Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation.

Cerebral cavernous malformations (CCMs) are vascular disorders that affect up to 0.5% of the total population. About 20% of CCMs are inherited because of familial mutations in CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10, whereas the etiology of a majority of simplex CCM-affected individuals remains unclear. Here, we report somatic mutations of MAP3K3, PIK3CA, MAP2K7, and CCM genes in CCM lesions. In particular, somatic hotspot mutations of PIK3CA are found in 11 of 38 individuals with CCMs, and a MAP3K3 somatic mutation (c.1323C>G [p.Ile441Met]) is detected in 37.0% (34 of 92) of the simplex CCM-affected individuals. Strikingly, the MAP3K3 c.1323C>G mutation presents in 95.7% (22 of 23) of the popcorn-like lesions but only 2.5% (1 of 40) of the subacute-bleeding or multifocal lesions that are predominantly attributed to mutations in the CCM1/2/3 signaling complex. Leveraging mini-bulk sequencing, we demonstrate the enrichment of MAP3K3 c.1323C>G mutation in CCM endothelium. Mechanistically, beyond the activation of CCM1/2/3-inhibited ERK5 signaling, MEKK3 p.Ile441Met (MAP3K3 encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement. Collectively, we identified several somatic activating mutations in CCM endothelium, and the MAP3K3 c.1323C>G mutation defines a primary CCM subtype with distinct characteristics in signaling activation and magnetic resonance imaging appearance.

New Diffusion Abnormalities Following Endovascular Treatment for Intracranial Atherosclerosis.

Background There are limited data on new ischemic brain lesions after endovascular treatment for symptomatic intracranial atherosclerotic stenosis (ICAS). Purpose To investigate the (a) characteristics of new ischemic brain lesions at diffusion-weighted MRI (new diffusion abnormalities) after endovascular treatment, (b) characteristics between those treated with balloon angioplasty and stent placement procedures, and (c) predictors of new ischemic brain lesions. Materials and Methods Patients with symptomatic ICAS in whom maximum medical therapy failed were prospectively enrolled between April 2020 and July 2021 from a national stroke center and underwent endovascular treatment. All study participants underwent thin-section diffusion-weighted MRI (voxel size, 1.4 × 1.4 × 2 mm3 with no section gap) before and after treatment. The characteristics of new ischemic brain lesions were recorded. Multivariable logistic regression analysis was performed to determine potential predictors of new ischemic brain lesions. Results A total of 119 study participants (mean age, 59 years ± 11 [SD]; 81 men; 70 treated with balloon angioplasty and 49 with stent placement) were enrolled. Of the 119 participants, 77 (65%) had new ischemic brain lesions. Five of the 119 participants (4%) had symptomatic ischemic stroke. New ischemic brain lesions were located in (61%, 72 of 119) and/or beyond (35%, 41 of 119) the territory of the treated artery. Of the 77 participants with new ischemic brain lesions, 58 (75%) had lesions located in peripheral brain areas. There was no evidence of a difference in the frequency of new ischemic brain lesions between the balloon angioplasty and stent groups (60% vs 71%, P = .20). In adjusted models, cigarette smoking (odds ratio [OR], 3.6; 95% CI: 1.3, 9.7) and more than one operative attempt (OR, 2.9; 95% CI: 1.2, 7.0) were independent predictors of new ischemic brain lesions. Conclusion New ischemic brain lesions on diffusion-weighted MRI scans were common after endovascular treatment for symptomatic intracranial atherosclerotic stenosis, and occurrence may be associated with cigarette smoking and the number of operative attempts. Clinical trial registration no. ChiCTR2100052925 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Russell in this issue.

De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation.

[Figure: see text].

Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated With Brain Arteriovenous Malformation Microhemorrhage.

BACKGROUND AND PURPOSE: In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding. METHODS: We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue. RESULTS: Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFß (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs. CONCLUSIONS: TGFß/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.

Aspirin and Growth of Small Unruptured Intracranial Aneurysm: Results of a Prospective Cohort Study.

BACKGROUND AND PURPOSE: The role of aspirin in unruptured intracranial aneurysm (UIA) growth remains largely unknown. We aim to identify whether aspirin is associated with a lower rate of UIA growth in patients with UIA <7 mm. METHODS: This prospective cohort study consecutively enrolled patients with UIAs <7 mm with ischemic cerebrovascular disease between January 2016 and December 2019. Baseline and follow-up patient information, including the use of aspirin and blood pressure level, were recorded. Patients were considered aspirin users if they took aspirin, including standard- and low-dose aspirin, ≥3× per week. The primary end point was aneurysm growth in any direction or an indisputable change in aneurysm shape. RESULTS: Among the 315 enrolled patients, 272 patients (86.3%) underwent imaging examinations during follow-up (mean follow-up time, 19.6±12.7 months). A total of 113 patients were continuously treated with aspirin. UIA growth occurred in 31 (11.4%) patients. In the multivariate Cox analysis, specific aneurysm locations (anterior communicating artery, posterior communicating artery, or middle cerebral artery; hazard ratio, 2.89 [95% CI, 1.22-6.88]; P=0.016) and a UIA size of 5 to <7 mm (hazard ratio, 7.61 [95% CI, 3.02-19.22]; P<0.001) were associated with a high risk of UIA growth, whereas aspirin and well-controlled blood pressure were associated with a low risk of UIA growth (hazard ratio, 0.29 [95% CI, 0.11-0.77]; P=0.013 and hazard ratio, 0.25 [95% CI, 0.10-0.66]; P=0.005, respectively). The cumulative annual growth rates were as high as 40.0 and 53.3 per 100 person-years in the high-risk patients (>1 risk factor) with and without aspirin, respectively. CONCLUSIONS: Aspirin therapy and well-controlled blood pressure are associated with a low risk of UIA growth; the incidence of UIA growth in high-risk patients in the first year is high, warranting intensive surveillance in this patient group. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02846259.

Semi-automatic computed tomography angiography quantification assessment is an alternative method to digital subtraction angiography in intracranial stenosis: a multicenter study.

Background: The recent randomized controlled trials studying intracranial atherosclerotic stenosis (ICAS) have used digital subtraction angiography (DSA) to quantify stenosis and enroll patients. However, some disadvantages of DSA such as invasive features, contrast agent overuse, and X-ray radiation overexposure, were not considered in these studies. This study aimed to explore whether computed tomography angiography (CTA) with semi-automatic analysis could be an alternative method to DSA in quantifying the absolute stenotic degree in clinical trials. Methods: Patients with 50-99% ICAS were consecutively screened, prospectively enrolled, and underwent CTA and DSA between March 2021 and December 2021 at 6 centers. This study was registered at www.chictr.org.cn (ChiCTR2100052925). The absolute stenotic degree of ICAS on CTA with semi-automatic analysis was calculated by several protocols using minimal/maximum/mean diameters of stenosis and reference site from a semi-automatic analysis software. Intraclass correlation coefficient (ICC) was used to evaluate the reliabilities of quantifying stenotic degree on CTA. The optimal protocol for quantifying ICAS on CTA was explored. The agreements of quantifying ICAS in calcified or non-calcified lesions and 50-69% or 70-99% stenosis on CTA and DSA were assessed. Results: A total of 191 participants (58.8±10.7 years; 148 men) with 202 lesions were enrolled. The optimal protocol for quantifying ICAS on CTA was calculated as (1 - the minimal diameter of stenosis/the mean diameter of reference) × 100% for its highest agreement with DSA [ICC, 0.955, 95% confidence interval (CI): 0.944-0.966, P<0.001]. Among the 202 lesions, 80.2% (162/202) exhibited severe stenosis on DSA. The accuracy of CTA in detecting severe ICAS was excellent (sensitivity =95.1%, positive predictive value =98.1%). The agreements between DSA and CTA in non-calcified lesions (ICC, 0.960 vs. 0.849) and severe stenosis (ICC, 0.918 vs. 0.841) were higher than those in calcified lesions and moderate stenosis. Conclusions: CTA with semi-automatic analysis demonstrated an excellent agreement with DSA in quantifying ICAS, making it promising to replace DSA for the measurement of absolute stenotic degree in clinical trials.

Carotid artery direct access for intracranial stenting of a stroke patient with an aberrant left common carotid artery and right aorta.

A right aortic arch is present in 0.1% of the population and can occur in isolation or be associated with congenital heart disease.1 Moreover, the most common form of right aortic arch in adults is associated with an aberrant left subclavian artery.1 An aberrant left common carotid artery that originated from the ascending aorta with the right aorta is very rare. In this situation, carotid direct access was considered to avoid access challenge due to a large curve from the ascending aorta to the left common carotid artery.2 3 Here we demonstrate carotid artery direct access for intracranial stenting of a stroke patient with aberrant left common carotid artery and right aorta. Manual compression with a long time under general anesthesia to avoid post-procedural puncture site hematoma is recommended (video 1).neurintsurg;jnis-2023-020535v1/V1F1V1Video 1 Carotid artery direct access.

Residual inflammatory risk predicts long-term outcomes following stenting for symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE: Residual inflammatory risk (RIR) can predict the unfavourable outcomes in patients with minor ischaemic stroke. However, the impact of preprocedural RIR on long-term outcomes in patients with symptomatic intracranial atherosclerotic stenosis (sICAS) who underwent stenting remains understudied. METHODS: This retrospective, single-centre cohort study evaluated consecutive patients with severe sICAS who underwent intracranial stenting. Patients were categorised into four groups based on preprocedural high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C): residual cholesterol inflammatory risk (RCIR, hs-CRP ≥3 mg/L and LDL-C ≥2.6 mmol/L), RIR (hs-CRP ≥3 mg/L and LDL-C <2.6 mmol/L), residual cholesterol risk (RCR, hs-CRP <3 mg/L and LDL-C ≥2.6 mmol/L) and no residual risk (NRR, hs-CRP <3 mg/L and LDL-C <2.6 mmol/L). The long-term clinical outcomes included recurrent ischaemic stroke and death. The long-term imaging outcomes consisted of in-stent restenosis (ISR) and symptomatic ISR (sISR) after stenting. RESULTS: In this study, 952 patients were included, with 751 (78.9%) being male. Forty-six cases were categorised into the RCIR group, 211 into the RIR group, 107 into the RCR group and 588 into the NRR group. Patients with RCIR (adjusted HR 6.163; 95% CI 2.603 to 14.589; p<0.001) and RIR (adjusted HR 2.205; 95% CI 1.294 to 3.757; p=0.004) had higher risks of recurrent ischaemic stroke than those with NRR during the 54 months of median follow-up time. Patients with RCIR (adjusted HR 3.604; 95% CI 1.431 to 9.072; p=0.007) were more likely to occur ISR, and patients in the RIR group showed a significant increase in the risk of sISR (adjusted HR 2.402; 95% CI 1.078 to 5.351; p=0.032) compared with those in the NRR group with a median follow-up time of 11.9 months. CONCLUSIONS: In patients with sICAS, preprocedural RIR may predict long-term recurrent ischaemic stroke, ISR and sISR following intracranial stenting.

Impact of cerebral small vessel disease on symptomatic in-stent restenosis in intracranial atherosclerosis.

OBJECTIVE: Cerebral small vessel disease (CSVD) commonly coexists with intracranial atherosclerotic stenosis (ICAS). In-stent restenosis (ISR) affects the nonprocedural outcome of severe symptomatic ICAS after intracranial stenting. However, only 8%-27% of ISR patients are symptomatic, which highlights the importance of the investigation of risk factors associated with symptomatic ISR (SISR) to improve long-term functional outcome. Whether CSVD is associated with SISR remains unclear. The authors tested the hypothesis that CSVD is associated with SISR in ICAS patients after intracranial stenting. METHODS: This retrospective study enrolled 97 patients who were symptomatic due to severe anterior circulation ICAS treated with intracranial stenting. SISR was evaluated with clinical and vascular imaging follow-up. CSVD subtypes, including white matter hyperintensities (WMHs), enlarged perivascular spaces, and chronic lacunar infarctions, were evaluated. Cox regression analysis was used to compare the incidence of SISR between patients with and without CSVD. RESULTS: Of the enrolled patients, 58.8% had CSVD. The 1- and 2-year ISR rates were 24.7% and 37.1%, respectively. Of the CSVD subtypes, SISR was associated with deep WMHs (DWMHs; HR 5.39, 95% CI 1.02-28.44). DWMH Fazekas scale grades 2 (HR 85.54, 95% CI 2.42-3018.93) and 3 (HR 66.24, 95% CI 1.87-2352.32) were associated with SISR, but DWMH Fazekas grades 0 and 1 were not. The proportions of SISR in patients with DWMH Fazekas grades 0, 1, 2, and 3 were 16.7%, 33.3%, 50%, and 100%, respectively. CONCLUSIONS: Patients with CSVD have a higher risk of SISR than those without CSVD. Of the CSVD subtypes, patients with DWMHs are associated with SISR. The DWMH Fazekas scale score is considered to be a predictor for SISR.

Predictors of hyperperfusion syndrome after stent implantation in symptomatic intracranial atherosclerotic stenosis.

Background: Hyperperfusion syndrome (HPS) is a serious complication after stent implantation in symptomatic intracranial atherosclerotic stenosis (ICAS). This study aims to explore the predictive value of preprocedural computed tomography perfusion (CTP) for HPS after intracranial stenting. Methods: In this retrospective case-control study we collected data from consecutive patients from June 2012 to September 2019 who underwent stent implantation due to severe symptomatic ICAS. Patients who underwent CTP before the procedure were enrolled. CTP was postprocessed using the automated RAPID software to assess the preoperative cerebral perfusion. According to the presence or absence of HPS, the patients were classified into two groups: the HPS group and the non-HPS group. The baseline data, lesion characteristics, and preoperative CTP parameters between the two groups were compared. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal predictor of HPS. Results: Among the 170 eligible patients, 6 patients (3.53%) had HPS, including 3 who presented with intracranial hemorrhages (ICHs), 1 who had dysphoria, 1 who had delirium, and 1 who had a headache. There were no significant differences in baseline and lesion characteristics between the HPS and non-HPS groups. Compared with the non-HPS group, the HPS group had a significantly higher volume of time-to-maximum (Tmax) >4 s (429.5 vs. 93 mL; P=0.006) and Tmax >6 s (200 vs. 0 mL; P=0.003). The optimal volume threshold for maximizing sensitivity in predicting HPS was 65.5 mL with Tmax >4 s [area under the curve (AUC), 0.832; 95% confidence interval (CI): 0.650 to 1.000; P=0.006]. Conclusions: Tmax >4 s volume may be a predictor of HPS after stent implantation in symptomatic ICAS. Further prospective studies should be conducted to confirm our conclusion.

Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma.

The role of brain immune compartments in glioma evolution remains elusive. We profile immune cells in glioma microenvironment and the matched peripheral blood from 11 patients. Glioblastoma exhibits specific infiltration of blood-originated monocytes expressing epidermal growth factor receptor (EGFR) ligands EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (p = 0.019), while co-occurring with mesenchymal subtype (p = 4.7 × 10-7) and marking worse prognosis (p = 0.004 and 0.032 in two cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveal association between elevated TAMo and glioma mesenchymal transformation. Further analyses identify FOSL2 as a TAMo master regulator and demonstrates that FOSL2-EREG/AREG-EGFR signaling axis promotes glioma invasion in vitro. Collectively, we identify TAMo in tumor microenvironment and reveal its driving role in activating EGFR signaling to shape glioma evolution.

Association of periprocedural perfusion non-improvement with recurrent stroke after endovascular treatment for Intracranial Atherosclerotic Stenosis.

Background: Predictors of recurrent stroke after endovascular treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) remain uncertain. Objectives: Among baseline characteristics, lesion features, and cerebral perfusion changes, we try to explore which factors are associated with the risk of recurrent stroke in symptomatic ICAS after endovascular treatment. Design: Consecutive patients with symptomatic ICAS of 70-99% receiving endovascular treatment were enrolled. All patients underwent whole-brain computer tomography perfusion (CTP) within 3 days before and 3 days after the endovascular treatment. Baseline characteristics, lesion features, and cerebral perfusion changes were collected. Methods: Cerebral perfusion changes were evaluated with RAPID software and calculated as preprocedural cerebral blood flow (CBF) < 30%, time to maximum of the residue function (Tmax) > 6 s, and Tmax > 4 s volumes minus postprocedural. Cerebral perfusion changes were divided into periprocedural perfusion improvement (>0 ml) and non-improvement (⩽ 0 ml). Recurrent stroke within 180 days was collected. The Cox proportional hazards analysis analyses were performed to evaluate factors associated with recurrent stroke. Results: From March 2021 to December 2021, 107 patients with symptomatic ICAS were enrolled. Of the 107 enrolled patients, 30 (28.0%) patients underwent balloon angioplasty alone and 77 patients (72.0%) underwent stenting. The perioperative complications occurred in three patients. Among CBF < 30%, Tmax > 6 s, and Tmax > 4 s volumes, Tmax > 4 s volume was available to evaluate cerebral perfusion changes. Periprocedural perfusion improvement was found in 77 patients (72.0%) and non-improvement in 30 patients (28.0%). Nine patients (8.4%) suffered from recurrent stroke in 180-day follow-up. In Cox proportional hazards analysis adjusted for age and sex, perfusion non-improvement was associated with recurrent stroke [hazards ratio (HR): 4.472; 95% CI: 1.069-18.718; p = 0.040]. Conclusion: In patients with symptomatic ICAS treated with endovascular treatment, recurrent stroke may be related to periprocedural cerebral perfusion non-improvement. Registration: http://www.chictr.org.cn. Unique identifier: ChiCTR2100052925.

Collateral Flow in Magnetic Resonance Angiography: Prognostic Value for Vertebrobasilar Stenosis With Stroke Recurrence.

BACKGROUND AND PURPOSE: Intracranial vertebrobasilar atherosclerotic stenosis (IVBAS) is a major cause of posterior circulation stroke. Some patients suffer from stroke recurrence despite receiving medical treatment. This study aimed to determine the prognostic value of a new score for the posterior communicating artery and the P1 segment of the posterior cerebral artery (PCoA-P1) for predicting stroke recurrence in IVBAS. METHODS: We retrospectively enrolled patients with severe IVBAS (70%-99%). According to the number of stroke recurrences, patients were divided into no-recurrence, single-recurrence, and multiple-recurrences groups. We developed a new 5-point grading scale, with the PCoA-P1 score ranging from 0 to 4 based on magnetic resonance angiography, in which primary collaterals were dichotomized into good (2-4 points) and poor (0 or 1 point). Stroke recurrences after the index stroke were recorded. Patients who did not experience stroke recurrence were compared with those who experienced single or multiple stroke recurrences. RESULTS: From January 2012 to December 2019, 176 patients were enrolled, of which 116 (65.9%) had no stroke recurrence, 35 (19.9%) had a single stroke recurrence, and 25 (14.2%) had multiple stroke recurrences. Patients with single stroke recurrence (odds ratio [OR]=4.134, 95% confidence interval [CI]=1.822-9.380, p=0.001) and multiple stroke recurrences (OR=6.894, 95% CI=2.489-19.092, p<0.001) were more likely to have poor primary collaterals than those with no stroke recurrence. CONCLUSIONS: The new PCoA-P1 score appears to provide improve predictions of stroke recurrence in patients with IVBAS.

Machine Learning-Enabled Determination of Diffuseness of Brain Arteriovenous Malformations from Magnetic Resonance Angiography.

The diffuseness of brain arteriovenous malformations (bAVMs) is a significant factor in surgical outcome evaluation and hemorrhagic risk prediction. However, there are still predicaments in identifying diffuseness, such as the judging variety resulting from different experience and difficulties in quantification. The purpose of this study was to develop a machine learning (ML) model to automatically identify the diffuseness of bAVM niduses using three-dimensional (3D) time-of-flight magnetic resonance angiography (TOF-MRA) images. A total of 635 patients with bAVMs who underwent TOF-MRA imaging were enrolled. Three experienced neuroradiologists delineated the bAVM lesions and identified the diffuseness on TOF-MRA images, which were considered the ground-truth reference. The U-Net-based segmentation model was trained to segment lesion areas. Eight mainstream ML models were trained through the radiomic features of segmented lesions to identify diffuseness, based on which an integrated model was built and yielded the best performance. In the test set, the Dice score, F2 score, precision, and recall for the segmentation model were 0.80 [0.72-0.84], 0.80 [0.71-0.86], 0.84 [0.77-0.93], and 0.82 [0.69-0.89], respectively. For the diffuseness identification model, the ensemble-based model was applied with an area under the Receiver-operating characteristic curves (AUC) of 0.93 (95% CI 0.87-0.99) in the training set. The AUC, accuracy, precision, recall, and F1 score for the diffuseness identification model were 0.95, 0.90, 0.81, 0.84, and 0.83, respectively, in the test set. The ML models showed good performance in automatically detecting bAVM lesions and identifying diffuseness. The method may help to judge the diffuseness of bAVMs objectively, quantificationally, and efficiently.

LncRNA PITPNA-AS1 stimulates cell proliferation and suppresses cell apoptosis in glioblastoma via targeting miR-223-3p/EGFR axis and activating PI3K/AKT signaling pathway.

Glioblastoma (GBM) is a kind of malignant primary brain tumor, which is difficult to cure. Continuous researches have underlined that long non-coding RNAs (lncRNAs) get widely involved in the occurrence and progression of tumors, and glioblastoma is included. In this paper, we identified lncRNA PITPNA antisense RNA 1 (PITPNA-AS1) and explored its in-depth regulatory mechanism in glioblastoma cells. Firstly, RT-qPCR examined that PITPNA-AS1 was highly expressed in glioblastoma. Then, PITPNA-AS1 role in glioblastoma was assessed via functional assays. The results demonstrated that depletion of PITPNA-AS1 inhibited the proliferation and promoted the apoptosis of glioblastoma cells. After confirming that PITPNA-AS1 mainly existed in cell cytoplasm, we conducted mechanism assays which disclosed that PITPNA-AS1 sequestered microRNA-223-3p (miR-223-3p) and modulated epidermal growth factor receptor (EGFR) expression, thereby participating in the activation of PI3K/AKT signaling pathway. Eventually, rescue assays validated PITPNA-AS1 sponged miR-223-3p to promote EGFR expression, thus activating PI3K/AKT signaling pathway to accelerate proliferation and inhibit apoptosis of GBM cells. Overall, PITPNA-AS1 played an oncogenic role in glioblastoma which might be developed as a potential biomarker for glioblastoma diagnosis and treatment in the future.[Figure: see text].

Classification of Pituitary Adenomas Invading the Cavernous Sinus Assisted by Three-Dimensional Multimodal Imaging and Its Clinical Application.

Introduction To help diagnose and evaluate the prognosis of pituitary adenoma with cavernous sinus (CS) invasion and guide endonasal endoscopic surgery (EES) assisted by intraoperative navigation (ION) with three-dimensional multimodal imaging (3D-MMI). We propose a classification of CS invasion based on 3D-MMI. Methods We picked some appropriate cases and reconstructed the 3D-MMI and then classified them into 3 grades according to the stereo relationship among ICA, tumor and CS in 3D-MMI. Then, we applied different strategies according to their grade to remove pituitary adenomas that invaded the CS. Results All 38 patients were divided into 3 grades. Tumors compressing the ICA and CS without CS invasion were divided into grade 1. Tumors encasing the ICA and invading the superior-posterior compartment and/or anterior-inferior compartment but without distinct separation of the ICA and CS lateral wall were deemed as grade 2. Tumors encasing the ICA and filling the lateral compartment of the CS that dissociated the lateral wall from the ICA were deemed as grade 3. The 3D-MMI enabled adequate spatial visualization of the ICA, CS and tumors. All patients were operated on under the guidance of ION with 3D-MMI. Conclusion Classification based on 3D-MMI can better demonstrate the relationships among tumor, ICA and CS in a stereo and multi-angle view, which will have significance in guiding the surgical strategy.

Classification of brain arteriovenous malformations located in motor-related areas based on location and anterior choroidal artery feeding.

OBJECTIVE: Surgical management of arteriovenous malformations (AVMs) involving motor cortex or fibre tracts (M-AVMs) is challenging. This study aimed to construct a classification system based on nidus locations and anterior choroidal artery (AChA) feeding to pre-surgically evaluate motor-related and seizure-related outcomes in patients undergoing resection of M-AVMs. METHODS AND MATERIALS: A total of 125 patients who underwent microsurgical resection of M-AVMs were retrospectively reviewed. Four subtypes were identified based on nidus location: (I) nidus involving the premotor area and/or supplementary motor areas; (II) nidus involving the precentral gyrus; (III) nidus involving the corticospinal tract (CST) and superior to the posterior limb of the internal capsule; (IV) nidus involving the CST at or inferior to the level of posterior limb of the internal capsule. In addition, we divided type IV into type IVa and type IVb according to the AChA feeding. Surgical-related motor deficit (MD) evaluations were performed 1 week (short-term) and 6 months (long-term) after surgery. RESULTS: The type I patients exhibited the highest incidence (62.0%) of pre-surgical epilepsy among the four subtypes. Multivariate analysis showed that motor-related area subtypes (p=0.004) and diffuse nidus (p=0.014) were significantly associated with long-term MDs. Long-term MDs were significantly less frequent in type I than in the other types. Type IV patients acquired the highest proportion (four patients, 25.0%) of long-term poor outcomes (mRS >2). Type IVb patients showed a significantly higher incidence of post-surgical MDs than type IVa patients (p=0.041). The MDs of type III or IV patients required more recovery time. Of the 62 patients who had pre-surgical seizures, 90.3% (56/62) controlled their seizures well and reached Engel class I after surgery. CONCLUSIONS: Combining the consideration of location and AChA feeding, the classification for M-AVMs is a useful approach for predicting post-surgical motor function and decision-making.

Machine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors.

Metastatic cancer is associated with poor patient prognosis but its spatiotemporal behavior remains unpredictable at early stage. Here we develop MetaNet, a computational framework that integrates clinical and sequencing data from 32,176 primary and metastatic cancer cases, to assess metastatic risks of primary tumors. MetaNet achieves high accuracy in distinguishing the metastasis from the primary in breast and prostate cancers. From the prediction, we identify Metastasis-Featuring Primary (MFP) tumors, a subset of primary tumors with genomic features enriched in metastasis and demonstrate their higher metastatic risk and shorter disease-free survival. In addition, we identify genomic alterations associated with organ-specific metastases and employ them to stratify patients into various risk groups with propensities toward different metastatic organs. This organotropic stratification method achieves better prognostic value than the standard histological grading system in prostate cancer, especially in the identification of Bone-MFP and Liver-MFP subtypes, with potential in informing organ-specific examinations in follow-ups.

Evaluating the association of preoperative parecoxib with acute pain trajectories after video-assisted thoracoscopic surgery: a single-centre cohort study in Taiwan.

OBJECTIVE: The efficacy of parecoxib as pre-emptive analgesia still remains controversial. This study aimed to investigate how pre-emptive analgesia with parecoxib affected postoperative pain trajectories over time in patients undergoing thoracic surgery. DESIGN: Retrospective cohort study. SETTING: A single medical centre in Taiwan. PARTICIPANTS: We collected 515 patients undergoing video-assisted thoracoscopic surgery at a tertiary medical centre between September 2016 and August 2017. INTERVENTIONS: Pre-emptive parecoxib before surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: Daily numeric rating pain scores in the first postoperative week. RESULTS: A total of 196 (38.1%) of the recruited patients received parecoxib preoperatively. The latent curve analysis revealed that woman, higher body weight and postoperative use of parecoxib were associated with increased baseline level of pain scores over time (p=0.035, 0.005 and 0.048, respectively) but epidural analgesia and preoperative use of parecoxib were inclined to decrease it (both p<0.001). Regarding the decreasing trends of changes in daily pain scores, older age and epidural analgesia tended to steepen the slope (p=0.014 and <0.001, respectively). Preoperative use of parecoxib were also related to decreased frequency of rescue morphine medication (HR=0.4; 95% CI 0.25 to 0.65). CONCLUSIONS: Pre-emptive analgesia with parecoxib was associated with decreased baseline pain scores but had no connection with pain decreasing trends over time. Latent curve analysis provided insights into the dynamic relationships among the analgesic modalities, patient characteristics and postoperative pain trajectories.

High-resolution magnetic resonance vessel wall imaging-guided endovascular recanalization for nonacute intracranial artery occlusion.

OBJECTIVE: On the basis of the characteristics of occluded segments on high-resolution magnetic resonance vessel wall imaging (MR-VWI), the authors evaluated the role of high-resolution MR-VWI-guided endovascular recanalization for patients with symptomatic nonacute intracranial artery occlusion (ICAO). METHODS: Consecutive patients with symptomatic nonacute ICAO that was refractory to aggressive medical treatment were prospectively enrolled and underwent endovascular recanalization. High-resolution MR-VWI was performed before the recanalization intervention. The characteristics of the occluded segments on MR-VWI, including signal intensity, occlusion morphology, occlusion angle, and occlusion length, were evaluated. Technical success was defined as arterial recanalization with modified Thrombolysis in Cerebral Infarction grade 2b or 3 and residual stenosis < 50%. Perioperative complications were recorded. The characteristics of the occluded segments on MR-VWI were compared between the recanalized group and the failure group. RESULTS: Twenty-five patients with symptomatic nonacute ICAO that was refractory to aggressive medical treatment were consecutively enrolled from April 2020 to February 2021. Technical success was achieved in 19 patients (76.0%). One patient (4.0%) had a nondisabling ischemic stroke during the perioperative period. Multivariable logistic analysis showed that successful recanalization of nonacute ICAO was associated with occlusion with residual lumen (OR 0.057, 95% CI 0.004-0.735, p = 0.028) and shorter occlusion length (OR 0.853, 95% CI 0.737-0.989, p = 0.035). CONCLUSIONS: The high-resolution MR-VWI modality could be used to guide endovascular recanalization for nonacute ICAO. Occlusion with residual lumen and shorter occlusion length on high-resolution MR-VWI were identified as predictors of technical success of endovascular recanalization for nonacute ICAO.