The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Recent Trends in the Withdrawal of Life-Sustaining Treatment in Patients with Acute Cerebrovascular Disease : 2017-2021.

OBJECTIVE: The Act on Life-Sustaining Treatment (LST) decisions for end-of-life patients has been effective since February 2018. An increasing number of patients and their families want to withhold or withdraw from LST when medical futility is expected. This study aimed to investigate the status of the Act on LST decisions for patients with acute cerebrovascular disease at a single hospital. METHODS: Between January 2017 and December 2021, 227 patients with acute cerebrovascular diseases, including hemorrhagic stroke (n=184) and ischemic stroke (n=43), died at the hospital. The study period was divided into the periods before and after the Act. RESULTS: The duration of hospitalization decreased after the Act was implemented compared to before (15.9±16.1 vs. 11.2±18.6 days, p=0.127). The rate of obtaining consent for the LST plan tended to increase after the Act (139/183 [76.0%] vs. 27/44 [61.4%], p=0.077). Notably, none of the patients made an LST decision independently. Ventilator withdrawal was more frequently performed after the Act than before (52/183 [28.4%] vs. 0/44 [0%], p<0.001). Conversely, the rate of organ donation decreased after the Act was implemented (5/183 [2.7%] vs. 6/44 [13.6%], p=0.008). Refusal to undergo surgery was more common after the Act was implemented than before (87/149 [58.4%] vs. 15/41 [36.6%], p=0.021) among the 190 patients who required surgery. CONCLUSION: After the Act on LST decisions was implemented, the rate of LST withdrawal increased in patients with acute cerebrovascular disease. However, the decision to withdraw LST was made by the patient's family rather than the patient themselves. After the execution of the Act, we also observed an increased rate of refusal to undergo surgery and a decreased rate of organ donation. The Act on LST decisions may reduce unnecessary treatments that prolong end-of-life processes without a curative effect. However, the widespread application of this law may also reduce beneficial treatments and contribute to a decline in organ donation.

Impact on Endovascular Thrombectomy for Acute Ischemic Stroke of Aortic Arch Calcification on Chest X-ray.

BACKGROUND: Vascular conditions can affect the recanalization rates after endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). Chest radiography can assess the conditions of the aortic arch based on the presence or absence of aortic arch calcification (AoAC). The aim of this study was to investigate the relationship between AoAC on chest radiography and first-pass successful recanalization (modified thrombolysis in cerebral infarction 2b/3 after the first-pass). METHODS: We compared the rate of first-pass successful recanalization between patients with and without AoAC. A total of 193 patients with anterior circulation occlusion who underwent EVT between January 2017 and December 2021 were included. RESULTS: AoAC was observed in 80 (41.5%) patients. Patients with AoAC were older (74.5 ± 7.78 vs. 63.9 ± 12.4 years, p < 0.001), had more EVT attempts (3.04 ± 1.95 vs. 2.01 ± 1.34 times, p < 0.001), and a longer procedural time (71.7 ± 31.2 vs. 48.7 ± 23.1 min, p < 0.001) than those without AoAC. Moreover, Patients with AoAC showed a lower incidence of first-pass successful recanalization (18.8% vs. 47.8%, p < 0.001) and a higher incidence of postprocedural hemorrhage (45.0% vs. 27.7%, p = 0.015) than those without AoAC. On multivariate analysis, AoAC was independently associated with first-pass successful recanalization (odds ratio: 0.239 [0.121-0.475], p < 0.001). CONCLUSIONS: AoAC on chest radiography can be used as a preoperative predictor of successful first-pass recanalization in patients undergoing EVT for AIS.

Dosimetric comparison between RapidArc and HyperArc in hippocampal-sparing whole-brain radiotherapy with a simultaneous integrated boost.

The HyperArc technique is known for generating high-quality radiosurgical treatment plans for intracranial lesions or hippocampal-sparing whole-brain radiotherapy (WBRT). However, there is no reported feasibility of using the HyperArc technique in hippocampal-sparing WBRT with a simultaneous integrated boost (SIB). This study aimed to compare dosimetric parameters of 2 commercially-available volumetric-modulated arc radiotherapy techniques, HyperArc and RapidArc, when using hippocampal-sparing WBRT with a SIB to treat brain metastases. Treatment plans using HyperArc and RapidArc techniques were generated retrospectively for 19 previously treated patients (1 to 3 brain metastases). The planning target volumes for the whole brain (excluding the hippocampal avoidance region; PTVWB) and metastases (PTVmet) were prescribed 25 and 45 Gy, respectively, in 10 fractions. Each plan included homogeneous and inhomogeneous delivery to the PTVmet. Dosimetric parameters for the target (conformity index [CI], homogeneity index [HI], target coverage [D95%]), and nontarget organs at risk were compared for the HyperArc and RapidArc plans. For homogeneous delivery, dosimetric parameters, including mean CI, HI, and target coverage in PTVWB and PTVmet, were superior for HyperArc than RapidArc plans (all p < 0.01). The PTVWB and PTVmet target coverage for HyperArc plans was significantly greater than for RapidArc plans (96.17% vs 93.38%, p < 0.01; 94.02% vs 92.21%, p < 0.01, respectively). HyperArc plans had significantly lower mean hippocampal Dmax and Dmin values than RapidArc plans (Dmax: 15.53 Gy vs, 16.71 Gy, p < 0.01; Dmin: 8.33 Gy vs 8.93 Gy, p < 0.01, respectively). Similarly, inhomogeneous delivery of hyperArc produced a superior target and lower hippocampal dosimetric parameters than RapidArc, except for the HI of PTVmet (all p < 0.01). HyperArc generated superior conformity and target coverage with lower hippocampal doses than RapidArc. HyperArc could be an attractive technique for hippocampal-sparing WBRT with an SIB.

Epigenetic Regulation of the Expression of T Cell Stimulatory and Inhibitory Factors by Histone H3 Lysine Modification Enzymes and Its Prognostic Roles in Glioblastoma.

BACKGROUND: This study aimed to identify the specific T cell co-stimulatory and co-inhibitory factors that play prognostic roles in patients with glioblastoma. Additionally, the unique histone H3 modification enzymes that regulate the expression levels of these specific co-stimulatory and co-inhibitory factors were investigated. METHODS: The medical records of 84 patients newly diagnosed with glioblastoma at our institution from January 2006 to December 2020 were retrospectively reviewed. Immunohistochemical (IHC) staining for T cell co-stimulatory factors (CD27, CD28, CD137, OX40, and ICOS), T cell co-inhibitory factors (CTLA4, PD1, PD-L1, TIM3, and CD200R), and histone H3 lysine modification enzymes (MLL4, RIZ, EZH1, NSD2, KDM5c, JMJD1a, UTX, and JMJD5) was performed on archived paraffin-embedded tissues obtained by biopsy or resection. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed for specific factors, which demonstrated causal relationships, in order to validate the findings of the IHC examinations. RESULTS: The mean follow-up duration was 27.5 months (range, 4.1-43.5 months). During this period, 76 patients (90.5%) died, and the mean OS was 19.4 months (95% confidence interval, 16.3-20.9 months). Linear positive correlations were observed between the expression levels of CD28 and JMJD1a (R2 linear = 0.982) and those of CD137 and UTX (R2 linear = 1.528). Alternatively, significant negative correlations were observed between the expression levels of CTLA4 and RIZ (R2 linear = -1.746) and those of PD-L1 and EZH1 (R2 linear = -2.118); these relationships were confirmed by qRT-PCR. In the multivariate analysis, increased expression levels of CD28 (P = 0.042), and CD137 (P = 0.009), and decreased expression levels of CTLA4 (P = 0.003), PD-L1 (P = 0.020), and EZH1 (P = 0.040) were significantly associated with longer survival. CONCLUSION: These findings suggest that the expression of certain T cell co-stimulatory factors, such as CD28 and CD 137, and co-inhibitory factors, such as CTLA4 and PD-L1 are associated with prognosis of glioblastoma patients.

Fully Automated Continuous Centrifugal Microfluidics Isolates Natural Killer Cells with High Performance and Minimal Stress.

Natural killer (NK) cells are a part of the innate immune system, providing the first line of defense against cancer cells and pathogens at an early stage. Hence, they are attracting attention as a valuable resource for allogeneic cell immunotherapy. However, NK cells exist with limited proportion in blood, and obtaining sufficient clinical-grade NK cells with highly viable and minimal stress is critical for successful immune cell therapy. Conventional purification methods via immunoaffinity or density gradient centrifugation had several limitations in yield, purity, and cellular stress, which might cause an increased risk for graft versus host disease and reduced efficacy due to NK cell malfunction, exhaustion, and apoptosis. Moreover, reducing the variations of isolation performance caused by the manual process is another unmet need for uniform quality of the living drug. Here, an automated system using an NK disc (NKD) based on continuous centrifugal microfluidics (CCM) technology was developed to isolate NK cells from whole blood with high yield, purity, reproducibility, and low stress. The CCM technology, which operates fluidic manipulation under disc rotation, enabled precise extraction of the ultra-thin target fluid layer generated by blood centrifugation. Compared to the conventional manual method, the CCM-NKD isolated NK cells with higher yield (recovery rate) and purity, while maintaining better reproducibility. Furthermore, since the CCM-NKD maintained substantially milder centrifugation conditions (120 ×g for 10 min) compared to the conventional approach (1200 ×g for 20 min), it showed reduced cellular stress and increased antioxidant capacity in the isolated NK cells. Based on the results, the CCM-NKD is expected to be a useful tool to provide highly intact and viable cell weapons for successful immune cell therapy.

Lossless Immunocytochemistry Based on Large-Scale Porous Hydrogel Pellicle for Accurate Rare Cell Analysis.

Rare cells, such as circulating tumor cells or circulating fetal cells, provide important information for the diagnosis and prognosis of cancer and prenatal diagnosis. Since undercounting only a few cells can lead to significant misdiagnosis and incorrect decisions in subsequent treatment, it is crucial to minimize cell loss, particularly for rare cells. Moreover, the morphological and genetic information on cells should be preserved as intact as possible for downstream analysis. The conventional immunocytochemistry (ICC), however, fails to meet these requirements, causing unexpected cell loss and deformation of the cell organelles which may mislead the classification of benign and malignant cells. In this study, a novel ICC technique for preparing lossless cellular specimens was developed to improve the diagnostic accuracy of rare cell analysis and analyze intact cellular morphology. To this end, a robust and reproducible porous hydrogel pellicle was developed. This hydrogel encapsulates cells to minimize cell loss from the repeated exchange of reagents and prevent cell deformation. The soft hydrogel pellicle allows stable and intact cell picking for further downstream analysis, which is difficult with conventional ICC methods that permanently immobilize cells. The lossless ICC platform will pave the way for robust and precise rare cell analysis toward clinical practice.

Brain Invasion and Trends in Molecular Research on Meningioma.

Meningiomas are the most common primary brain tumors in adults. The treatment of non-benign meningiomas remains a challenging task, and after the publication of the 2021 World Health Organization classification, the importance of molecular biological classification is emerging. In this article, we introduce the mechanisms of brain invasion in atypical meningioma and review the genetic factors involved along with epigenetic regulation. First, it is important to understand the three major steps for brain invasion of meningeal cells: 1) degradation of extracellular matrix by proteases, 2) promotion of tumor cell migration to resident cells by adhesion molecules, and 3) neovascularization and supporting cells by growth factors. Second, the genomic landscape of meningiomas should be analyzed by major categories, such as germline mutations in NF2 and somatic mutations in non-NF2 genes (TRAF7, KLF4, AKT1, SMO, and POLR2A). Finally, epigenetic alterations in meningiomas are being studied, with a focus on DNA methylation, histone modification, and RNA interference. Increasing knowledge of the molecular landscape of meningiomas has allowed the identification of prognostic and predictive markers that can guide therapeutic decision-making processes and the timing of follow-up.

Role of Neurosurgeons in the Treatment of Acute Ischemic Stroke in the Emergency Room.

OBJECTIVE: With the recent increase in mechanical thrombectomy (MT) for acute ischemic stroke (AIS), the role of neurosurgeons in AIS treatment has become increasingly important. This study aimed to assess the outcomes of patients with AIS treated by neurosurgeons and neurologists in the emergency room (ER) of a tertiary hospital in South Korea. METHODS: From January 2020 to June 2021, 536 patients with AIS within 24 hours of symptom onset were admitted to our hospital via the ER. Based on the type of doctors who provided initial care for AIS in the ER, patients were divided into two groups : (a) neurosurgeon group (n=119, 22.2%) and (b) neurologist group (n=417, 77.8%). RESULTS: Intravenous tissue plasminogen activator (tPA) was administered in 82 (15.3%) of 536 patients (n=17 [14.3%] in the neurosurgeon group and n=65 [15.6%] in the neurologist group). The door-to-tPA time was not significantly different between both groups (median, 53 minutes; interquartile range [IQR], 45-58 vs. median, 54 minutes; IQR, 46-74; p=0.372). MT was performed in 69 patients (12.9%) (n=25, 36.2% in the neurosurgeon group and n=44, 63.8% in the neurologist group). The neurosurgeon group achieved a shorter door-to-puncture time than the neurologist group (median, 115 minutes; IQR, 107-151 vs. median, 162 minutes; IQR, 117-189; p=0.049). Good clinical outcomes (3-month modified Rankin Scale 0-2) did not differ significantly between the two groups (96/119 [80.7%] vs. 322/417 [77.2%], p=0.454). CONCLUSION: The neurosurgeon group showed similar door-to-treatment time and clinical outcomes to the neurologist group in patients with AIS in the ER. This study suggests that neurosurgeons have comparable abilities to care for patients with AIS in the ER.

Clinical Application of the Association between Genetic Alteration and Intraoperative Fluorescence Activity of 5-Aminolevulinic Acid during the Resection of Brain Metastasis of Lung Adenocarcinoma.

The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM of lung adenocarcinoma at our institute for five years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.

Diffusion-weighted imaging-positive lesions following endovascular treatment for ruptured and unruptured aneurysms: Its incidence according to antithrombotic drugs.

OBJECTIVE: Microembolic infarcts are frequently observed on diffusion-weighted imaging (DWI) following endovascular treatment. We investigated DWI-positive lesions and symptomatic ischemic complications (SICs) in patients with ruptured and unruptured aneurysms following coiling and the relationship between DWI-positive lesions and antithrombotic drugs. METHODS: Between January 2016 and December 2020, 83 patients underwent DWI within 48 h following endovascular treatment for ruptured (n=30) and unruptured (n=53) aneurysms. RESULTS: The overall rate of DWI-positive lesions was 55.4%. There were no significant differences in the occurrence rate (45.3% vs. 43.3%, p=1.000) and the number of lesions (2.7±4.6 vs. 4.0±5.3, p=0.237) between unruptured and ruptured aneurysms. SIC occurred more frequently in patients with ruptured aneurysms than unruptured ones (20.0% vs. 1.9%, p=0.015). The cutoff value of DWI-positive lesions for predicting SIC was 5 (sensitivity 100%, specificity 78.9%). The procedure time was significantly longer in patients with DWI-positive lesions ≥5 than those with DWI-positive lesions <5 (104.1±43.8 vs. 85.1±30.8 min, p=0.030). Patients with DWI-positive lesions <5 were more frequently observed in the postprocedural heparinization group than in the no heparinization group (85.7% vs. 58.5%, p=0.012). CONCLUSIONS: The incidence of DWI-positive lesions did not differ significantly between the ruptured and unruptured aneurysms. However, SIC occurred more frequently in patients with ruptured aneurysms. Longer procedure time is a risk factor for DWI-positive lesions, and postprocedural heparinization seems to reduce the incidence of DWI-positive lesions.

Nintedanib induces senolytic effect via STAT3 inhibition.

Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing RS. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity. Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated ß-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts. Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.

Continuous centrifugal microfluidics (CCM) isolates heterogeneous circulating tumor cells via full automation.

Understanding cancer heterogeneity is essential to finding diverse genetic mutations in metastatic cancers. Thus, it is critical to isolate all types of CTCs to identify accurate cancer information from patients. Moreover, full automation robustly capturing the full spectrum of CTCs is an urgent need for CTC diagnosis to be routine clinical practice. Methods: Here we report the full capture of heterogeneous CTC populations using fully automated, negative depletion-based continuous centrifugal microfluidics (CCM). Results: The CCM system demonstrated high performance (recovery rates exceeding 90% and WBC depletion rate of 99.9%) across a wide range of phenotypes (EpCAM(+), EpCAM(-), small-, large-sized, and cluster) and cancers (lung, breast, and bladder). Applied in 30 lung adenocarcinoma patients harboring epidermal growth factor receptor (EGFR) mutations, the system isolated diverse phenotypes of CTCs in marker expression and size, implying the importance of unbiased isolation. Genetic analyses of intra-patient samples comparing cell-free DNA with CCM-isolated CTCs yielded perfect concordance, and CTC enumeration using our technique was correlated with clinical progression as well as response to EGFR inhibitors. Conclusion: Our system also introduces technical advances which assure rapid, reliable, and reproducible results, thus enabling a more comprehensive application of robust CTC analysis in clinical practice.

The Overview of Practical Guidelines for Gliomas by KSNO, NCCN, and EANO.

Gliomas have been histologically diagnosed as the third most common primary tumor of the central nervous system (CNS) in a relatively small portion of Korea. Despite the rarity of gliomas, the disease entity is very dynamic due to its various molecular characteristics, compared with other CNS tumors. The practice of managing glioma patients is not globally established as a precise standard guideline because of the different socio-medical environments of individual countries. The Korean Society for Neuro-Oncology (KSNO) published guidelines for managing adult glioma in 2019, and the National Comprehensive Cancer Network and European Association of Neuro-Oncology published guidelines in September 2021 and March 2021, respectively. However, these guidelines have several different recommendations in practice, including tissue management, adjuvant treatment after surgical resection, and salvage treatment for recurrent/progressive gliomas. Currently, the KSNO guideline working group is preparing an updated version of the guideline for managing adult gliomas. In this review, common features have been verified and different points are analyzed. Consequently, this review is expected to be informative and helpful to provide high quality evidence and a strong recommendation level for the establishment of new KSNO guidelines for managing gliomas.

Association of aortic arch calcification on chest X-ray with procedural thromboembolism after coil embolization of cerebral aneurysm.

Procedural thromboembolism after coil embolization of a cerebral aneurysm can occur because of fragmented atherosclerotic plaques in the aortic arch. The purpose of this study was to investigate the relationship between aortic arch calcification (AoAC) observed using preoperative chest X-ray and procedural thromboembolisms after coil embolization of cerebral aneurysms. Between January 2019 and December 2020, 66 patients underwent coil embolization for cerebral aneurysms at our hospital. AoAC was assessed based on the presence of calcification using a preoperative chest X-ray. A procedural thromboembolism was defined as a new positive lesion on diffusion-weighted imaging within 7 days post-procedure. A procedural thromboembolism occurred in 34 (51.5%) patients. The thromboembolism was associated with AoAC (calcification [52.9%] vs. no calcification [6.3%], p < 0.001), aneurysm type (aneurysm with incorporated branches [63.9%] vs. sidewall aneurysm [36.7%], p = 0.047), and a longer procedural time (100.2 ± 34.1 min vs. 79.7 ± 24.9 min, p = 0.007). Multivariable logistic regression analysis showed that AoAC (adjusted odds ratio [OR], 23.566; adjusted 95% confidence interval [CI], 3.921-141.654; p = 0.001) and aneurysm type (adjusted OR, 5.501; adjusted 95% CI, 1.455-20.799; p = 0.012) were independent risk factors for procedural thromboembolism. AoAC on preoperative chest X-ray was associated with a significant increase in the procedural thromboembolism rate. Our study suggests that a procedural thromboembolism after coil embolization of cerebral aneurysms might result primarily from fragmented atherosclerotic plaques in the aortic arch. Preoperative chest X-ray could be a useful tool to predict the risk of procedural thromboembolisms.

Ki67 Index Is the Most Powerful Factor for Predicting the Recurrence in Atypical Meningioma : Retrospective Analysis of 99 Patients in Two Institutes.

OBJECTIVE: The primary objective of this study was to identify predicting factors for local control (LC) of atypical meningioma, and we validated them with comparing the predicting factors for recurrence-free survival (RFS). We also examined the rate of LC after surgical resection with or without adjuvant treatment and RFS. METHODS: Clinical and radiological records of patients with atypical meningiomas diagnosed at two institutes from January 2000 to December 2018 were reviewed retrospectively. Histopathological features were also reviewed using formalin-fixed paraffin embedded samples from pathological archives. RESULTS: Of the 99 atypical meningiomas eligible for analysis, 36 (36.4%) recurred during the follow-up period (mean, 83.3 months; range, 12-232 months). The rate of 3-year LC and 5-year LC was 80.8% and 74.7%, respectively. The mean time-to-recurrence was 49.4 months (range, 12-150). The mean RFS was 149.3 months (95% confidence interval, 128.8-169.8 months) during the mean follow-up duration of 83.3 months (range, 12-232 months). Multivariate analysis using Cox proportional-hazard regression model showed that the extent of resection (hazard ratio [HR], 4.761; p=0.013), Ki67 index (HR, 8.541; p=0.004), mitotic index (HR, 3.275; p=0.044), and tumor size (HR, 3.228; p=0.041) were independently associated with LC. These factors were also statistically associated with RFS. In terms of radiotherapy after surgical resection, the recurrence was not prevented by immediate radiotherapy because of the strong effect of proliferative index on recurrence. CONCLUSION: The present study suggests that the extent of resection, proliferative index (according to Ki67 expression) and mitotic index, and tumor size are associated with recurrence of atypical meningiomas. However, our results should be further validated through prospective and randomized clinical trials to overcome the inborn bias of retrospective nature of the study design.

Impact of the Coronavirus Disease Pandemic on Patients with Head Injuries in South Korea.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic is affecting the characteristics of patients with head injuries. This study aimed to evaluate the effect of the COVID-19 pandemic on patients with head injuries at a regional emergency medical center in South Korea. METHODS: From April 2019 to November 2020, 350 patients with head injuries were admitted to our hospital. The study period was divided into the pre-COVID-19 (n=169) and COVID-19 (n=181) eras (10 months each). Patients with severe head injuries requiring surgery (n=74) were categorized into those who underwent surgery (n=41) and those who refused surgery (n=33). RESULTS: Head injuries in pediatric patients (<3 years) were more frequent in the COVID-19 era than in the pre-COVID-19 era (8.8% vs. 3.6%, p=0.048). More patients refused surgery in the COVID-19 era than in the pre-COVID-19 era (57.9% vs. 30.6%, p=0.021). Refusal of surgery was associated with old age (67.7±14.5 vs. 52.4±19.1, p<0.001), marital status (married, 84.8% vs. 61.0%, p=0.037), unemployment (42.4% vs. 68.3%, p=0.034), COVID-19 era (66.7% vs. 39.0%, p=0.021), and lower Glasgow coma scale scores (6.12±3.08 vs. 10.6±3.80, p<0.001). Multivariable logistic regression analysis revealed that refusal of surgery was independently associated with old age (adjusted odds ratio [OR], 1.084; 95% confidence interval [CI], 1.030-1.140; p=0.002), COVID-19 era (adjusted OR, 6.869; 95% CI, 1.624-29.054; p=0.009), and lower Glasgow coma scale scores (adjusted OR, 0.694; 95% CI, 0.568-0.848; p<0.001). CONCLUSION: We observed an increased prevalence of head injuries in pediatric patients (<3 years) during the COVID-19 pandemic. Additionally, among patients with severe head injuries requiring surgery, more patients refused to undergo surgery during the COVID-19 pandemic.

Effect of Antiplatelet Preparation Before Endovascular Thrombectomy for Cerebral Infarction on Procedural Thromboembolism.

AIM: To compare an antiplatelet-preparation group with a no-preparation group to evaluate the effect of the antiplatelet preparation on procedural thromboembolism during endovascular thrombectomy (EVT) with diffusion-weighted imaging (DWI), retrospectively. MATERIAL AND METHODS: From January 2017 to April 2020, EVT was performed in 60 patients with cerebral infarction. Patients were categorized into the antiplatelet-preparation group (n=25) or the no-preparation group (n=35). Procedural thromboembolism was defined as new DWI-positive lesions in other areas of the occluded artery after EVT. RESULTS: The antiplatelet-preparation and no-preparation groups did not differ in the rate of procedural thromboembolism occurrence (6/25 [24.0%] vs. 6/35 [17.1%]; p=0.532). Procedural thromboembolism was associated with age (74.4 ± 6.95 years vs. 65.7 ± 12.9 years; p=0.028), atherosclerotic occlusion (66.7% vs. 29.2%; p=0.022), and procedural time (97.4 ± 45.7 min vs. 60.1 ± 28.8 min; p=0.001). Multivariable logistic regression analysis showed that factors affecting procedural thromboembolism during EVT for cerebral infarction were old age (odds ratio [OR], 1.133; 95% confidence interval [CI], 1.009-1.273; p=0.035), atherosclerotic occlusion (OR, 7.434; 95% CI, 1.272-43.431; p=0.026), and longer procedural time (OR, 1.023; 95% CI, 1.001 - 1.046; p=0.006). CONCLUSION: The antiplatelet preparation had no significant protective effect on procedural thromboembolism during EVT for cerebral infarction. Old age, atherosclerotic occlusion, and longer procedural time were independent risk factors for procedural thromboembolism during EVT for cerebral infarction.

Hypo-trimethylation of Histone H3 Lysine 4 and Hyper-tri/dimethylation of Histone H3 Lysine 27 as Epigenetic Markers of Poor Prognosis in Patients with Primary Central Nervous System Lymphoma.

PURPOSE: This study aimed to investigate the methylation status of major histone modification sites in primary central nervous system lymphoma (PCNSL) samples and examine their prognostic roles in patients with PCNSL. MATERIALS AND METHODS: Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL. We performed immunohistochemical staining of the formalin-fixed paraffin-embedded samples of PCNSL for major histone modification sites, such as H3K4, H3K9, H3K27, H3K14, and H3K36. After detection of meaningful methylation sites, we examined histone modification enzymes that induce methylation or demethylation at each site using immunohistochemical staining. The meaningful immunoreactivity was validated by western blotting using fresh tissue of PCNSL. RESULTS: More frequent recurrences were found in hypomethylation of H3K4me3 (p=0.004) and hypermethylation of H3K27me2 (p<0.001) and H3K27me3 (p=0.002). These factors were also statistically related to short PFS and overall survival in the univariate and multivariate analyses. Next, histone modification enzymes inducing the demethylation of H3K4 (lysine-specific demethylase-1/2 and Jumonji AT-rich interactive domain [JARID] 1A-D]) and methylation of H3K27 (enhancer of zeste homolog [EZH]-1/2) were immu- nohistochemically stained. Among them, the immunoreactivity of JARID1A inversely associated with the methylation status of H3K4me3 (R2=-1.431), and immunoreactivity of EZH2 was directly associated with the methylation status of H3K27me2 (R2=0.667) and H3K27me3 (R2=0.604). These results were validated by western blotting in fresh PCNSL samples. CONCLUSION: Our study suggests that hypomethylation of H3K4me3 and hypermethylation of H3K27me2 and H3K27me3 could be associated with poor outcomes in patients with PCNSL and that these relationships are modified by JARID1A and EZH2.

Clinical Outcomes of RTOG 9310 Protocol for Primary Central Nervous System Lymphoma: Single-Center Experience with 87 Patients.

The Radiation Therapy Oncology Group (RTOG) 9310 protocol clinical trial established high-dose methotrexate (HDMTX) as the standard for primary central nervous system lymphoma (PCNSL). We aimed to investigate the RTOG 9310 protocol's PCNSL outcomes by examining progression-free survival (PFS) and overall survival (OS) rates and determining the influential factors. Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL and treated with the RTOG 9310 protocol. All received HDMTX 2.5 g/m2 and vincristine 1.4 mg/m2/day for 1 day during weeks 1, 3, 5, 7, and 9, and procarbazine 100 mg/m2/day for 1 day during weeks 1, 5, and 9. Dexamethasone was administered on a standard tapering schedule from the first week to the sixth week. Whole brain radiotherapy (WBRT), consisting of 45 Gy for patients with less than a complete response to the chemotherapy or 36 Gy for complete responders, was started 1 week after the last dose of chemotherapy was administered. Within three weeks of the completion of WBRT, patients received two courses of cytarabine, which were separated by 3-4 weeks. Clinical, radiological, and histopathological characteristics were retrospectively reviewed. All patients completed five HDMTX cycles and a mean follow-up of 60.2 (range, 6-150) months. Twenty-eight (32.2%) patients experienced recurrence during follow-up. The mean time to recurrence was 21.8 months, while the mean PFS was 104.3 (95% confidence interval (CI), 90.6-118.0) months. Eleven (12.6%) patients died; the mean OS was 132.1 (95% CI, 122.2-141.9) months. The 3- and 5-year survival rates were 92.0% and 87.4%, respectively. One patient experienced acute renal failure, while the remainder tolerated any cytotoxic side effects. On multivariate analysis, the Eastern Cooperative Oncology Group performance score ≤ 2; the International Extranodal Lymphoma Study Group low-risk status; XBP-1, p53, and c-Myc negativity; homogenous enhancement; gross total resection, independently correlated with long PFS and OS. The RTOG 9310 protocol is effective for PCNSL and features good outcomes.