Beijing Sanbo Brain Hospital

The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China.

Background: Treatment of cancers with programmed cell death protein 1 (PD-1) pathway inhibitors can lead to immune-related adverse events (irAEs), which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs. Methods: The MEDLINE, EMBASE, and Cochrane databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1 treatment; irAEs; and cancer. R© package Meta was used to pool incidence. Results: Forty-six studies representing 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents were included in the meta-analysis. The anti-PD-1/PD-L1 agents included nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and BMS-936559. The tumor types were melanomas, Hodgkin lymphomas, urothelial carcinomas, breast cancers, non-small cell lung cancers, renal cell carcinomas, colorectal cancers, and others. We described irAEs according to organ systems, namely, the skin (pruritus, rash, maculopapular rash, vitiligo, and dermatitis), endocrine system (hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency), digestive system (colitis, diarrhea, pancreatitis, and increased AST/ALT/bilirubin), respiratory system (pneumonitis, lung infiltration, and interstitial lung disease), and urinary system (increased creatinine, nephritis, and renal failure). In patients treated with the PD-1 signaling inhibitors, the overall incidence of irAEs was 26.82% (95 % CI, 21.73–32.61; I2, 92.80) in any grade and 6.10% (95 % CI, 4.85–7.64; I2, 52.00) in severe grade, respectively. The development of irAEs was unrelated to the dose of anti-PD-1/PD-L1 agents. The incidence of particular irAEs varied when different cancers were treated with different drugs. The incidence of death due to irAEs was around 0.17%. Conclusion: The occurrence of irAEs was organ-specific and related to drug and tumor types.

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.

Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.

BACKGROUND: Patients afflicted with low-grade glioma (LGG) frequently suffer from seizures. The mechanisms of seizure initiation in these patients remain poorly understood. Tumor location has been correlated with seizure initiation. However, these correlative studies relied on dichotomized data analysis based on arbitrary lobe assignments. As a result, the lesion-symptom correlation may be incorrectly interpreted. Here, we present the first study that used a voxel-wise quantitative lesion analysis to investigate the spatial correlation between tumor location and seizure susceptibility. METHODS: We collected the medical records and magnetic resonance images of 410 LGG patients. The dataset was divided into a discovery set and a validation set. A voxel-based lesion-symptom correlative analysis was performed to determine whether tumor location was associated with seizure risk and could be related to the specific type of seizure. RESULTS: For all seizure types, increased seizure risks were identified for LGGs that involved the left premotor area. The LGGs that involved the posterior portion of the left inferior and middle frontal gyrus were associated with increased risk of simple partial seizures. LGGs that involved the right temporal-insular region were associated with an increased risk of complex partial seizures. LGGs that involved the left premotor area were more likely to be associated with seizures that generalize. These correlations were consistently observed in both the discovery and the validation datasets. CONCLUSIONS: Our quantitative neuroimaging analyses support the concept that the anatomic location of an LGG is a contributing factor in tumor-related seizure.

BACKGROUND: Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research. METHODS: To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question. RESULTS: Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established. CONCLUSION: This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG .

Abstract Background The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N 6,2′- O -dimethyladenosine (m 6 A) reader, YTH N 6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. Methods YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. Results YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m 6 A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. Conclusions Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m 6 A modification.

Scant understanding of the glioblastoma microenvironment and molecular bases hampers development of efficient treatment strategies. Analyses of gene signatures of human gliomas demonstrate that the SETD2 mutation is correlated with poor prognosis of IDH1/2 wild-type (IDH-WT) adult glioblastoma patients. To better understand the crosstalk between SETD2 mutant (SETD2-mut) glioblastoma cells and the tumor microenvironment, we leverage single-cell transcriptomics to comprehensively map cellular populations in glioblastoma. In this study, we identify a specific subtype of high-grade glioma-associated microglia (HGG-AM). Further analysis shows that transforming growth factor (TGF)-β1 derived from SETD2-mut/IDH-WT tumor cells activates HGG-AM, exhibiting pro-inflammation and proliferation signatures. Particularly, HGG-AM secretes interleukin (IL)-1β via the apolipoprotein E (ApoE)-mediated NLRP1 inflammasome, thereby promoting tumor progression. HGG-AM present extensive proliferation and infiltration to supplement the activated microglia pool. Notably, TGF-β1/TβRI depletion dramatically reduces HGG-AM density and suppresses tumor growth. Altogether, our studies identify a specific microglia subpopulation and establish the cellular basis of interactions between HGG-AM and glioblastoma cells.

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

// Pei Yang 1, 2, * , Wei Zhang 1, 2, * , Yinyan Wang 1, 2 , Xiaoxia Peng 3 , Baoshi Chen 2 , Xiaoguang Qiu 4 , Guilin Li 6 , Shouwei Li 7 , Chenxing Wu 7 , Kun Yao 8 , Wenbin Li 9 , Wei Yan 10 , Jie Li 11 , Yongping You 10 , Clark C. Chen 11 , Tao Jiang 1, 2, 5 1 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China 4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 5 China National Clinical Research Center for Neurological Diseases, Beijing, China 6 Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 7 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 8 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 9 Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 10 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China 11 Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Tao Jiang, e-mail: taojiang1964@163.com Clark Chen, e-mail: clarkchen@ucsd.edu Yongping You, e-mail: yypl9@njmu.edu.cn Keywords: glioblastomas, IDH, MGMT, temozolomide, radiation Received: June 10, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 13, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: October 12, 2015 ABSTRACT Background: The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. Methods: We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. Results: For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p &lt; 0.001; PFS: 9.9 mo v 6.5 mo, p &lt; 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3&ndash;10 fold increase in TMZ resistance after long-term passage. Conclusion: Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.

Glioblastoma (GBM) is highly invasive and the deadliest brain tumor in adults. It is characterized by inter-tumor and intra-tumor heterogeneity, short patient survival, and lack of effective treatment. Prognosis and therapy selection is driven by molecular data from gene transcription, genetic alterations and DNA methylation. The four GBM molecular subtypes are proneural, neural, classical, and mesenchymal. More effective personalized therapy heavily depends on higher resolution molecular subtype signatures, combined with gene therapy, immunotherapy and organoid technology. In this review, we summarize the principal GBM molecular classifications that guide diagnosis, prognosis, and therapeutic recommendations.

Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor progression, mainly through immune suppression. Inverse correlations have been observed between MDSC levels and patient survival for various malignancies. The purpose of this meta-analysis was to evaluate the prognostic value of pretreatment circulating MDSCs. We searched MEDLINE and EMBASE from their inceptions to September 2017 to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) were estimated for overall survival (OS) and combined disease-free survival, progression-free survival, and recurrence-free survival (DFS/PFS/RFS). A total of 40 studies comprising 2721 were included. For solid tumors, high levels of pretreatment circulating MDSCs were significantly associated with worse OS (HR = 1.796, 95% CI = 1.587-2.032) and DFS/PFS/RFS (HR = 2.459, 95% CI = 2.018-2.997). Breast cancer showed the largest association between high MDSC levels and worse OS (pooled HR = 3.053). Elevated MDSCs were also associated with worse OS for mixed-stage tumors (pooled HR = 1.659) and advanced-stage tumors (pooled HR = 2.337). Furthermore, both monocytic-MDSCs (M-MDSCs) and granulocytic or polymorphonuclear (PMN-MDSCs) showed negative associations with survival outcomes. Overall, high levels of pretreatment circulating MDSCs negatively influenced survival in most cancers. Pretreatment circulating MDSCs should be taken into account to further improve prognostic evaluation and develop novel therapeutic strategies.

Abstract Background Gliomas are based on a genetic abnormality and present with a dismal prognosis. MicroRNAs (miRNAs) are considered to be important mediators of gene expression in glioma tissues. Methods Real-time PCR was used to analyze the expression of microRNA-423-5p (miR-423-5p) in human glioma samples and normal brain tissue. Apoptosis, cell cycle, proliferation, immunostaining, transwell, in vitro 2D and 3D migration, and chemosensitivity assays were performed to assess the phenotypic changes in glioma cells overexpressing miRNA-423-5p. Western blotting was used to determine the expression of inhibitor of growth 4 (ING-4)in glioma tissues, and a luciferase reporter assay was conducted to confirm whether ING-4 is a direct target of miR-423-5p. Western blotting was used to identify the potential signaling pathways that are affected in glioma cell growth by miR-423-5p. Xenograft tumors were examined in vivo for the carcinogenic effects of miR-423-5p in glioma tissues. Results We first reported that miR-423-5p expression was increased in gliomas and was a potential tumor promoter via targeting ING-4. The overexpression of miR-423-5p resulted in upregulation of important signaling molecules such as p-AKT and p-ERK1/2. In clinical samples, miR-423-5p was dysregulated, and a corresponding alteration in ING-4 expression was observed (P = .0207). Furthermore, the overexpression of miR-423-5p strengthened glioma cell proliferation, angiogenesis, and invasion. Finally, miR-423-5p overexpression also strengthened GBM neurosphere formation and rendered glioma cells resistant to temozolomide (TMZ). Conclusion This study establishes that miR-423-5p functions as an oncogene in glioma tissues by suppressing ING-4 and suggests that it has therapeutic potential for glioma.

BACKGROUND: Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma. METHODS: Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles. RESULTS: We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively. CONCLUSIONS: Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.

BACKGROUND: Nemo-like kinase (NLK) is an evolutionarily conserved protein kinase involved in Wnt/beta-catenin signaling, which has been reported to be associated with gliomagenesis. In the present study, we aimed to identify a concrete mechanism of Wnt/beta-catenin pathway regulation by microRNAs (miRNAs) in glioma. METHODS: Quantitative reverse-transcription polymerase chain reaction and in situ hybridization were conducted to detect the expression of miR-92b. The cell proliferation rate and cell cycle kinetics were detected using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and flow cytometry, cell invasion and migration were evaluated using Transwell assay and wound healing assay, and cell apoptosis was detected using annexin V staining. Furthermore, the relevant molecules regulating proliferation and invasion were examined using Western blot analysis, immunohistochemistry, and immunofluorescence staining. Luciferase reporter assay was used to identify the direct regulation of NLK by miR-92b and beta-catenin/TCF4 activity. RESULTS: We first showed that the expression of miR-92b was elevated in both glioma samples and glioma cells. Furthermore, down-regulation of miR-92b triggered growth inhibition, induced apoptosis, and suppressed invasion of glioma in vitro and in vivo. Luciferase assay and Western blot analysis revealed that NLK is a direct target of miR-92b. Restoring expression of NLK inhibited glioma proliferation and invasion. Mechanistic investigation revealed that miR-92b deletion suppressed beta-catenin/TCF-4 transcription activity by targeting NLK. Moreover, expression of NLK was inversely correlated with miR-92b in glioma samples and was predictive of patient survival in a retrospective analysis. CONCLUSIONS: Our findings identify a role for miR-92b in glioma proliferation and invasion after activation of Wnt/beta-catenin signaling via NLK.

OBJECTIVE: The aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy. METHODS: The Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit). RESULTS: Ten study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR = 2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE). INTERPRETATION: In comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939.

BACKGROUND.: During the outbreak of coronavirus disease 2019 (COVID-19), people are under the dual pressure of interpersonal isolation and concerns about infection. An evaluation of people's psychological status and risk factors is needed to conduct target interventions. METHODS.: This was a nationwide, multicenter, cross-sectional study using quota and snowball sampling methods during the COVID-19 epidemic in China. Participants' characteristics and experiences were obtained by an online questionnaire and telephone review. Psychological distress and sleep problems were measured by the Generalized Anxiety Disorder-7, the Patient Health Questionnaire-9, and the Insomnia Severity Index. RESULTS.: A total of 23,500 participants were recruited, and 19,372 valid questionnaires were received from 11 centers. Overall, 11.0-13.3% of the participants had anxiety, depression, or insomnia symptoms, and 1.9-2.7% had severe symptoms. The prevalence of psychological and sleep problems has increased. Working as frontline medical staff (Odds Ratio OR = 3.406), living in Hubei Province (OR = 2.237), close contacts with COVID-19 (OR = 1.808), and age 35-49 years (OR = 1.310) were risk factors for anxiety symptoms; no outside activity for 2 weeks (OR = 2.167) and age 35-49 years (OR = 1.198) were risk factors for depression symptoms; and living in Hubei Province (OR = 2.376), no outside activity for 2 weeks (OR = 1.927), and age 35-49 years (OR = 1.262) were risk factors for insomnia symptoms. Only 1.9% of participants received counseling during the epidemic. CONCLUSIONS.: Psychological and sleep problems increased during interpersonal isolation due to COVID-19. Current psychological interventions are far from sufficient.

BACKGROUND: Ki-67 is a typical immunohistochemical marker for cell proliferation. Higher expression of Ki-67 is correlated with poor clinical outcomes in several cancers. However, the prognostic value of Ki-67 on the prognosis of meningiomas is still controversial. The purpose of this meta-analysis was to evaluate the prognostic value of Ki-67 in meningiomas. METHODS AND MATERIALS: We searched Medline and EMBASE from inception to December 31, 2018, to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) for overall survival (OS) and disease/progression/recurrence-free survival (D/P/RFS) were estimated. RESULTS: A total of 43 studies, comprising 5012 patients, were included in this analysis. Higher Ki-67 expression levels were significantly associated with worse OS (HR = 1.565; 95% CI: 1.217-2.013) and D/P/RFS (HR = 2.644; 95% CI: 2.264-3.087) in meningiomas. Subgroup analysis revealed that all the included factors (ethnicity, tumor grade, HR sources, definition of cutoffs, cutoff values) for heterogeneity investigation can affect the pooled results. Among them, the definitions of cutoffs and cutoff values factor are the two main contributors toward heterogeneity. Multivariable meta-regression analysis also showed that methodologies used for cutoff value definition contributed to the high inner-study heterogeneity. CONCLUSIONS: Higher Ki-67 expression levels negatively influenced survival in meningiomas. A higher cutoff value (>4%) is more appropriate for prognosis prediction. It is highly recommended that Ki-67 expression profile could be assessed in meningiomas treatment for predicting survival. And patients with elevated expression of Ki-67 need to have close follow-ups.

BACKGROUND: Magnetic resonance imaging (MRI) plays an irreplaceable role in the preoperative diagnosis of glioma, and its imaging features are the base of making treatment decisions in patients with glioma, but it is still controversial whether peritumoral edema shown by MRI from preoperative routine scans are associated with patient survival. The aim of this study was to assess the prognostic value of preoperative MRI features in patients with glioblastoma. METHODS: A retrospective review of 87 patients with newly diagnosed supratentorial glioblastoma was performed using medical records and MRI data from routine scans. The Kaplan-Meier method and COX proportional hazard model were applied to evaluate the prognostic impact on overall survival of pretreatment MRI features (including peritumoral edema, edema shape, necrosis, cyst, enhancement, tumor crosses midline, edema crosses midline, and tumor size). RESULTS: In addition to patient age, Karnofsky performance status (KPS) and postoperative chemoradiotherapy, peritumoral edema extent and necrosis on preoperative MRI were independent prognostic indicator for poor survival. Furthermore, patients with two unfavorable conditions (major edema and necrosis) had a shorter overall survival compared with the remainder. CONCLUSIONS: Our data confirm that peritumoral edema extent and necrosis are helpful for predicting poor clinical outcome in glioblastoma. These features were easy to determine from routine MRI scans postoperatively and therefore could provide a certain instructive significance for clinical activities.

PURPOSE: Glioblastoma multiforme (GBM) is the most malignant primary type of brain tumor in adults. There has been increased focus on the immunotherapies to treat GBM patients, the therapeutic value of natural killer (NK) cells is still unknown. Programmed death-1 (PD-1) is a major immunological checkpoint that can negatively regulate the T-cell-mediated immune response. We tested the combination of the inhibiting the PD-1/B7H1 pathway with a NK-cell mediated immune response in an orthotopic mouse model of GBM. METHODS AND MATERIALS: Mouse glioma stem cells (GL261GSCs) and mouse NK cells were isolated and identified. A lactate dehydrogenase (LDH) assay was perfomed to detect the cytotoxicity of NK cells against GL261GSCs. GL261GSCs were intracranially implanted into mice, and the mice were stratified into 3 treatment groups: 1) control, 2) NK cells treatment, and 3) PD-1 inhibited NK cells treatment group. Overall survival was quantified, and animal magnetic resonance imaging (MRI) was performed to determine tumor growth. The brains were harvested after the mice were euthanized, and immunohistochemistry against CD45 and PCNA was performed. RESULTS: The mouse NK cells were identified as 90% CD3- NK1.1+CD335+ by flow cytometric analysis. In the LDH assay, the ratios of the damaged GL261GSCs, with the E:T ratios of 2.5:1, 5:1, and 10:1, were as follows: 1) non-inhibited group: 7.42%, 11.31%, and 15.1%, 2) B7H1 inhibited group: 14.75%, 18.25% and 29.1%, 3) PD-1 inhibited group: 15.53%, 19.21% and 29.93%, 4) double inhibited group: 33.24%, 42.86% and 54.91%. In the in vivo experiments, the mice in the PD-1 inhibited NK cells treatment group and IL-2-stimulated-NK cells treatment group displayed a slowest tumor growth (F = 308.5, P<0.01) and a slower tumor growth compared with control group (F = 118.9, P<0.01), respectively. The median survival of the mice in the three groups were as follows: 1) conrol group: 29 days, 2) NK cells treatment group: 35 days (P = 0.0012), 3) PD-1 inhibited NK cells treatment group: 44 days (P = 0.0024). Immunologic data of PCNA-positive cell ratios and CD45-positive cell ratios of the tumor specimens in the three groups were as follows: 1) control group: 65.72% (PCNA) and 0.92% (CD45), 2) NK treatment group: 27.66% (PCNA) and 13.46% (CD45), and 3) PD-1 inhibited NK cells treatment group: 13.66% (PCNA) and 23.66% (CD45) (P<0.001). CONCLUSION: The results demonstrated that blockade of PD-1/B7H1 pathway could promote mouse NK cells to kill the GL261GSCs, and the PD-1-inhibited NK cells could be a feasible immune therapeutic approach against GBM.