Impact of the extent of resection on the survival of patients with grade II and III gliomas using awake brain mapping.

PURPOSE: The aim of this study was to assess the effect of the extent of resection (EOR) of tumors on survival in a series of patients with grade II and III gliomas (GII/III-gliomas) who underwent awake brain mapping. METHODS: We retrospectively analyzed 126 patients with GII/III-gliomas in the dominant and non-dominant hemisphere who underwent awake brain surgery at the same institution between December 2012 and May 2020. RESULTS: EOR cut-off values for improved progression-free survival (PFS) were determined by a receiver operator characteristic (ROC) analysis of 5-year PFS. The ROC for EOR showed a cut-off value of ≥ 85.3%. The median PFS rate of patients with GII/III-gliomas in the group with an EOR ≥ 100%, including supratotal resection (n = 47; median survival [MS], not reached), was significantly higher than that in the group with an EOR < 90% (n = 52; MS, 43.1 months; 95% CI 37.7-48.5 months; p = 0.03). In patients with diffuse astrocytomas and anaplastic astrocytomas, the group with EOR ≥ 100%, including supratotal resection (n = 25; MS, not reached), demonstrated a significantly better PFS rate than did the group with an EOR < 100% (n = 45; MS, 35.8 months; 95% CI 19.9-51.6 months; p = 0.03). Supratotal or gross total resection was correlated with better PFS in IDH-mutant type of diffuse astrocytomas and anaplastic astrocytomas (n = 19; MS, not reached vs. n = 35; MS, 40.6 months; 95% CI 22.3-59.0 months; p = 0.02). By contrast, supratotal or gross total resection was not associated with longer PFS rates in patients with IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas. CONCLUSIONS: The present study demonstrates a significant association between tumor EOR and survival in patients with GII/III gliomas. The EOR cut-off value for 5-year PFS was ≥ 85.3%. It is noteworthy that supratotal or gross total resection significantly correlated with better PFS in IDH-mutant type of WHO grade II and III astrocytic tumors. In light of our finding that EOR did not correlate with PFS in patients with aggressive IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas, we suggest treatments that are more intensive will be needed for the control of these tumors.

Multiacquisition Variable-Resonance Image Combination Selective Can Improve Image Quality and Reproducibility for Metallic Implants in the Lumbar Spine.

The aim of this study is to evaluate how metallic artifacts in the lumbar spine can affect images obtained from magnetic resonance (MR) sequences. We performed a phantom experiment by scanning an agar containing an orthopedic metallic implant using 64-channel multidetector row computed tomography (CT) and a 3-tesla MR unit. We compared the reproducibility in each measurement, enlargement or reduction ratio of the CT and MR measurements, and signal deviation in each voxel from the control. The reproducibility on CT and multiacquisition variable-resonance image combination selective (MAVRIC SL) was good, but that on the other MR sequences showed either fixed bias or proportional bias. The reduction ratios of the distance between the nails were significantly smaller in MAVRIC SL than in the other MR sequences after CT measurements (p<0.001, respectively). MAVRIC SL was able to reduce the metallic artifact, permitting observation of the tissue surrounding the metal with good reproducibility.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

Next Generation Sequencing-Based Transcriptome Predicts Bevacizumab Efficacy in Combination with Temozolomide in Glioblastoma.

Glioblastoma (GBM), the most common and malignant brain tumor, is classified according to its isocitrate dehydrogenase (IDH) mutation status in the 2016 World Health Organization (WHO) brain tumor classification scheme. The standard treatment for GBM is maximal resection, radiotherapy, and Temozolomide (TMZ). Recently, Bevacizumab (Bev) has been added to basic therapy for newly diagnosed GBM, and monotherapy for recurrent GBM. However, the effect of IDH1 mutation on the combination of Bev and TMZ is unknown. In this study, we performed transcriptomic analysis by RNA sequencing with next generation sequencing (NGS), a newly developed powerful method that enables the quantification of the expression level of genome-wide genes. Extracellular matrix and immune cell migration genes were mainly upregulated whereas cell cycle genes were downregulated in IDH1-mutant U87 cells but not in IDH1-wildtype U87 cells after adding Bev to TMZ. In vitro and in vivo studies were conducted for further investigations to verify these results, and the addition of Bev to TMZ showed a significant antitumor effect only in the IDH1-mutant GBM xenograft model. Further studies of gene expression profiling in IDH1 mutation gliomas using NGS will provide more genetic information and will lead to new treatments for this refractory disease.

Synthesis of PET probe O6-[(3-[11C]methyl)benzyl]guanine by Pd0-mediated rapid C-[11C]methylation toward imaging DNA repair protein O6-methylguanine-DNA methyltransferase in glioblastoma.

O6-Benzylguanine (O6-BG) is a substrate of O6-methylguanine-DNA methyltransferase (MGMT), which is involved in drug resistance of chemotherapy in the majority of glioblastoma multiform. For clinical diagnosis, it is hoped that the MGMT expression level could be determined by a noninvasive method to understand the detailed biological properties of MGMT-specific tumors. We synthesized 11C-labeled O6-[(3-methyl)benzyl]guanine ([11C]mMeBG) as a positron emission tomography probe. Thus, a mixed amine-protected stannyl precursor, N9-(tert-butoxycarbonyl)-O6-[3-(tributylstannyl)benzyl]-N2-(trifluoroacetyl)guanine, was subjected to rapid C-[11C]methylation under [11C]CH3I/[Pd2(dba)3]/P(o-CH3C6H4)3/CuCl/K2CO3 in NMP, followed by quick deprotection with LiOH/H2O, giving [11C]mMeBG with total radioactivity of 1.34GBq and ≥99% radiochemical and chemical purities.

Efficacy of the transtemporal approach with awake brain mapping to reach the dominant posteromedial temporal lesions.

BACKGROUND: Surgeries for lesions in the dominant hippocampal and parahippocampal gyrus involving the posteromedial temporal regions are challenging to perform because they are located close to Wernicke's area; white matter fibers related with language; the optic radiations; and critical neurovascular structures. We performed a transtemporal approach with awake functional mapping for lesions affecting the dominant posteromedial temporal regions. The aim of this study was to assess the feasibility, safety, and efficacy of awake craniotomy for these lesions. METHODS: We retrospectively reviewed four consecutive patients with tumors or cavernous angiomas located in the left hippocampal and parahippocampal gyrus, which further extended to the posteromedial temporal regions, who underwent awake surgery between December 2014 and January 2016. RESULTS: Four patients with lesions associated with the left hippocampal and parahippocampal gyrus, including the posteromedial temporal area, who underwent awake surgery were registered in the study. In all four patients, cortical and subcortical eloquent areas were identified via direct electrical stimulation. This allowed determination of the optimal surgical route to the angioma or tumor, even in the language-dominant hippocampal and parahippocampal gyrus. In particular, this approach enabled access to the upper part of posteromedial temporal lesions, while protecting the subcortical language-related fibers, such as the superior longitudinal fasciculus. CONCLUSIONS: This study revealed that awake brain mapping can enable the safe resection of dominant posteromedial temporal lesions, while protecting cortical and subcortical eloquent areas. Furthermore, our experience with four patients demonstrates the feasibility, safety, and efficacy of awake surgery for these lesions.

An immuno-wall microdevice exhibits rapid and sensitive detection of IDH1-R132H mutation specific to grade II and III gliomas.

World Health Organization grade II and III gliomas most frequently occur in the central nervous system (CNS) in adults. Gliomas are not circumscribed; tumor edges are irregular and consist of tumor cells, normal brain tissue, and hyperplastic reactive glial cells. Therefore, the tumors are not fully resectable, resulting in recurrence, malignant progression, and eventual death. Approximately 69-80% of grade II and III gliomas harbor mutations in the isocitrate dehydrogenase 1 gene (IDH1), of which 83-90% are found to be the IDH1-R132H mutation. Detection of the IDH1-R132H mutation should help in the differential diagnosis of grade II and III gliomas from other types of CNS tumors and help determine the boundary between the tumor and normal brain tissue. In this study, we established a highly sensitive antibody-based device, referred to as the immuno-wall, to detect the IDH1-R132H mutation in gliomas. The immuno-wall causes an immunoreaction in microchannels fabricated using a photo-polymerizing polymer. This microdevice enables the analysis of the IDH1 status with a small sample within 15 min with substantially high sensitivity. Our results suggested that 10% content of the IDH1-R132H mutation in a sample of 0.33 µl volume, with 500 ng protein, or from 500 cells is theoretically sufficient for the analysis. The immuno-wall device will enable the rapid and highly sensitive detection of the IDH1-R132H mutation in routine clinical practice.

[Efficacy of tramadol/acetaminophen medication for central post-stroke pain].

OBJECTIVE: Central post-stroke pain(CPSP)is the most difficult type of central neuropathic pain to control with medical treatment. Opioids are commonly used for chronic neuropathic pain, but their efficacy in treating central neuropathic pain, particularly CPSP, is not clear. Tramadol is an opioid analgesic that, in combination with acetaminophen, has been approved since 2011 for the treatment of non-cancer pain in Japan. In this study we evaluated the efficacy of tramadol/acetaminophen medication for CPSP. METHODS: We retrospectively reviewed nine cases of CPSP that received oral tramadol/acetaminophen medication. All cases received tramadol/acetaminophen medication after first taking pregabalin then antidepressant medication. Pain levels were assessed before tramadol/acetaminophen medication began and one month after a maintenance dose was reached, using a visual analogue scale(VAS)and the McGill pain questionnaire(MPQ). RESULTS: The mean dose of tramadol was 121±61.6 mg/day. Tramadol/acetaminophen medication was effective in reducing pain in seven of nine cases(77.8%). The VAS improved 32.9±13.8% from pre-to post-medication, and the MPQ improved from 15.4±9.1 pre-medication to 8.1±4.7 post-medication(p<0.05). These effects continued 9.3±4.5 months during follow up periods. Side effects were observed in six cases(one severe, one moderate, two mild, two transient), but medication was continued in eight cases. CONCLUSION: Oral tramadol/acetaminophen medication was effective at reducing pain levels in patients with CPSP, and is a medication option for the treatment of CPSP.

Quantitative evaluation of the reduction of distortion and metallic artifacts in magnetic resonance images using the multiacquisition variable­resonance image combination selective sequence.

Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in determining changes in tissue structure, such as those observed following inflammation and infection. However, when metal implants or other metal objects are present, MRI exhibits more distortion and artifacts compared with CT, which hinders the accurate measurement of the implants. A limited number of reports have examined whether the novel MRI sequence, multiacquisition variable-resonance image combination selective (MAVRIC SL), can accurately measure metal implants without distortion. Therefore, the present study aimed to demonstrate whether MAVRIC SL could accurately measure metal implants without distortion and whether the area around the metal implants could be well delineated without artifacts. An agar phantom containing a titanium alloy lumbar implant was used for the present study and was imaged using a 3.0 T MRI machine. A total of three imaging sequences, namely MAVRIC SL, CUBE and magnetic image compilation (MAGiC), were applied and the results were compared. Distortion was evaluated by measuring the screw diameter and distance between the screws multiple times in the phase and frequency directions by two different investigators. The artifact region around the implant was examined using a quantitative method following standardization of the phantom signal values. It was revealed that MAVRIC SL was a superior sequence compared with CUBE and MAGiC, as there was significantly less distortion, a lack of bias between the two different investigators and significantly reduced artifact regions. These results suggested the possibility of utilizing MAVRIC SL for follow-up to observe metal implant insertions.

Evaluation of the accuracy of heart dose prediction by machine learning for selecting patients not requiring deep inspiration breath­hold radiotherapy after breast cancer surgery.

Increased heart dose during postoperative radiotherapy (RT) for left-sided breast cancer (BC) can cause cardiac injury, which can decrease patient survival. The deep inspiration breath-hold technique (DIBH) is becoming increasingly common for reducing the mean heart dose (MHD) in patients with left-sided BC. However, treatment planning and DIBH for RT are laborious, time-consuming and costly for patients and RT staff. In addition, the proportion of patients with left BC with low MHD is considerably higher among Asian women, mainly due to their smaller breast volume compared with that in Western countries. The present study aimed to determine the optimal machine learning (ML) model for predicting the MHD after RT to pre-select patients with low MHD who will not require DIBH prior to RT planning. In total, 562 patients with BC who received postoperative RT were randomly divided into the trainval (n=449) and external (n=113) test datasets for ML using Python (version 3.8). Imbalanced data were corrected using synthetic minority oversampling with Gaussian noise. Specifically, right-left, tumor site, chest wall thickness, irradiation method, body mass index and separation were the six explanatory variables used for ML, with four supervised ML algorithms used. Using the optimal value of hyperparameter tuning with root mean squared error (RMSE) as an indicator for the internal test data, the model yielding the best F2 score evaluation was selected for final validation using the external test data. The predictive ability of MHD for true MHD after RT was the highest among all algorithms for the deep neural network, with a RMSE of 77.4, F2 score of 0.80 and area under the curve-receiver operating characteristic of 0.88, for a cut-off value of 300 cGy. The present study suggested that ML can be used to pre-select female Asian patients with low MHD who do not require DIBH for the postoperative RT of BC.

Mutation detection of urinary cell-free DNA via catch-and-release isolation on nanowires for liquid biopsy.

Cell-free DNA (cfDNA) and extracellular vesicles (EVs) are molecular biomarkers in liquid biopsies that can be applied for cancer detection, which are known to carry information on the necessary conditions for oncogenesis and cancer cell-specific activities after oncogenesis, respectively. Analyses for both cfDNA and EVs from the same body fluid can provide insights into screening and identifying the molecular subtypes of cancer; however, a major bottleneck is the lack of efficient and standardized techniques for the isolation of cfDNA and EVs from clinical specimens. Here, we achieved catch-and-release isolation by hydrogen bond-mediated binding of cfDNA in urine to zinc oxide (ZnO) nanowires, which also capture EVs by surface charge, and subsequently we identified genetic mutations in urinary cfDNA. The binding strength of hydrogen bonds between single-crystal ZnO nanowires and DNA was found to be equal to or larger than that of conventional hydrophobic interactions, suggesting the possibility of isolating trace amounts of cfDNA. Our results demonstrated that nanowire-based cancer screening assay can screen cancer and can identify the molecular subtypes of cancer in urine from brain tumor patients through EV analysis and cfDNA mutation analysis. We anticipate our method to be a starting point for more sophisticated diagnostic models of cancer screening and identification.

CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in primary central nervous system lymphoma.

BACKGROUND: Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R-MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. METHODS: We investigated the long-term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R-MPV or HD-MTX treatment, and the correlation of these genetic mutations with prognosis. RESULTS: R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p < 0.05). However, the association of CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. CONCLUSIONS: In conclusion, CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in PCNSL. The rapid identification of MYD88 L265P and CD79B Y196 mutations can be helpful not only for the accurate molecular diagnosis of PCNSL but also for the prediction of response to R-MPV.

Simultaneous surgical resections of two distant metastatic malignant melanoma lesions--case report.

A 41-year-old woman presented with disturbance of consciousness, right hemiparesis, and symptoms of Gerstmann syndrome. She had a history of malignant melanoma resections of an ear mole and her right neck lymph nodes and parotid gland, with subsequent chemotherapy and radiotherapy. Computed tomography showed two large lesions in the right frontal and left parietal lobes surrounded by severe brain edema. Magnetic resonance images revealed that the two lesions were strongly enhanced with cystic change, and a small round lesion was located in the left head of the caudate nucleus. (18F) fluoro-2-deoxyglucose positron emission tomography showed high accumulation in both lesions, and no sign of metastatic lesions except within the brain. The two lesions were large, causing increased intracranial pressure. Simultaneous surgical resections were performed using two approaches. The patient's neurological symptoms were greatly improved after surgery, and her Karnofsky Performance Status improved from 20% to 90%. She was discharged to her home almost completely free of neurological deficits. Although, simultaneous one-stage tumor resections for multiple metastatic brain tumors do not extend the survival period, they improve the quality of the patient's limited remaining life, and may be a treatment choice for young patients with well-controlled systemic disease.

[Dual lead spinal cord stimulation using octad lead for central post-stroke pain].

Spinal cord stimulation (SCS) has become the preferred option for neurosurgical management of several intractable pains. To evaluate effects of dual lead SCS using two quad leads for central post-stroke pain (CPSP), we retrospectively reviewed eight consecutive patients with CPSP who underwent SCS. Six (75%) of eight patients obtained more than 50% pain relief during test stimulation, and the efficacies continued for about 12 months in five (83%) of six patients. There were no significant complications. SCS is less invasive neurostimulation treatment and provides pain relief for some cases of CPSP.

11C-methionine- and 18F-FDG-PET double-negative metastatic brain tumor from lung adenocarcinoma with paradoxical high 18F-FDG uptake: A case report.

Background: Imaging with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and 11C-methionine (MET)-PET can delineate primary and metastatic brain tumors. Lesion size affects the sensitivity of both scans and histopathological features can also influence FDG-PET, but the effects on MET-PET have not been elucidated. Case Description: We report an unusual case of metastatic brain tumors without accumulation of FDG or MET, contrasting with high FDG uptake in the primary lung lesion. The brain lesions were identified as adenocarcinoma with a more mucus-rich background, contributing to the indistinct accumulation of both FDG and MET. Conclusion: Histopathological characteristics can affect both MET and FDG accumulation, leading to findings contradicting those of the primary lesion.

Reliability of IDH1-R132H and ATRX and/or p53 immunohistochemistry for molecular subclassification of Grade 2/3 gliomas.

Since the World Health Organization 2016 classification (2016 WHO), genetic status has been incorporated into the diagnosis of Grade 2/3 gliomas (lower-grade gliomas). Therefore, immunohistochemistry (IHC) of IDH1-R132H, ATRX, and p53 have been used in place of genetic status. We report the associations between histological findings, IHC, and genetic status. We performed IHC of IDH1-R132H, ATRX, and p53 in 76 lower-grade gliomas and discussed its validity based on the 2016 WHO and the upcoming 2021 WHO classification. The sensitivity and specificity of anti-ATRX, p53, and IDH1-R132H IHC were 40.9%/98.1%, 78.6%/85.4%, and 90.5%/84.6%, respectively. Among 21 IDH1-mutant gliomas without 1p/19q codeletion, two gliomas (9.5%) mimicked the so-called classic for oligodendroglioma (CFO) in their morphology. Of the 42 gliomas with 1p/19q codeletion, four cases were difficult to diagnose as oligodendroglioma through morphological examination. Moreover, there were three confusing cases with ATRX mutations but with retained ATRX-IHC positivity. The lessons learned from this study are as follows: (1) ATRX-IHC and p53-IHC should be supplementary to morphological diagnosis, (2) rare IDH mutations other than IDH1 R132H should be considered, and (3) there is no complete alternative test to detect molecular features of glioblastoma under the 2021 WHO classification.

Intraoperative seizure outcome of levetiracetam combined with perampanel therapy in patients with glioma undergoing awake brain surgery.

OBJECTIVE: This study aimed to evaluate the efficacy of levetiracetam (LEV) combined with perampanel (PER) therapy for intraoperative seizure treatment to determine whether a combination of LEV and PER can aid in the prevention of intraoperative intractable seizures during awake surgery. METHODS: The authors performed a retrospective cohort study in 78 consecutive patients with glioma who underwent awake surgery using intraoperative direct electrical stimulation mapping. To prevent intraoperative seizures, 50 patients were treated with the antiepileptic drug LEV only (LEV group) from January 2017 to January 2019, while the remaining 28 patients were treated with LEV plus PER (LEV + PER group) between March 2019 and January 2020. LEV (1000-3000 mg) and/or PER (2-4 mg) were administered before the surgery. RESULTS: Preoperative seizures with International League Against Epilepsy (ILAE) class II-VI occurred in 44% of the patients in the LEV group and in 35.7% of patients in the LEV + PER group, with no significant difference between groups (p = 0.319). Total intraoperative seizures occurred in 18 patients (36.0%) in the LEV therapy group and in 2 patients (7.1%) in the LEV + PER group (p = 0.009). Of these, there were no patients (0%) with intractable seizures in the LEV + PER group. Regarding factors that influence intraoperative seizures in glioma patients during awake brain surgery, multivariate logistic regression models revealed that the occurrence of intraoperative seizures was significantly related to the involvement of motor-related regions (positive vs negative, HR 6.98, 95% CI 1.71-28.56, p = 0.007), preoperative seizure (ILAE class II-VI vs ILAE class I, HR 4.44, 95% CI 1.22-16.11, p = 0.024), and LEV + PER group (positive vs negative, HR 0.07, 95% CI 0.01-0.44, p = 0.005). Treatment-related adverse effects were rare and mild, including sleepiness, tiredness, and dizziness in both treatment groups. CONCLUSIONS: This study demonstrates that LEV + PER therapy is significantly associated with a lower risk of intraoperative seizures compared with LEV therapy alone in patients with glioma during awake brain mapping. These findings will help neurosurgeons conduct safe and reliable awake surgeries and reduce the rate of intraoperative intractable seizures during such procedures.

Survival Benefit of Supratotal Resection in a Long-term Survivor of IDH-wildtype Glioblastoma: A Case Report and Literature Review.

Glioblastoma multiforme (GBM) is an aggressive cancer type, with fewer than 3-5% of patients surviving for more than 3 years. We describe a 48-year-old right-handed man who presented with generalized seizure attacks. Magnetic resonance imaging (MRI) revealed a heterogeneous gadolinium-enhancing lesion in the left inferior parietal lobule. The patient underwent awake surgery, and tumor resection included abnormalities on T2-weighted MRI, with subcortical mapping used to identify the deep functional boundaries. After supratotal resection, the tumor was diagnosed as GBM without isocitrate dehydrogenase (IDH) 1 and 2 mutations. At a follow-up evaluation, 9 years and 2 months after the surgery, the patient appeared healthy, and no relapse or recurrence was observed. We present the case of a long-term survivor of IDH-wildtype GBM. This case suggests that supratotal resection with intraoperative awake brain mapping can improve survival without impairing the patient's neurological functions.

Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumors Using Nanowire Scaffolds.

There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood-brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.

Newly established patient-derived organoid model of intracranial meningioma.

BACKGROUND: Recent comprehensive studies have revealed several molecular alterations that are frequently found in meningiomas. However, effective treatment reagents targeting specific molecular alterations have not yet been identified because of the limited number of representative research models of meningiomas. METHODS: We performed organoid cultures using meningioma cells and meningioma tumor tissues. Using immunohistochemistry and molecular analyses consisting of whole-exome sequencing, RNA-seq, and DNA methylation analyses, we compared the histological findings and molecular profiling of organoid models with those of parental tumors. Further, using these organoid models together with a public database of meningiomas, we explored molecular alterations, which are a potent treatment target for meningioma. RESULTS: We established 18 organoid models comprising of two malignant meningioma cells (HKBMM and IOMM-Lee), 10 benign meningiomas, four malignant meningiomas, and two solitary fibrous tumors (SFTs). The organoids exhibited consistent histological features and molecular profiles with those of the parental tumors. Using a public database, we identified that upregulated forkhead box M1 (FOXM1) was correlated with increased tumor proliferation. Overexpression of FOXM1 in benign meningioma organoids increased organoid proliferation; depletion of FOXM1 in malignant organoids decreased proliferation. Additionally, thiostrepton, a FOXM1 inhibitor combined with radiation therapy, significantly inhibited the proliferation of malignant meningioma organoid models. CONCLUSIONS: An organoid model for meningioma enabled us to elucidate the tumor biology of meningioma along with potent treatment targets for meningioma.