with supratentorial glioma confirmed by molecular genetics and histopathology. The ratio of the maximum lesion MET accumulation to the mean normal frontal cortex MET accumulation (T/N) was measured. The presence or absence of the T2-FLAIR mismatch sign was determined. The presence or absence of the T2-FLAIR mismatch sign and the MET T/N ratio were compared between glioma subtypes to evaluate individual and combined utility in identifying gliomas with IDH mutations and no 1p/19q codeletion (IDHmut-Noncodel) or gliomas with IDH mutations (IDHmut). RESULTS: The addition of MET-PET to MRI for the presence of the T2-FLAIR mismatch sign improved diagnostic accuracy, with the area under the curve values increasing from .852 to .871 for IDHmut-Noncodel and from .688 to .808 for IDHmut. CONCLUSIONS: The combination of the T2-FLAIR mismatch sign and MET-PET may provide improved diagnostic utility in differentiating gliomas according to molecular subtype, particularly in determining IDH mutation status.

Methionine-PET to differentiate between brain lesions appearing similar on conventional CT/MRI scans.

BACKGROUND AND PURPOSE: 11 C-Methionine (MET)-PET is a useful tool in neuro-oncology. This study aimed to examine whether a combination of diagnostic variables associated with MET uptake could help distinguish between brain lesions that are often difficult to discriminate in conventional CT and MRI. METHODS: MET-PET was assessed in 129 patients with glioblastoma multiforme, primary central nervous lymphoma, metastatic brain tumor, tumefactive multiple sclerosis, or radiation necrosis. The accuracy of the differential diagnosis was analyzed using five diagnostic characteristics in combination: higher maximum standardized uptake value (SUV) of MET in the lesion/the mean normal cortical SUV of MET ratio, overextension beyond gadolinium, peripheral pattern indicating abundant MET accumulation in the peripheral region, central pattern denoting abundant MET accumulation in the central region, and dynamic-up suggesting increased MET accumulation during dynamic study. The analysis was conducted on sets of two of the five brain lesions. RESULTS: Significant differences in the five diagnostic traits were observed among the five brain lesions, and differential diagnosis could be achieved by combining these diagnostic features. The area under the curve between each set of two of the five brain lesions using MET-PET features ranged from .85 to 1.0. CONCLUSIONS: According to the findings, combining the five diagnostic criteria could help with the differential diagnosis of the five brain lesions. MET-PET is an auxiliary diagnostic technique that could help in distinguishing these five brain lesions.

Differentiation of astrocytoma between grades II and III using a combination of methionine positron emission tomography and magnetic resonance spectroscopy.

Objective: This study aimed to establish a method for differentiating between grades II and III astrocytomas using preoperative imaging. Methods: We retrospectively analyzed astrocytic tumors, including 18 grade II astrocytomas (isocitrate dehydrogenase (IDH)-mutant: IDH-wildtype = 8:10) and 56 grade III anaplastic astrocytomas (37:19). We recorded the maximum methionine (MET) uptake ratios (tumor-to-normal: T/N) on positron emission tomography (PET) and three MRS peak ratios: choline (Cho)/creatine (Cr), N-acetyl aspartate (NAA)/Cr, and Cho/NAA, between June 2015 and June 2020. We then evaluated the cut-off values to differentiate between grades II and III. We compared the grading results between contrast enhancement effects on MR and combinational diagnostic methods (CDM) on a scatter chart using the cutoff values of the T/N ratio and MRS parameters. Results: The IDH-mutant group showed significant differences in the Cho/NAA ratio between grades II and III using univariate analysis; however, multiple regression analysis results negated this. The IDH-wildtype group showed no significant differences between the groups. Contrast enhancement effects also showed no significant differences in IDH status. Accordingly, regardless of the IDH status, no statistically independent factors differentiated between grades II and III. However, CDMs showed higher sensitivity and negative predictive value in distinguishing them than MRI contrast examinations for both IDH statuses. We demonstrated a significantly higher diagnostic rate of grade III than of grade II with CDM, which was more striking in the IDH-mutant group than in the wild-type group. Conclusions: CDM could be valuable in differentiating between grade II and III astrocytic tumors.

Brainstem volume, diffusion, and metabolism are associated with chronic consciousness disorders after traumatic brain injury.

BACKGROUND AND PURPOSE: We aimed to identify reliable neuroradiological features of the brainstem reflecting the neurological symptoms of patients with chronic disorders of consciousness (DOCs) due to severe traumatic brain injury (TBI). METHODS: We retrospectively examined 86 patients with chronic DOCs due to severe TBI caused by automobile accidents. We studied the relationships among (1) neurological symptoms, including consciousness level, (2) integrated cognitive/physical condition, and (3) neuroradiological features of the brainstem (brainstem volume on MRI, fractional anisotropy [FA] value in the brainstem, and standardized uptake value [SUV] of 18F-fluorodeoxyglucose [FDG] on positron emission tomography in the brainstem). RESULTS: Brainstem volume was significantly larger and FA values were significantly higher in patients with a better level of consciousness. However, brainstem volumes were significantly decreased and the maximum SUV (SUVmax ) of FDG significantly increased at 2 years following admission regardless of the level of consciousness at admission. The brainstem volume was significantly larger and the FA value and SUVmax of FDG were significantly higher in patients with better National Agency for Automotive Safety and Victims' Aid (NASVA) scores at admission. The decrease in the brainstem volume was significantly minimized and the SUVmax of FDG significantly increased in patients with more improvement in the NASVA score 2 years after admission. CONCLUSIONS: The volume, FA value, and SUVmax of FDG of the brainstem are important neuroradiological features associated with the neurological conditions of patients with chronic DOCs due to severe TBI.

Cerebral Glucose Metabolism in Patients with Chronic Disorders of Consciousness.

OBJECTIVE: To measure regional cerebral metabolic rate of glucose (CMRGlu) in patients with chronic disorders of consciousness (DOCs) using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: This retrospective cohort study examined 50 patients (mean age: 40.9 ± 20.1 years) with traumatic brain injury (TBI)-induced chronic DOCs [minimally conscious state (MCS)+, n = 20; MCS-, n = 15 and vegetative state (VS), n = 15]. We measured FDG-PET-based CMRGlu values in 12 regions of both brain hemispheres and compared those among MCS+, MCS - and VS patients. RESULTS: In both hemispheres, the regional CMRGlu reduced with consciousness deterioration in 11 of 12 regions (91.7%). In seven right hemisphere regions, CMRGlu values were markedly higher in MCS+ patients than in MCS- patients. Furthermore, CMRGlu was suggestively higher in the left occipital region in MCS- patients than in VS patients. CONCLUSION: Functional preservation in the left occipital region in patients with chronic DOCs might reflect an awareness of external environments, whereas extensive functional preservation in the right cerebral hemisphere might reflect communication motivation.

Spastic muscle stiffness evaluated using ultrasound elastography and evoked electromyogram in patients following severe traumatic brain injury: an observational study.

OBJECTIVE: To determine the relationship between muscle stiffness assessed using ultrasound shear wave elastography, spinal motor neuron excitability assessed using the F wave, and clinical findings of spasticity in patients with spastic muscle overactivity following severe traumatic brain injury. METHODS: This study enrolled 17 inpatients with severe traumatic brain injury and 20 healthy volunteers. Biceps brachii muscle stiffness was then evaluated using ultrasound shear wave speed. Spinal motor neuron excitability was evaluated using the F/M ratio recorded from abductor pollicis brevis muscle. Clinical parameters, such as the modified Ashworth scale and modified Tardieu scale, were assessed in the patient with traumatic brain injury. RESULTS: The patients with traumatic brain injury group had a significantly higher shear wave speed and F/M ratio compared with the healthy group. A higher shear wave speed was correlated with higher clinical spastic severity in patients with traumatic brain injury. The F/M ratio was not significantly correlated with clinical spastic severity. CONCLUSION: Ultrasound shear wave elastography might be helpful for assessing muscle stiffness in patients with spastic muscle overactivity following severe traumatic brain injury. Further studies comprising larger cohorts are warranted.

Radiological Prediction of Isocitrate Dehydrogenase (IDH) Mutational Status and Pathological Verification for Lower-Grade Astrocytomas.

Background and objective The isocitrate dehydrogenase (IDH) status of patients with World Health Organization (WHO) grade II or III astrocytoma is essential for understanding its biological features and determining therapeutic strategies. This study aimed to use radiological analysis to predict the IDH status of patients with lower-grade astrocytomas and to verify the pathological implications. Methods In this study, 47 patients with grade II (17 cases) or III astrocytomas (30 cases), based on 2016 WHO Classification, underwent methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) on the same day between January 2013 and June 2020. The patients were retrospectively assessed. Immunohistochemistry showed 23 cases of IDH-mutant and 24 of IDH-wildtype. Based on fluid-attenuated recovery inversion (FLAIR)/T2 imaging, three doctors blinded to clinical data independently allocated 18 patients to the clear boundary group between the tumor and the normal brain and 29 to the unclear boundary group. The peak ratios of N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and Cho/NAA and the tumor-to-normal region (T/N) ratio for maximum accumulation in MET-PET were calculated. For statistical analysis, Fisher's exact test was used to assess associations between two variables, and the Mann-Whitney U test to compare the values between the IDH-wildtype and IDH-mutant groups. The optimal cut-off values of MET T/N ratio and MRS parameters for discriminating IDH-wildtype from IDH-mutant were obtained using receiver operating characteristics curves. Results The unclear boundary group had significantly more IDH-wildtype cases than the clear boundary group (P<0.001). The IDH-wildtype group had significantly lower Cho/Cr (<1.84) and Cho/NAA (<1.62) ratios (P=0.02 and P=0.047, respectively) and a higher MET T/N ratio (>1.44, P=0.02) than the IDH-mutant group. The odds for the IDH-wildtype were 0.22 for patients who fulfilled none of the four criteria, including boundary status and three ratios, and 0.9 for all four criteria. Conclusions These results suggest that the combination of MRI, MRS, and MET-PET examination could be helpful for the prediction of IDH status in WHO grade II/III gliomas.

Prediction of nuclide accumulation spread based on the volume of enhancing MRI lesion in glioblastoma patients.

BACKGROUND: 11C-methionine-PET (MET) and Thallium-201 chloride-SPECT (TL) are useful for predictive proliferation ability and tumor invasion range identification in glioma patients, however they are not always possible in any hospital or country. Our study aimed to assess whether the range of MET and Tl accumulation could be predicted from the contrast-enhanced lesions in Gadolinium (Gd)-T1 weighted MR image (Gd-MRI) in glioblastoma multiforme (GBM) patients. METHODS: In 25 cases, the MET-Area, TL-Area, O-Area where MET and TL overlap, and all accumulation area (AA-Area) were measured in the same axial cross section as the Gd enhanced maximum area (Gd-Area). This tracing operation was repeated with all axial fusion slices, and each volume was also measured (Gd-V, MET-V, TL-V, O-V, AA-V). RESULTS: The maximum accumulation distance of MET and TL beyond the Gd-Area was limited to within 30 mm, 35 mm, respectively. Significant positive correlations were showed in all combinations with Gd-Area: MET-Area (r=0.851, p<0.0001), TL-Area (r=0.955, p<0.0001), O-Area (r=0.935, p<0.0001) and AA-Area (r=0.893, p<0.0001), respectively. All combinations with Gd-V showed significant positive correlation: MET-V (r=0.867, p<0.0001), TL-V (r=0.952, p<0.0001), O-V (r=0.935, p<0.0001) and AA-V (r=0.897, p<0.0001), respectively. CONCLUSIONS: Approximate tumor volume Gd-V can be calculated using the formula A * B * C / 2, where A, B, and C represent the dimensions of Gd-enhanced lesion in 3 axes perpendicular to each other. The nuclide accumulation predictive table created using the obtained linear approximation functions can be used to predict the average tumor invasion range from the Gd-V without preoperative nuclear examinations.

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.

BACKGROUND: Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. METHODS: We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. RESULTS: Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. CONCLUSIONS: Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

Pediatric Giant Cell Glioblastoma Presenting with Intracranial Dissemination at Diagnosis: A Case Report.

Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma multiforme (GBM), and it often occurs in younger patients; however, its onset in children is extremely noticeable. A 7-year-old girl presented with a headache and restlessness. A giant tumor that was 7 cm in diameter was found by magnetic resonance imaging (MRI) in the left frontal lobe with intracranial dissemination. Because the tumor had extended to the lateral ventricles and occluded the foramen of Monro causing hydrocephalus, she underwent ventricular drainage and neuro-endoscopic biopsy from the left posterior horn of the lateral ventricle. The initial pathological diagnosis was an atypical teratoid/rhabdoid tumor (AT/RT). When the dissemination subsided after the first chemotherapy with vincristine, doxorubicin, and cyclophosphamide, she underwent the first tumor resection via a left frontal transcortical approach. After surgery, the second chemotherapy with ifosfamide, cisplatin, and etoposide was not effective for the residual tumor and intracranial dissemination. The second surgery via a transcallosal approach achieved nearly total resection leading to an improvement of the hydrocephalus. The definitive pathological diagnosis was GCG. Despite chemo-radiation therapy, the dissemination in the basal cistern reappeared and the hydrocephalus worsened. She was obliged to receive a ventriculo-peritoneal (VP) shunt and palliative care at home; however, her poor condition prevented her discharge. Ten months after admission, she died of tumor progression. The peritoneal dissemination was demonstrated by cytology of ascites. In conclusion, although unusual, pediatric GCG may be disseminated at diagnosis, in which case both tumor and hydrocephalus control need to be considered.

Diffuse midline glioma in the spinal cord with rapid respiratory deterioration.

BACKGROUND: Neurogenic acute respiratory failure is usually caused by either infection or vascular insufficiency. We report the case of a patient who developed acute respiratory failure secondary to a spinal tumor. CASE PRESENTATION: A 32-year-old man, presenting with numbness and muscle weakness in his legs for 2 weeks, was transferred to our hospital with worsening quadriplegia and development of respiratory symptoms. We carried out emergent spinal decompression and initiated steroid pulse therapy, with no resolution of symptoms; a tumor incision biopsy after contrast cervical magnetic resonance imaging revealed an intraspinal tumor with a pathological diagnosis of World Health Organization grade IV glioma. The patient developed bradycardia, severe sepsis, status epilepticus, and cardiopulmonary arrest due to hypoxemia and was treated with chemoradiotherapy under mechanical ventilation. He was later transferred to another hospital for subacute care. CONCLUSION: Acute respiratory failure caused by spinal tumors is uncommon. However, acute care practitioners should be mindful of neoplastic lesions as a potential cause.

Expression of microRNAs in plasma and in extracellular vesicles derived from plasma for dogs with glioma and dogs with other brain diseases.

OBJECTIVE: To measure expression of microRNAs (miRNAs) in plasma and in extracellular vesicles (EVs) derived from plasma for dogs with glioma and dogs with other brain diseases. SAMPLE: Plasma samples from 11 dogs with glioma and 19 control dogs with various other brain diseases. PROCEDURES: EVs were isolated from plasma samples by means of ultracentrifugation. Expression of 4 candidate reference miRNAs (let-7a, miR-16, miR-26a, and miR-103) and 4 candidate target miRNAs (miR-15b, miR-21, miR-155, and miR-342-3p) was quantified with reverse transcription PCR assays. Three software programs were used to select the most suitable reference miRNAs from among the 4 candidate reference miRNAs. Expression of the 4 target miRNAs was then calculated relative to expression of the reference genes in plasma and EVs, and relative expression was compared between dogs with glioma and control dogs with other brain diseases. RESULTS: The most suitable reference miRNAs were miR-16 for plasma and let-7a for EVs. Relative expression of miR-15b in plasma and in EVs was significantly higher in dogs with glioma than in control dogs. Relative expression of miR-342-3p in EVs was significantly higher in dogs with glioma than in control dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that miR-15b and miR-342-3p have potential as noninvasive biomarkers for differentiating glioma from other intracranial diseases in dogs. However, more extensive analysis of expression in specific glioma subtypes and grades, compared with expression in more defined control populations, will be necessary to assess their clinical relevance.

Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma.

OBJECTIVE: Glutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo. METHODS: Three GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells. RESULTS: Riluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05). CONCLUSIONS: Riluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

Usefulness of positron emission tomography for differentiating gliomas according to the 2016 World Health Organization classification of tumors of the central nervous system.

OBJECTIVE: Positron emission tomography (PET) is important in the noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 WHO classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification). Here, the authors investigated the relationship between uptake of 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) on PET imaging and isocitrate dehydrogenase (IDH) status (wild-type [IDH-wt] or mutant [IDH-mut]) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification. METHODS: In total, 105 patients with newly diagnosed cerebral gliomas (6 diffuse astrocytomas [DAs] with IDH-wt, 6 DAs with IDH-mut, 7 anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, 5 GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake value (SUV) of the tumor/mean SUV of normal cortex (T/N) ratios for MET, CHO, and FDG were calculated, and the mean T/N ratios of DA, AA, and GBM with IDH-wt and IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the 3 PET tracers. RESULTS: There were significant differences in the mean T/N ratios for all 3 PET tracers between the IDH-wt and IDH-mut groups of all histological classifications (p < 0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all 3 PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all 3 PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p < 0.01). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that in the IDH-mut group for both MET (p = 0.034) and CHO (p = 0.01). However, there was no significant difference in the ratio for FDG. CONCLUSIONS: PET imaging using MET, CHO, and FDG was suggested to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.

Identification of reference genes for microRNAs of extracellular vesicles isolated from plasma samples of healthy dogs by ultracentrifugation, precipitation, and membrane affinity chromatography methods.

OBJECTIVE: To compare ultracentrifugation, precipitation, and membrane affinity chromatography methods for isolation of extracellular vesicles (EVs) from canine plasma samples and to identify suitable reference genes for incorporation into a quantitative reverse transcription PCR assay of microRNA expression in plasma EVs of healthy dogs. ANIMALS: 6 healthy Beagles. PROCEDURES: Plasma samples were obtained from each dog, and EVs were isolated from 0.3 mL of these samples via ultracentrifugation, precipitation, and membrane-affinity chromatographic methods. Nanoparticle tracking analysis was performed to determine the concentration and size distribution of EVs isolated by the ultracentrifugation method. Expression levels (cycle threshold values) of 4 microRNAs (let-7a, miR-16, miR-26a, and miR-103) were then compared by means of quantitative reverse transcription PCR assay. Three statistical programs were used to identify the microRNAs most suitable for use as reference genes. RESULTS: Results indicated that ultracentrifugation was the most stable of all 3 methods for isolating microRNAs from 0.3 mL of plasma. Nanoparticle tracking revealed that EV samples obtained by the ultracentrifugation method contained a mean ± SD of approximately 1.59 × 1010 vesicles/mL ± 4.2 × 108 vesicles/mL. Of the 4 microRNAs in plasma EVs isolated by ultracentrifugation, miR-103 was the most stable. CONCLUSIONS AND CLINICAL RELEVANCE: The ultracentrifugation method has potential as a stable method for isolating EVs from canine plasma samples with a high recovery rate, and miR-103 may provide the most stable reference gene for normalizing microRNA expression data pertaining to plasma EVs isolated by ultracentrifugation.

Dissociation Between 11C-Methionine-Positron Emission Tomography and Gadolinium-Enhanced Magnetic Resonance Imaging in Longitudinal Features of Glioblastoma After Postoperative Radiotherapy.

The aims of the present study were to compare the longitudinal changes of glioblastoma multiforme after radiotherapy (RT) between 11C-methionine positron emission tomography (MET-PET) and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) and to clarify whether these changes were predictive of survival. We included 30 patients, who had undergone MET-PET and Gd-MRI before and every 3 months after RT. The lesion/normal brain uptake (L/N) ratio and contrast-enhancing lesion volume were examined. The L/N ratio was decreased until 9 months after RT with significance until 3 months. The contrast-enhancing lesion volume was decreased until 3 months and thereafter increased until 9 months with significance. The variation rates of the L/N ratio between pre-RT and 3 months differentiated survival of >23 months from ≤23 months. A dissociation could exist in the longitudinal changes of GBM after RT between MET-PET and Gd-MRI. The variation rate of the L/N ratio could be related to survival.