Methyltransferase-Like 3-Mediated N6-Methyladenosine RNA Methylation Regulates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Pyroptosis by Targeting PTEN.

BACKGROUND: Pulmonary hypertension is a rare, progressive disorder that can lead to right ventricular hypertrophy, right heart failure, and even sudden death. N6-methyladenosine modification and the main methyltransferase that mediates it, methyltransferase-like (METTL) 3, exert important effects on many biological and pathophysiological processes. However, the role of METTL3 in pyroptosis remains unclear. METHODS AND RESULTS: Here, we characterized the role of METTL3 and the underlying cellular and molecular mechanisms of pyroptosis, which is involved in pulmonary hypertension. METTL3 was downregulated in a pulmonary hypertension mouse model and in hypoxia-exposed pulmonary artery smooth muscle cell. The small interfering RNA-induced silencing of METTL3 decreased the m6A methylation levels and promoted pulmonary artery smooth muscle cell pyroptosis, mimicking the effects of hypoxia. In contrast, overexpression of METTL3 suppressed hypoxia-induced pulmonary artery smooth muscle cell pyroptosis. Mechanistically, we identified the phosphate and tension homology deleted on chromosome 10 (PTEN) gene as a target of METTL3-mediated m6A modification, and methylated phosphate and tension homology deleted on chromosome 10 mRNA was subsequently recognized by the m6A "reader" protein insulin-like growth factor 2 mRNA-binding protein 2, which directly bound to the m6A site on phosphate and tension homology deleted on chromosome 10 mRNA and enhanced its stability. CONCLUSIONS: These results identify a new signaling pathway, the METTL3/phosphate and tension homology deleted on chromosome 10/insulin-like growth factor 2 mRNA-binding protein 2 axis, that participates in the regulation of hypoxia-induced pyroptosis.

Brainstem Gliomas With Isocitrate Dehydrogenase Mutation: Natural History, Clinical-Radiological Features, Management Strategy, and Long-Term Outcome.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical, radiological, pathological features, treatment options, and outcomes of isocitrate dehydrogenase (IDH)-mutant brainstem gliomas (BSG-IDHmut). METHODS: A retrospective analysis of 22 patients diagnosed with BSG-IDHmut and treated at our institution from January 2011 to January 2017 was performed. Their clinical, radiological data, and long-term outcomes were collected and analyzed. RESULTS: The median age of patients was 38.5 years, with a male predominance (63.6%). All patients had IDH1 and TP53 mutations, with noncanonical IDH mutations in 59.1% of cases, 06-methylguanine-DNA methyltransferase promoter methylation in 55.6%, and alpha-thalassemia mental retardation X-linked loss in 63.2%, respectively. Tumors were primarily located in the pontine-medullary oblongata (54.5%) and frequently involved the pontine brachium (50%). Most tumors exhibited ill-defined boundaries (68.2%), no T2-FLAIR mismatch (100%), and no contrast enhancement (86.3%). Two radiological growth patterns were also identified: focal and extensively infiltrative, which were associated with the treatment strategy when tumor recurred. Seven patients (31.8%) received surgery only and 15 (68.2%) surgery plus other therapy. The median overall survival was 124.8 months, with 1-year, 2-year, 5-year, and 10-year survival rates of 81.8%, 68.2%, 54.5%, and 13.6%, respectively. Six patients experienced tumor recurrence, and all retained their radiological growth patterns, with 2 transformed into central nervous system World Health Organization grade 4. CONCLUSION: BSG-IDHmut represents a unique subgroup of brainstem gliomas with distinctive features and more favorable prognosis compared with other brainstem gliomas. Further research is required to better understand the molecular mechanisms and optimize treatment strategies for this rare and complex disease.

Intraoperative quantitative crystalline lens nuclear opacities analysis based on crystalline lenSx platform.

PURPOSE: The main objective is to quantify the lens nuclear opacity using spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with Lens Opacities Classification System III (LOCS-III) system, lens thickness (LT), and surgical parameters. The secondary objective is to assess the diagnostic model performance for hard nuclear cataract. METHODS: This study included 70 eyes of 57 adults with cataract, with 49 (70%) and 21 (30%) in training and validation cohort, respectively. Correlations of the average nuclear density (AND) /maximum nuclear density (MND) with LOCS-III scores, LT, and surgical parameters were analyzed. Univariate and multivariate logistic regression analysis, receiver operating characteristic curves and calibration curves were performed for the diagnostic of hard nuclear cataract. RESULTS: The pre-operative uncorrected distance visual acuity (UDVA), intraocular pressure (IOP), mean axial length (AL), and LT were 1.20 ± 0.47 log MAR, 15.50 ± 2.87 mmHg, 27.34 ± 3.77 mm and 4.32 ± 0.45 mm, respectively. The average nuclear opalescence (NO) and nuclear colour (NC) scores were 3.61 ± 0.94 and 3.50 ± 0.91 (ranging from 1.00 to 6.90), respectively. The average AND and MND were 137.94 ± 17.01 and 230.01 ± 8.91, respectively. NC and NO scores both significantly correlated with the AND (rNC = 0.733, p = 0.000; rNO = 0.755, p = 0.000) and MND (rNC = 0.643, p = 0.000; rNO = 0.634, p = 0.000). In the training cohort, the area under the curve (AUC) of the model was 0.769 (P < 0.001, 95%CI 0.620-0.919), which had a good degree of differentiation (Fig. 2a). The calibration curve showed good agreement between predicted and actual probability. CONCLUSION: The nuclear density measurement on SD-OCT images can serve as an objective and reliable indicator for quantifying nuclear density.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Insufficiency of plasmatic arginine/homoarginine during the initial postoperative phase among patients with tumors affecting the medulla oblongata heightens the likelihood of neurogenic pulmonary oedema following surgery.

BACKGROUND: This prospective clinical study aims to investigate the fluctuations of neurotransmitters in peripheral venous blood during the perioperative period and to identify independent predictors for postoperative neurogenic pulmonary oedema (NPE) in patients with medulla oblongata-involved tumours. MATERIALS AND METHODS: Peripheral venous blood samples of the enroled patients at seven perioperative time points, as well as their medical records and radiologic data were collected. High-performance liquid chromatography-tandem mass spectrometry was utilized to detect the concentrations of 39 neurotransmitters in these samples. The study applied univariate and multivariate generalized estimating equation (GEE) logistic regression analyses to explore independent predictors of postoperative NPE, and one-way repeated-measures ANOVA to compare the concentrations of the same neurotransmitter at different perioperative time points. RESULTS: The study included 36 patients with medulla oblongata-involved tumours from January to December 2019, and found that 13.9% of them experienced postoperative NPE. The absence of intraoperative use of sevoflurane ( P =0.008), decreased concentrations of arginine ( P =0.026) and homoarginine ( P =0.030), and prolonged postoperative tracheal extubation ( P <0.001) were identified as independent risk factors for postoperative NPE in medulla oblongata-involved tumour patients. Pairwise comparison analysis revealed that the perioperative decreases in arginine and homoarginine concentrations mainly occurred within the postoperative 8 h. CONCLUSION: This study demonstrates that NPE is not uncommon in patients with medulla oblongata-involved tumours. The absence of intraoperative use of sevoflurane, decreased concentrations of plasmatic arginine and homoarginine, and prolonged postoperative tracheal extubation are independent predictors of postoperative NPE. These two neurotransmitters' concentrations dropped mainly within the early postoperative hours and could serve as potential early warning indicators of postoperative NPE in clinical practice.

A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management: a single-institution experience of 57 cases.

OBJECTIVE: Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decision-making and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up. METHODS: Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed. RESULTS: The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0-12.8 years); the largest tumor volume (median 31.9 cm3, IQR 17.2-42.6 cm3); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50-70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image-guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8-33 years); tumor volume (median 13.9 cm3, IQR 9.5-20.5 cm3); a good preoperative KPS score (median 80, IQR 70-80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm3, IQR 5.1-17.4 cm3 and median 11.84 cm3, IQR 5.7-18.3 cm3, respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches. CONCLUSIONS: A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Primary adult choroid plexus carcinomas: a single-center experience with a systematic review.

Objective: Primary adult choroid plexus carcinomas (PACPCs) are extremely rare brain tumors. The existing literature primarily comprises case reports, which limits our understanding of this uncommon disease. This study aims to describe the clinical characteristics and prognosis of PACPCs, as well as to identify optimal treatment strategies. Methods: We conducted a comprehensive analysis of clinical data from 7 patients with PACPCs who underwent surgical treatment at the Department of Neurosurgery, Beijing Tiantan Hospital, between March 2011 and March 2023. Additionally, a thorough search of the PubMed database was performed using the keywords "choroid plexus carcinoma" or "choroid plexus carcinomas" within the time frame of August 1975 to April 2023, which yielded a total of 28 identified cases. Subsequently, we evaluated risk factors for progression-free survival (PFS) and overall survival (OS) based on the pooled cases. Results: The pooled cohort, consisting of 7 cases from our institution and 28 cases from the literature, included 20 males and 15 females with a mean age of 44.3 ± 14.7 years (range: 21-73 years). Gross-total resection (GTR) and non-GTR were achieved in 22 (62.9%) and 13 (37.1%) patients, respectively. Radiotherapy and chemotherapy were administered to 29 (90.6%) and 13 (40.6%) patients, respectively. After a mean follow-up of 21.0 ± 26.7 months (range: 2-132 months), 18 patients were alive, and 11 patients had died. The multivariate Cox regression model demonstrated that non-GTR (HR 5.262, 95% CI 1.350-20.516, p=0.017) was a negative prognostic factor for OS. However, we did not find any risk factors for PFS. Conclusion: Complete surgical resection should be considered as the primary treatment approach for this rare disease. Chemotherapy and radiotherapy appear to have limited effectiveness in treating this condition. Further research with large cohorts is needed to validate our conclusions.

Decoding meningioma heterogeneity and neoplastic cell-macrophage interaction through single-cell transcriptome profiling across pathological grades.

BACKGROUND: Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment. METHODS: We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, and gene set enrichment analysis. Additionally, we conducted cell-cell communication analyses to characterize interactions among different clusters and validated a crucial interaction using multiple immunofluorescence staining. RESULTS: The single-cell transcriptomic profiles for five meningioma of different pathological types demonstrated that neoplastic cells exhibited high inter-sample heterogeneity and diverse biological functions featured by metabolic regulation. A small cluster of neoplastic cells (N5 cluster, < 3%) was most proliferative, indicated by high expression of MKI67 and TOP2A. They were primarily observed in our atypical and transitional meningioma samples and located at the beginning of the pseudotime differentiation branch for neoplastic cells. Macrophages, the most abundant immune cells present, showed two distinct developmental trajectories, one promoting and the other suppressing meningioma growth, with the MIF-CD74 interaction serving as the primary signaling pathway for MIF signals in the tumor environment. Unexpectedly, despite its small cluster size, the N5 cluster demonstrated a significant contribution in this interaction. By staining pathological sections of more samples, we found that this interaction was widely present in different types of meningiomas. CONCLUSIONS: Meningioma neoplastic cells' diverse types cause inter-sample heterogeneity and a wide range of functions. Some proliferative neoplastic cell may educate macrophages, which promotes tumorigenesis possibly through the MIF-CD74 interaction. It provides novel clues for future potential therapeutic avenues.

Clinical characteristics and surgical outcomes of primary intracranial angiosarcomas.

OBJECTIVE: Primary intracranial angiosarcomas (PIAs) are exceedingly uncommon, with the literature predominantly comprising case reports. The clinical characteristics and prognosis of this condition remain elusive. Our objective is to describe the clinical characteristics and surgical prognosis of this rare disease while offering insights into the most effective contemporary treatment strategy. METHODS: The authors of this article incorporated a cohort of 28 cases of PIAs, consisting of 3 from our institution and 25 from previously documented literature sources. Subsequently, we conducted both Cox univariate and multivariate analyses to assess the potential risk factors influencing overall survival (OS). RESULTS: The cohort include 19 males and 9 females with a mean age of 39.6 ± 23.5 years (range: 0.03-73 years). Radiologically, 24 cases were located at supratentorial area, while only 4 cases were located at infratentorial area. 17 cases underwent gross total resection (GTR), and 11 cases underwent Non-GTR. Postoperative radiotherapy was administered to 17 cases, and postoperative chemotherapy was administered to 6 cases. After a mean follow-up time of 21.5 ± 26.4 months, 19 (67.9%) patients died. The 1-year, 2-year, 5-year OS is 55.3%, 50.7% and 24.6%, respectively. Univariate and multivariate Cox regression analysis showed that Non-GTR was the sole factor predicting a shorter OS (p = 0.004). CONCLUSION: In this study, we found that PIAs have a higher incidence in males than in females, and most cases show evidence of old hemorrhage on preoperative MRI. Through our statistical analysis, GTR plays a crucial role in for treating this rare disease. Further clinical data are needed to validate our conclusions.

Postoperative trigeminal neuropathy outcomes following surgery for tumors involving the trigeminal nerve.

OBJECTIVE: To observe the evolution and outcomes of postoperative trigeminal neuropathy following surgery of tumor involving the trigeminal nerve. METHODS: A prospective observational study was conducted between October 2018 and February 2019 involving 25 patients with tumors confirmed to involve the trigeminal nerve during surgery by senior author. Pre- and postoperative trigeminal nerve function status and clinical data were recorded. RESULTS: This study included 18 cases of meningioma and seven of trigeminal schwannoma. Among the meningioma cases, 55.6% of the patients reported facial sensory dysfunction before surgery, 33.3% presented ocular discomfort, and 5.6% had masticatory muscle atrophy. Postoperatively, all patients experienced facial paresthesia, 94.4% complained of eye dryness, and one (5.56%) exhibited keratitis. Additionally, one patient (5.56%) showed new-onset masticatory weakness. During follow-up, 50.0% of patients reported improvement in facial paresthesia, and one (5.56%) experienced deterioration. Eye dryness resolved in 35.3% of patients, and keratitis remission was observed in one patient. However, one patient (5.56%) developed neurotrophic keratitis. Overall, 55.6% of patients displayed mild masticatory weakness without muscle atrophy. In the cases of schwannoma, 28.6% of patients had facial paresthesia before surgery, 42.9% showed ocular discomfort, and one (14.3%) complained of masticatory dysfunction. Postoperatively, 85.7% of patients reported facial paresthesia and eye dryness, with one patient (16.7%) experiencing keratitis. During follow-up, 66.7% of patients demonstrated improvement in facial paresthesia, 28.6% showed eye dryness remission, and one patient (16.7%) recovered from keratitis. However, one patient (16.7%) developed new-onset neurotrophic keratitis. One patient (16.7%) experienced relief of masticatory dysfunction, but 42.9% reported mild deterioration. Another patient (14.3%) had facial anesthesia that had not improved. CONCLUSION: Postoperative trigeminal neuropathy is a common complication with a high incidence rate and poor recovery outcomes after surgery for tumors involving the trigeminal nerve. When trigeminal nerve damage is unavoidable, it is essential to provide a multidisciplinary and careful follow-up, along with active management strategy, to mitigate the more severe effects of postoperative trigeminal neuropathy.

Clinical features and surgical outcomes of high grade pleomorphic xanthoastrocytomas: a single-center experience with a systematic review.

Purpose: High grade pleomorphic xanthoastrocytomas (HGPXAs) are very rare and their management and prognostic outcomes remain unclear. To better understand the disease, we aimed to evaluate the risk factors for progression-free survival (PFS) and overall survival (OS), and propose a treatment protocol based on cases from our institute and cases from the literature. Methods: The authors reviewed the clinical data of 26 patients with HGPXAs who underwent surgical treatment in Department of Neurosurgery of Beijing Tiantan Hospital between August 2014 and September 2021. We also searched the PubMed database using the keywords "anaplastic" combined with "pleomorphic xanthoastrocytoma(s)" between January 1997 and October 2022. Risk factors for PFS and OS were evaluated in the pooled cases. Results: The authors' cohort included 11 males and 15 females with a mean age of 36.7 ± 20.3 years (range: 5.5-71 years). Gross-total resection (GTR) and non-GTR were achieved in 17 (65.4%) and 9 (34.6%) patients, respectively. Radiotherapy and chemotherapy were administered to 22 and 20 patients, respectively. After a mean follow-up of 20.5 ± 21.2 months (range: 0.5-78.1 months), 7 patients suffered tumor recurrence and 6 patients died with a mean OS time of 19.4 ± 10.8 months (range: 8-36 months). In the literature between January 1997 and October 2022, 56 cases of HGPXAs were identified in 29 males and 27 females with a mean age of 29.6 ± 19.6 years (range; 4-74 years). Among them, 24 (44.4%) patients achieved GTR. Radiotherapy and chemotherapy was administered to 31 (62%) patients and 23 (46%) patients, respectively. After a median follow-up of 31.4 ± 35.3 months (range: 0.75-144 months), the mortality and recurrence rates were 32.5% (13/40) and 70% (28/40), respectively. Multivariate Cox regression model demonstrated that non-GTR (HR 0.380, 95% CI 0.174-0.831, p=0.015), age≥30 (HR 2.620, 95% CI 1.183-5.804, p=0.018), no RT (HR 0.334,95% CI 0.150-0.744, p=0.007) and no CT (HR 0.422, 95% CI 0.184-0.967, p=0.042) were negative prognostic factors for PFS. Non-GTR (HR 0.126, 95% CI 0.037-0.422, p=0.001), secondary HGPXAs (HR 7.567, 95% CI 2.221-25.781, p=0.001), age≥30 (HR 3.568, 95% CI 1.190-10.694, p=0.023) and no RT (HR 0.223,95% CI 0.073-0.681, p=0.008) were risk factors for OS. Conclusion: High grade pleomorphic xanthoastrocytomas are very rare brain tumors. Children and younger adults have better clinical outcome than elderly patients. Secondary HGPXAs had worse OS than primary HGPXAs. Complete surgical excision plus RT and CT is recommended for this entity. The frequency of BRAF mutations in HGPXAs is 47.5% (19/40) in this study, however, we do not find the connections between BRAF mutations and clinical outcomes. Future studies with larger cohorts are necessary to verify our findings.

Primary intracranial histiocytic sarcomas: a report of six cases and a pooled analysis of individual patient data.

OBJECTIVE: Primary intracranial histiocytic sarcomas (PIHSs) are extremely rare with limited reported cases, making their prognostic factors and management uncertain. This study aims to describe the clinical characteristics of PIHSs and propose a treatment protocol for this entity. METHODS: Clinical data were collected from six patients diagnosed with PIHSs at Beijing Tiantan Hospital between March 2011 and October 2022. Additionally, a comprehensive search of the PubMed database was conducted using the keywords "primary intracranial" or "primary central nervous system" combined with "histiocytic sarcoma" or "histiocytic sarcomas" between 1996 and 2022, identifying 24 cases. A pooled analysis of individual patient data was performed to assess risk factors for overall survival (OS). RESULTS: The six cases included four males and two females, with a mean age of 42.2 ± 13.3 years. In total, 24 cases of PIHSs were identified from previous studies. Multivariate Cox regression analysis revealed that gross total resection (GTR) was the only factor predicting a longer OS (p = 0.027). Kaplan-Meier analysis demonstrated that GTR (p = 0.0013), solitary lesions (p = 0.0048), and radiotherapy (p = 0.0492) were associated with a longer OS. CONCLUSION: PIHSs are rare brain tumors with poor clinical prognosis. Patients with solitary lesions have a longer OS than those with multifocal lesions. Gross total resection must be the first choice. Radiotherapy may bring benefits for these patients, but chemotherapy may not be useful. Further studies involving larger cohorts are necessary to validate these findings.

A multimodal imaging-based classification for pediatric diffuse intrinsic pontine gliomas.

OBJECT: Pediatric diffuse intrinsic pontine glioma (DIPG) is a radiologically heterogeneous disease entity, here we aim to establish a multimodal imaging-based radiological classification and evaluate the outcome of different treatment strategies under this classification frame. METHODS: This retrospective study included 103 children diagnosed with DIPGs between January 2015 and August 2018 in Beijing Tiantan Hospital (Beijing, China). Multimodal radiological characteristics, including conventional magnetic resonance imaging (MRI), diffuse tensor imaging/diffuse tensor tractography (DTI/DTT), and positron emission tomography (PET) were reviewed to construct the classification. The outcome of different treatment strategies was compared in each DIPG subgroup using Kaplan-Meier method (log-rank test) to determine the optimal treatment for specific DIPGs. RESULTS: Four radiological DIPG types were identified: Type A ("homocentric", n=13), Type B ("ventral", n=41), Type C ("eccentric", n=37), and Type D ("dorsal", n=12). Their treatment modalities were grouped as observation (43.7%), cytoreductive surgery (CRS) plus radiotherapy (RT) (24.3%), RT alone (11.7%), and CRS alone (20.4%). CRS+RT mainly fell into type C (29.7%), followed by type B1 (21.9%) and type D (50%). Overall, CRS+RT exhibited a potential survival advantage compared to RT alone, which was more pronounced in specific type, but this did not reach statistical significance, due to limited sample size and unbalanced distribution. CONCLUSION: We proposed a multimodality imaging-based radiological classification for pediatric DIPG, which was useful for selecting optimal treatment strategies, especially for identifying candidates who may benefit from CRS plus RT. This classification opened a window into image-guided integrated treatment for pediatric DIPG.

Different clinical and cytogenetic features of primary skull base meningiomas and non-skull base meningiomas.

PURPOSE: To investigate the different clinical and cytogenetic features of skull base meningiomas (SBMs) and non-SBMs (NSBMs). METHODS: We conducted a retrospective study on a series of 316 patients with primary intracranial meningiomas. The t-test and the Chi-square test were used to analyze the differences between 194 SBMs and 122 NSBMs. The Cox analysis was used to determine prognostic factors for tumor recurrence. RESULTS: Compared with NSBMs, on average, the age of patients with SBMs was about 2.88 years younger (p = 0.024); the duration of operation of SBMs was 2.73 h longer (p < 0.001); the duration of hospital stays of patients with SBMs was about 6.76 days longer (p < 0.001); the tumor volume was 7.69 cm3 smaller (p = 0.025); the intraoperative blood loss was 147.61ml more (p = 0.039); the total cost of SBMs was 1.39 times more (p < 0.001); the preoperative KPS, postoperative KPS, and follow-up KPS of patients with SBMs were all respectively lower (p < 0.001); Gross total resection was less achieved (p < 0.001). SBMs (average of 20.80 per sample) had a smaller total number of copy number variations (CNVs) than NSBMs (29.98 per sample) (p = 0.009). Extremely large CNVs (> 5 Mb) were more likely to present in NSBMs (p < 0.001). Cox analysis showed that subtotal resection (p = 0.002) and the total number of CNVs (p = 0.015) were independent risk factors for tumor recurrence. CONCLUSIONS: The clinical and cytogenetic features of SBMs were different from NSBMs. Moreover, the degree of resection and the total number of whole-genome CNVs were independent prognostic factors for tumor recurrence.

Anti-tumor efficacy of anti-GD2 CAR NK-92 cells in diffuse intrinsic pontine gliomas.

Background: Diffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG. Methods: Five patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo. Results: Among the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression). Conclusion: Our study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.

A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma.

OBJECTIVE: Diffuse midline glioma, H3 K27-altered (DMG) is a lethal pediatric brainstem tumor. Despite numerous efforts to improve survival benefits, its prognosis remains poor. This study aimed to design and synthesize a novel CDK4/6 inhibitor YF-PRJ8-1011, which exhibited more potent antitumor activity against a panel of patient-derived DMG tumor cells in vitro and in vivo compared with palbociclib. METHODS: Patient-derived DMG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The liquid chromatography tandem-mass spectrometry method was used to measure the activity of YF-PRJ8-1011 passing through the blood-brain barrier. DMG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011. RESULTS: The results showed that YF-PRJ8-1011 could inhibit the growth of DMG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood-brain barrier. It also significantly inhibited the growth of DMG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DMG in vitro and in vivo compared with palbociclib. In addition, we also found that YF-PRJ8-1011 combined with radiotherapy also showed more significant inhibition of DMG xenograft tumor growth than radiotherapy alone. CONCLUSION: Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DMG treatment.

Role of neuronavigation in the surgical management of brainstem gliomas.

Objective: NeuroNavigation (NN) is a widely used intraoperative imaging guidance technique in neurosurgical operations; however, its value in brainstem glioma (BSG) surgery is inadequately reported and lacks objective proof. This study aims to investigate the applicational value of NN in BSG surgery. Method: A retrospective analysis was performed on 155 patients with brainstem gliomas who received craniotomy from May 2019 to January 2022 at Beijing Tiantan Hospital. Eighty-four (54.2%) patients received surgery with NN. Preoperative and postoperative cranial nerve dysfunctions, muscle strength, and Karnofsky (KPS) were evaluated. Patients' radiological features, tumor volume, and extent of resection (EOR) were obtained from conventional MRI data. Patients' follow-up data were also collected. Comparative analyses on these variables were made between the NN group and the non-NN group. Result: The usage of NN is independently related to a higher EOR in diffuse intrinsic pontine glioma (DIPG) (p=0.005) and non-DIPG group (p<0.001). It was observed that fewer patients in the NN group suffered from deterioration of KPS (p=0.032) and cranial nerve function (p=0.017) in non-DIPG group, and deterioration of muscle strength (p=0.040) and cranial nerve function (p=0.038) in DIPG group. Moreover, the usage of NN is an independent protective factor for the deterioration of KPS (p=0.04) and cranial nerve function (p=0.026) in non-DIPG patients and the deterioration of muscle strength (p=0.009) in DIPG patients. Furthermore, higher EOR subgroups were found to be independently related to better prognoses in DIPG patients (p=0.008). Conclusion: NN has significant value in BSG surgery. With the assistance of NN, BSG surgery achieved higher EOR without deteriorating patients' functions. In addition, DIPG patients may benefit from the appropriate increase of EOR.

Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas.

OBJECTIVE: Extra-axial cavernous hemangiomas (ECHs) are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus. The aetiology of ECHs remains unknown. METHODS: Whole-exome sequencing was performed on ECH lesions from 12 patients (discovery cohort) and droplet digital polymerase-chain-reaction (ddPCR) was used to confirm the identified mutation in 46 additional cases (validation cohort). Laser capture microdissection (LCM) was carried out to capture and characterise subgroups of tissue cells. Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model. RESULTS: We detected somatic GJA4 mutation (c.121G>T, p.G41C) in 5/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort (16/46). LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium. In vitro experiments in endothelial cells demonstrated that the GJA4 mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification. Compared with wild-type littermates, mice overexpressing the GJA4 mutation developed ECH-like pathological morphological characteristics (dilated venous lumen and elevated vascular density) in the retinal superficial vascular plexus at the postnatal 3 weeks, which were reversed by an SGK1 inhibitor, EMD638683. CONCLUSIONS: We identified a somatic GJA4 mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to GJA4-induced activation of the SGK1 signalling pathway in brain endothelial cells.