A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

Gelsolin knockdown confers radiosensitivity to glioblastoma cells.

OBJECTIVE: Radiotherapy (RT) is a cornerstone of the glioblastoma (GBM) treatment. However, the resistance of tumour cells to radiation results in early recurrence. The mechanisms underlying GBM radioresistance remain unclear. Screening for differentially expressed genes (DEGs) related to radiation might be a potential solution to this problem. METHOD: RT-associated DEGs were screened based on the RNA sequencing of 15 paired primary and recurrent GBMs. The mRNA and protein expression of candidate genes were validated in RNA sequencing of The Chinese Genome Atlas (CGGA) dataset and 18 cases of GBM samples. The relationship between the candidate gene and radiation was confirmed in irradiated GBM cells. The association of candidate gene with clinical characteristics and survival was investigated in the CGGA and TCGA dataset. Biological function and pathway analysis were explored by gene ontology analysis. The association of the candidate gene with radiosensitivity was verified using cell counting Kit-8, comet, and colony formation assays in vitro and subcutaneous tumour xenograft experiments in vivo. RESULTS: Gelsolin (GSN) was selected for further study. GSN expression was significant elevated in recurrent GBM and up-regulated in irradiated GBM cell lines. High expression of GSN was enriched in malignant phenotype of glioma. Moreover, high expression of GSN was associated with poor prognosis. Further investigation demonstrated that GSN-knockdown (GSN-KD) combined with RT significantly inhibited cell proliferation and enhanced radiosensitivity in vivo and in vitro. Mechanistically, GSN-KD could lead to more serious DNA damage and promotes apoptosis after RT. CONCLUSION: Radiation induced up-regulated of GSN. GSN-KD could enhance the radiosensitivity of GBM.

Timing of microsurgical resection for ruptured brain arteriovenous malformations: a propensity score-matched analysis using prospective single-center registry data.

OBJECTIVE: The optimal microsurgical timing in ruptured brain arteriovenous malformations (AVMs) is not well understood and is surrounded by controversy. This study aimed to elucidate the impacts of microsurgical resection timing on clinical outcomes. METHODS: The authors retrieved and reviewed the records on all ruptured AVMs treated at their institution and registered in a nationwide multicenter prospective collaboration registry between August 2011 and August 2021. Patients were dichotomized into an early resection group (≤ 30 days from the last hemorrhagic stroke) and a delayed resection group (> 30 days after the last hemorrhagic stroke). Propensity score-matched analysis was used to compare long-term outcomes. The primary outcome was neurological status as assessed using the modified Rankin Scale (mRS). The secondary outcomes were complete obliteration rate, postoperative seizure, and postoperative hemorrhage. RESULTS: Of the 3649 consecutive AVMs treated at the authors' institution, a total of 558 ruptured AVMs were microsurgically resected and had long-term follow-up. After propensity score matching, 390 ruptured AVMs (195 pairs) were included in the comparison of outcomes. The mean (± standard deviation) clinical follow-up duration was 4.93 ± 2.94 years in the early resection group and 5.61 ± 2.56 years in the delayed resection group. Finally, as regards the distribution of mRS scores, short-term neurological outcomes were better in the delayed resection group (risk difference [RD] 0.3%, 95% CI -0.1% to 0.6%, p = 0.010), whereas long-term neurological outcomes were similar between the two groups (RD 0.0%, 95% CI -0.2% to 0.2%, p = 0.906). Long-term favorable neurological outcomes (early vs delayed: 90.8% vs 90.3%, p > 0.999; RD 0.5%, 95% CI -5.8% to 6.9%; RR 1.01, 95% CI 0.94-1.07) and long-term disability (9.2% vs 9.7%, p > 0.999; RD -0.5%, 95% CI -6.9% to 5.8%; RR 0.95, 95% CI 0.51-1.75) were also similar between these groups. In terms of secondary outcomes, postoperative seizure (early vs delayed: 8.7% vs 5.6%, p = 0.239; RD 3.1%, 95% CI -2.6% to 8.8%; RR 1.55, 95% CI 0.74-3.22), postoperative hemorrhage (1.0% vs 1.0%, p > 0.999; RD 0.0%, 95% CI -3.1% to 3.1%; RR 1.00, 95% CI 0.14-7.04), and hospitalization time (16.4 ± 8.5 vs 19.1 ± 7.9 days, p = 0.793) were similar between the two groups, whereas early resection had a lower complete obliteration rate (91.3% vs 99.0%, p = 0.001; RD -7.7%, 95% CI -12.9% to 3.1%; RR 0.92, 95% CI 0.88-0.97). CONCLUSIONS: Early and delayed resection of ruptured AVMs had similar long-term neurological outcomes. Delayed resection can lead to a higher complete obliteration rate, although the risk of rerupture during the resection waiting period should be vigilantly monitored.

IDH-mutant grade 4 astrocytoma: a comparison integrating the clinical, pathological, and survival features between primary and secondary patients.

OBJECTIVE: IDH-mutant grade 4 astrocytomas (AIDHmut/G4) are divided into primary de novo (pAIDHmut/G4) and secondary with a history of prior lower-grade gliomas (LGGs; sAIDHmut/G4). The mutational spectrum and DNA methylation patterns are homogeneous within de novo pAIDHmut/G4 and evolved sAIDHmut/G4, but the two groups have different diagnoses, management, and outcomes. This study sought to systematically compare the clinical, pathological, and survival characteristics between them. METHODS: Of the 871 grade 4 astrocytomas with data for IDH mutation, 698 (80.1%) were primary and 173 (19.9%) were secondary. Of the 698 primary tumors, 103 (14.8%) were pAIDHmut/G4, and of the 173 secondary tumors, 108 (62.4%) were sAIDHmut/G4. Clinical, pathological, and survival features were compared between pAIDHmut/G4 and sAIDHmut/G4. Multivariate analyses were performed to identify prognostic factors. RESULTS: Patients with sAIDHmut/G4 had significantly shorter median overall survival (OS; 11.8 vs 34.2 months, hazard ratio [HR] 2.69, 95% confidence interval [CI] 1.367-5.306, p = 0.004) and progression-free survival (PFS; 8.5 vs 24.3 months, HR 2.83, 95% CI 1.532-5.235, p = 0.001) than patients with pAIDHmut/G4. In patients with sAIDHmut/G4, resection status and chemotherapy were independent prognostic factors for OS and PFS; in patients with pAIDHmut/G4, LGG component, resection status, and O6-methylguanine DNA methyltransferase promoter methylation were independent prognostic factors. The therapeutic strategies of LGGs did not influence survival of patients with sAIDHmut/G4, but patients who had not received radiotherapy or chemotherapy when they were diagnosed with LGGs were found to benefit from radiotherapy or chemotherapy when they progressed to sAIDHmut/G4. CONCLUSIONS: The different clinical characteristics, survival, and risk factors between sAIDHmut/G4 and pAIDHmut/G4 provide a reference to guide treatment decisions in AIDHmut/G4.

Comparison of conservative management, microsurgery only, and microsurgery with preoperative embolization for unruptured arteriovenous malformations: A propensity score weighted prospective cohort study.

AIMS: To compare the efficacy and deficiency of conservative management (CM), microsurgery (MS) only, and microsurgery with preoperative embolization (E + MS) for unruptured arteriovenous malformations (AVMs). METHODS: We prospectively included unruptured AVMs undergoing CM, MS, and E + MS from our institution between August 2011 and August 2021. The primary outcomes were long-term neurofunctional outcomes and hemorrhagic stroke and death. In addition to the comparisons among CM, MS, and E + MS, E + MS was divided into single-staged hybrid and multi-staged E + MS for further analysis. Stabilized inverse probability of treatment weighting using propensity scores was applied to control for confounders by treatment indication across the three groups. RESULTS: Of 3758 consecutive AVMs admitted, 718 patients were included finally (266 CM, 364 MS, and 88 E + MS). The median follow-up duration was 5.4 years. Compared with CM, interventions (MS and E + MS) were associated with neurological deterioration. MS could lower the risk of hemorrhagic stroke and death. Multi-staged E + MS was associated with neurological deterioration and higher hemorrhagic risks compared with MS, but the hybrid E + MS operation significantly reduced the hemorrhage risk. CONCLUSION: In this study, unruptured AVMs receiving CM would expect better neurofunctional outcomes but bear higher risks of hemorrhage than MS or E + MS. The single-staged hybrid E + MS might be promising in reducing inter-procedural and subsequent hemorrhage.

Recurrence of Cerebral Arteriovenous Malformation Following Complete Obliteration Through Endovascular Embolization.

Arteriovenous malformation (AVM) recurrence after embolization was rarely reported. This study aimed to explore the potential risk factors of recurrence in angiographically obliterated AVMs treated with endovascular embolization. This study reviewed AVMs treated with embolization only in a prospective multicenter registry from August 2011 to December 2021, and ultimately included 92 AVMs who had achieved angiographic obliteration. Recurrence was assessed by follow-up digital subtraction angiography (DSA) or magnetic resonance imaging (MRI). Hazard ratios (HRs) with 95% confidence intervals were calculated using Cox proportional hazards regression models. Nineteen AVMs exhibited recurrence on follow-up imaging. The recurrence rates after complete obliteration at 6 months, 1 year, and 2 years were 4.35%, 9.78%, and 13.0%, respectively. Multivariate Cox regression analysis identified diffuse nidus (HR 3.208, 95% CI 1.030-9.997, p=0.044) as an independent risk factor for recurrence. Kaplan-Meier analysis confirmed a higher cumulative risk of recurrence with diffuse nidus (log-rank, p=0.016). Further, in the exploratory analysis of the effect of embolization timing after AVM rupture on recurrence after the complete obliteration, embolization within 7 days of the hemorrhage was found as an independent risk factor (HR 4.797, 95% CI 1.379-16.689, p=0.014). Kaplan-Meier analysis confirmed that embolization within 7 days of the hemorrhage was associated with a higher cumulative risk of recurrence in ruptured AVMs (log-rank, p<0.0001). This study highlights the significance of diffuse nidus as an independent risk factor for recurrence after complete embolization of AVMs. In addition, we identified a potential recurrent risk associated with early embolization in ruptured AVMs.

Re-rupture in ruptured brain arteriovenous malformations: a retrospective cohort study based on a nationwide multicenter prospective registry.

BACKGROUND: This study aimed to investigate the natural history of re-rupture in ruptured brain arteriovenous malformations (AVMs) and to provide comprehensive insights into its associated factors and prevention. METHODS: This study included 1712 eligible ruptured AVMs from a nationwide multicenter prospective collaboration registry between August 2011 and September 2021. The natural rupture risk before intervention and the annual rupture risk after intervention were both assessed. Cox proportional hazard regression models and Kaplan-Meier survival curves were used to explore independent factors associated with AVM re-rupture. The correlation between these factors and AVM re-rupture was verified in multiple independent cohorts, and the prevention effect of intervention timing and intervention strategies on AVM re-rupture was further analyzed. RESULTS: The annual re-rupture risk in ruptured AVMs was 7.6%, and the cumulative re-rupture risk in the first 1, 3, 5, and 10 years following the initial rupture were 10%, 25%, 37.5%, and 50%, respectively. Cox proportional hazard regression analysis confirmed adult patients, ventricular system involvement, and any deep venous drainage as independent factors associated with AVM re-rupture. The intervention was found to significantly reduce the risk of AVM re-rupture (annual rupture risk 11.34% vs 1.70%, p<0.001), especially in those who underwent surgical resection (annual rupture risk 0.13%). CONCLUSIONS: The risk of re-rupture in ruptured AVMs is high. Adult patients, ventricular system involvement, and any deep venous drainage are independent risk factors for re-rupture. Applying the results universally to all ruptured AVM cases may be biased. Intervention could effectively reduce the risk of re-rupture.

Bevacizumab reduces peritumoral brain edema in lung cancer brain metastases after radiotherapy.

BACKGROUND: The aim of this study was to investigate the efficacy of bevacizumab (Bev) in reducing peritumoral brain edema (PTBE) after stereotactic radiotherapy (SRT) for lung cancer brain metastases. METHODS: A retrospective analysis was conducted on 44 patients with lung cancer brain metastases (70 lesions) who were admitted to our oncology and Gamma Knife center from January 2020 to May 2022. All patients received intracranial SRT and had PTBE. Based on treatment with Bev, patients were categorized as SRT + Bev and SRT groups. Follow-up head magnetic resonance imaging was performed to calculate PTBE and tumor volume changes. The edema index (EI) was used to assess the severity of PTBE. Additionally, the extent of tumor reduction and intracranial progression-free survival (PFS) were compared between the two groups. RESULTS: The SRT + Bev group showed a statistically significant difference in EI values before and after radiotherapy (p = 0.0115), with lower values observed after treatment, but there was no difference in the SRT group (p = 0.4008). There was a difference in the distribution of EI grades in the SRT + Bev group (p = 0.0186), with an increased proportion of patients at grades 1-2 after radiotherapy, while there was no difference in the SRT group (p > 0.9999). Both groups demonstrated a significant reduction in tumor volume after radiotherapy (p < 0.05), but there was no difference in tumor volume changes between the two groups (p = 0.4089). There was no difference in intracranial PFS between the two groups (p = 0.1541). CONCLUSION: Bevacizumab significantly reduces the severity of PTBE after radiotherapy for lung cancer. However, its impact on tumor volume reduction and intracranial PFS does not reach statistical significance.

Comparison of Long-Term Outcomes in Ruptured Diffuse Brain Arteriovenous Malformations Between Interventional Therapy and Conservative Management.

Brain arteriovenous malformations (AVMs) with a diffuse nidus structure present a therapeutic challenge due to their complexity and elevated risk of hemorrhagic events. This study examines the long-term effectiveness of interventional therapy versus conservative management in reducing hemorrhagic stroke or death in patients with ruptured diffuse AVMs. The analysis was conducted based on a multi-institutional database in China. Patients were divided into two groups: conservative management and interventional therapy. Using propensity score matching, patients were compared for the primary outcome of hemorrhagic stroke or death and the secondary outcomes of disability and neurofunctional decline. Out of 4286 consecutive AVMs in the registry, 901 patients were eligible. After matching, 70 pairs of patients remained with a median follow-up of 4.0 years. The conservative management group showed a trend toward higher rates of the primary outcome compared to the interventional group (4.15 vs. 1.87 per 100 patient-years, P = 0.090). While not statistically significant, intervention reduced the risk of hemorrhagic stroke or death by 55% (HR, 0.45 [95% CI 0.18-1.14], P = 0.094). No significant differences were observed in secondary outcomes of disability (OR, 0.89 [95% CI 0.35-2.26], P = 0.813) and neurofunctional decline (OR, 0.65 [95% CI 0.26 -1.63], P = 0.355). Subgroup analysis revealed particular benefits in interventional therapy for AVMs with a supplemented S-M grade of II-VI (HR, 0.10 [95% CI 0.01-0.79], P = 0.029). This study suggests a trend toward lower long-term hemorrhagic risks with intervention when compared to conservative management in ruptured diffuse AVMs, especially within supplemented S-M grade II-VI subgroups. No evidence indicated that interventional approaches worsen neurofunctional outcomes.

Long-term outcomes of microsurgery and stereotactic radiosurgery as the first-line treatment for arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data.

BACKGROUND: This study aimed to compare the risk and benefit profile of microsurgery (MS) and stereotactic radiosurgery (SRS) as the first-line treatment for unruptured and ruptured arteriovenous malformations (AVMs). MATERIALS AND METHODS: The authors included AVMs underwent MS or SRS as the first-line treatment from a nationwide prospective multicenter registry in mainland China. The authors used propensity score-matched methods to balance baseline characteristics between the MS and SRS groups. The primary outcomes were long-term hemorrhagic stroke or death, and the secondary outcomes were long-term obliteration and neurological outcomes. Subgroup analyses and sensitivity analyses with different study designs were performed to confirm the stability of our findings. RESULTS: Of the 4286 consecutive AVMs in the registry from August 2011 to December 2021; 1604 patients were eligible. After matching, 244 unruptured and 442 ruptured AVMs remained for the final analysis. The mean follow-up duration was 7.0 years in the unruptured group and 6.1 years in the ruptured group. In the comparison of primary outcomes, SRS was associated with a higher risk of hemorrhagic stroke or death both in the unruptured and ruptured AVMs (unruptured: hazard ratio 4.06, 95% CI: 1.15-14.41; ruptured: hazard ratio 4.19, 95% CI: 1.58-11.15). In terms of the secondary outcomes, SRS was also observed to have a significant disadvantage in long-term obliteration [unruptured: odds ratio (OR) 0.01, 95% CI: 0.00-0.04; ruptured: OR 0.09, 95% CI: 0.05-0.15]. However, it should be noted that SRS may have advantages in preventing neurofunctional decline (unruptured: OR 0.56, 95% CI: 0.27-1.14; ruptured: OR 0.41, 95% CI: 0.23-0.76). The results of subgroup analyses and sensitivity analyses were consistent in trend but with slightly varied powers. CONCLUSIONS: This clinical practice-based real-world study comprehensively compared MS and SRS for AVMs with long-term outcomes. MS is more effective in preventing future hemorrhage or death and achieving obliteration, while the risk of neurofunctional decline should not be ignored.

Expression of TMEM59L associated with radiosensitive in glioblastoma.

Radiotherapy is one of the cornerstone of the glioblastoma treatment paradigm. However, the resistance of tumor cells to radiation results in poor survival. The mechanism of radioresistance has not been fully elucidated. This study aimed to screen the differential expressed genes related with radiosensitivity. The differentially expressed genes were screened based on RNA sequencing in 15 pairs of primary and recurrent glioblastoma that have undergone radiotherapy. Candidate genes were validated in 226 primary and 134 recurrent glioblastoma (GBM) obtained from the Chinese Glioma Genome Atlas (CGGA) database. RNA and protein expression were verified by Quantitative Real-time PCR (qPCR) and western blot in irradiated GBM cell lines. The candidate gene was investigated to explore the relationship between mRNA levels and clinical characteristics in the CGGA and The Cancer Genome Atlas dataset. Kaplan-Meier survival analysis and Cox regression analysis were used for survival analysis. Gene ontology and KEGG pathway analysis were used for bioinformatics analysis. Four genes (TMEM59L, Gelsolin, ZBTB7A and ATX) were screened. TMEM59L expression was significantly elevated in recurrent glioblastoma and lower in normal brain tissue. We selected TMEM59L as the target gene for further study. The increasing of TMEM59L expression induced by radiation was confirmed by mRNA and western blot in irradiated GBM cell. Further investigation revealed that high expression of TMEM59L was enriched in IDH mutant and MGMT methylated gliomas and associated with a better prognosis. Gene ontology and KEGG pathway analysis revealed that TMEM59L was closely related to the DNA damage repair and oxidative stress respond process. We speculated that the high expression of TMEM59L might enhance radiotherapy sensitivity by increasing ROS-induced DNA damage and inhibiting DNA damage repair process.

Association of the combined stereotactic radiosurgery and embolization strategy and long-term outcomes in brain arteriovenous malformations with a volume ≤10 mL: a nationwide multicenter observational prospective cohort study.

BACKGROUND: To compare the long-term outcomes of stereotactic radiosurgery (SRS) with or without prior embolization in brain arteriovenous malformations (AVMs) (volume ≤10 mL) for which SRS is indicated. METHODS: Patients were recruited from a nationwide multicenter prospective collaboration registry (the MATCH study) between August 2011 and August 2021, and categorized into combined embolization and SRS (E+SRS) and SRS alone cohorts. We performed propensity score-matched survival analysis to compare the long-term risk of non-fatal hemorrhagic stroke and death (primary outcomes). The long-term obliteration rate, favorable neurological outcomes, seizure, worsened mRS score, radiation-induced changes, and embolization complications were also evaluated (secondary outcomes). Hazard ratios (HRs) were calculated using Cox proportional hazards models. RESULTS: After study exclusions and propensity score matching, 486 patients (243 pairs) were included. The median (IQR) follow-up duration for the primary outcomes was 5.7 (3.1-8.2) years. Overall, E+SRS and SRS alone were similar in preventing long-term non-fatal hemorrhagic stroke and death (0.68 vs 0.45 per 100 patient-years; HR=1.46 (95% CI 0.56 to 3.84)), as well as in facilitating AVM obliteration (10.02 vs 9.48 per 100 patient-years; HR=1.10 (95% CI 0.87 to 1.38)). However, the E+SRS strategy was significantly inferior to the SRS alone strategy in terms of neurological deterioration (worsened mRS score: 16.0% vs 9.1%; HR=2.00 (95% CI 1.18 to 3.38)). CONCLUSIONS: In this observational prospective cohort study, the combined strategy of E+SRS does not show substantial advantages over SRS alone. The findings do not support pre-SRS embolization for AVMs with a volume ≤10 mL.

Association of embolization with long-term outcomes in brain arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data.

BACKGROUND: Brain arteriovenous malformations (AVMs) account for 25% of hemorrhagic strokes in young adults. Although embolization has been widely performed as a stand-alone procedure to cure brain AVM, it is undermined whether patients benefit from this treatment. This study aimed to compare the long-term outcome of hemorrhagic stroke or death in patients with either conservative management or stand-alone embolization for AVM. METHODS: The study population was derived from a nationwide multicenter prospective collaboration registry (the MATCH registry) between August 2011 and August 2021. The propensity score-matched survival analysis was performed in the overall and stratified AVM cases (unruptured and ruptured), respectively, to compare the long-term outcome of hemorrhagic stroke or death, and neurological status. The efficacy of distinct embolization strategies was also evaluated. Hazard ratios (HRs) with 95% CI were calculated using Fine-Gray competing risk models. RESULTS: Of the 3682 consecutive AVMs, 906 underwent either conservative management or embolization as the stand-alone management strategy. After propensity score matching, a total of 622 (311 pairs) patients constituted an overall cohort. The unruptured and ruptured subgroups were composed of 288 cases (144 pairs) and 252 cases (126 pairs), respectively. In the overall cohort, embolization did not prevent long-term hemorrhagic stroke or death compared with conservative management [2.07 vs. 1.57 per 100 patient-years; HR, 1.28 (95% CI, 0.81-2.04)]. Similar results were maintained in both unruptured AVMs [1.97 vs. 0.93 per 100 patient-years; HR, 2.09 (95% CI, 0.99-4.41)] and ruptured AVMs [2.36 vs. 2.57 per 100 patient-years; HR, 0.76 (95% CI, 0.39-1.48)]. Stratified analysis showed that the target embolization might be beneficial for unruptured AVMs [HR, 0.42 (95% CI, 0.08-2.29)], while the curative embolization improved the outcome of ruptured AVMs [HR, 0.29 (95% CI, 0.10-0.87)]. The long-term neurological status was similar between these two strategies. CONCLUSIONS: This prospective cohort study did not support a substantial superiority of embolization over conservative management for AVMs in preventing long-term hemorrhagic stroke or death.

Development and Validation of a Scoring System for Hemorrhage Risk in Brain Arteriovenous Malformations.

Importance: The dilemma between natural rupture risk and adverse outcomes of intervention is of major concern for patients with unruptured arteriovenous malformations (AVMs). The existing risk score for AVM rupture includes factors that are controversial and lacks prospective validation. Objective: To develop and robustly validate a reliable scoring system to predict the rupture risk of AVMs. Design, Setting, and Participants: This prognostic study developed a prediction model derived from a single-center cohort (derivation cohort) and validated in a multicenter external cohort (multicenter external validation cohort) and a cohort of patients receiving conservative treatment management (conservative treatment validation cohort). Patients were recruited from a nationwide multicenter prospective collaboration registry in China. A total of 4135 patients were enrolled in the registry between August 1, 2011, and September 1, 2021. Of those, 3962 patients were included in the study (3585 in the derivation cohort and 377 in the multicenter external validation cohort); 1028 patients from the derivation cohort who had time-to-event data and prerupture imaging results were included in the conservative treatment validation cohort. Data were analyzed from March 10 to June 21, 2022. Main Outcomes and Measures: A scoring system was developed based on risk factors identified from a literature review and a robust selection process. Patients were stratified into different risk groups based on scores to calculate hemorrhage-free probability in future years, and Kaplan-Meier curves were plotted to visualize risk stratification. Receiver operating characteristic curves were used to assess the discrimination of models. Univariable analyses (logistic regression analysis for descriptive data and Cox regression analysis for survival data) were used to compare baseline information and assess bias. Results: Among 3962 patients (2311 men [58.3%]; median [IQR] age, 26.1 [14.6-35.5] years), 3585 patients (2100 men [58.6%]; median [IQR] age, 25.9 [14.6-35.0] years) were included in the derivation cohort, and 377 patients (211 men [56.0%]; median [IQR] age, 26.4 [14.5-39.2] years) were included in the multicenter external validation cohort. Thirty-six hemorrhages occurred over a median (IQR) follow-up of 4.2 (0.3-6.0) years among 1028 patients in the conservative treatment validation cohort. Four risk factors were used to develop the scoring system: ventricular system involvement, venous aneurysm, deep location, and exclusively deep drainage (VALE). The VALE scoring system performed well in all 3 cohorts, with areas under the receiver operating characteristic curve of 0.77 (95% CI, 0.75-0.78) in the derivation cohort, 0.85 (95% CI, 0.81-0.89) in the multicenter external validation cohort, and 0.73 (95% CI, 0.65-0.81) in the conservative treatment validation cohort. The 10-year hemorrhage-free rate was 95.5% (95% CI, 87.1%-100%) in the low-risk group, 92.8% (95% CI, 88.8%-97.0%) in the moderate-risk group, and 75.8% (95% CI, 65.1%-88.3%) in the high-risk group; the model discrimination was significant when comparing these rates between the high-risk group and the low- and moderate-risk groups (P < .001 for both comparisons). Conclusions and Relevance: In this prognostic study, the VALE scoring system was developed to distinguish rupture risk among patients with AVMs. The stratification of unruptured AVMs may enable patients with low risk of rupture to avoid unnecessary interventions. These findings suggest that the scoring system is a reliable and applicable tool that can be used to facilitate patient and physician decision-making and reduce unnecessary interventions or unexpected AVM ruptures.

Multimodality treatment for brain arteriovenous malformation in Mainland China: design, rationale, and baseline patient characteristics of a nationwide multicenter prospective registry.

BACKGROUND: Brain arteriovenous malformation (AVM) is an important cause of hemorrhagic stroke in young adults, which can lead to severe neurological impairment. The registry of Multimodality treatment for brain ArTeriovenous malformation in mainland CHina (MATCH) is a national prospective registry to identify the natural history of AVMs in Asian population; to investigate traditional and emerging hemorrhagic predictors; and to explore the superiority of the multidisciplinary assessment in improving the long-term outcomes.  METHODS: Consecutive AVM patients will be enrolled from 52 participating hospitals in mainland China. Baseline demographic, clinical and imaging data will be collected prospectively. Conservation, microsurgery, embolization, stereotactic radiosurgery (SRS), and multimodal strategies are all included in this study. Patients will be divided into experimental and control group according to whether the treatment protocols are formulated by multidisciplinary team. Neurofunctional status, subsequent hemorrhage, seizure, and novel neurofunctional deficit will be queried at 3 months, annually (1 and 2 years), 3 years, and 10 years follow-up. RESULTS: Between August 2011 and April 2021, 3241 AVMs were enrolled in 11 participating sites. Among them, 59.0% were male with an average age of 28.4 ± 14.6 years, 61.2% had rupture history and 2268 hemorrhagic events occurred before admission. The median Spetzler-Martin grade and Lawton-Young grade was 3 and 5, respectively. Microsurgery is the dominant strategy (35.7%), with a similar proportion of embolization, SRS, and a combination of both (12.7%; 14.8%; 11.8%; respectively). Among them, 15.43% underwent multidisciplinary assessment and received standardized treatment. At the most recent follow-up, 7.8% were lost and the median follow-up duration was 5.6 years. CONCLUSIONS: The MATCH study is a large-sample nationwide prospective registry to investigate multimodality management strategy for AVMs. Data from this registry may also provide the opportunity for individualized risk assessment and the development of optimal individual management strategies. TRIAL REGISTRATION: ClinicalTrials.gov Registry ( NCT04572568 ).

Assessment of gamma knife radiosurgery for unruptured cerebral arterioveneus malformations based on multi-parameter radiomics of MRI.

OBJECTIVE: The treatment of Gamma knife radiosurgery (GKS) for unruptured Arteriovenous Malformations (AVM) remains controversial. A safe, effective and non-invasive method to predict outcome seems attractive for GKS. The purpose of this study was to develop and validate a MRI based multi-parameter radiomics model predicting the outcome of GKS for unruptured AVM. METHODS: Eighty-eight unruptured AVM patients who initial underwent GKS between January 2011 and December 2016 in our hospital were included in this retrospective study. Patients were divided into two groups named as favourable and unfavourable outcome, according to the clinical outcome. Favourable outcome was defined as obliteration without post-SRS hemorrhage or permanent radiation-induced changes (RIC). Multivariate logistic regression analysis was used to select appropriate clinical features and construct a clinical predicting model. In terms of radiomic model, manually segmentation and radiomics extracted were performed on each AVM lesions. Finally, 1684 radiomics features were extracted and Recursive Feature Elimination (RFE) method combined with Random forest classifier were used for feature selection and model construction. The performance of the radiomics model was evaluated by the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, the favourable group was further divided into early and late respond subgroup according to the time of obliteration evaluated by 2 years. The selected features were further compared according the respond time. RESULTS: The median duration of neuroimaging follow-up was 65 months, 56 patients showed favourable outcome and 17 patients were observed obliteration within 2 years. The radiomics model constructed by 12 selected features achieved significant higher AUC of 0.88 (95% confidence interval 0.87-0.90) than traditional scoring system for predicting AVM outcome. Two selected radiomics features named "Dependence Variance" and "firstorder-Skewness" were found significant difference between the patients with early or late-respond. CONCLUSIONS: The results suggest that the radiomics features could be successfully used for the pretreatment prediction of outcome for GKS in unruptured AVMs, which is helpful for decision-making process on unruptured AVM patients.

A Machine Learning Model Predicts the Outcome of SRS for Residual Arteriovenous Malformations after Partial Embolization: A Real-World Clinical Obstacle.

OBJECTIVE: To propose a machine learning (ML) model predicting the favorable outcome of stereotactic radiosurgery (SRS) for residual brain arteriovenous malformation (bAVM) after partial embolization. METHODS: One hundred and thirty bAVM patients who underwent partial embolization followed by SRS were reviewed retrospectively. Patients were split at random split into training datasets (n = 100) and testing datasets (n = 30). Radiomics and dosimetric features were extracted from pre-SRS treatment images. Feature selection was performed to select appropriate radiomics and dosimetric features. Three ML algorithms were applied to construct models using selected features respectively. A total of 9 models were trained to predict favorable outcomes (obliteration without complication) of bAVMs. The efficacy of these models was evaluated on the testing dataset using mean accuracy (ACC) and area under the receiver operating characteristic curve (AUC). RESULTS: The obliteration rate of this cohort was 70.77% (92 of 130) with a mean follow-up of 43.8 months (range, 12-108 months). Favorable outcomes were achieved in 89 patients (68.46%). Four radiomics features and 7 dosimetric features were selected for ML model construction. The dosimetric support vector machines (SVM) model showed the best performance on the training dataset, with an ACC of 0.74 and AUC of 0.78. The dosimetric SVM model also showed the best performance on the testing dataset, with an ACC of 0.83 and AUC of 0.77. CONCLUSIONS: Dosimetric features are good predictors of prognosis for patients with partially embolized bAVM followed by SRS therapy. The use of ML models is an innovative method for predicting favorable outcomes of partially embolized bAVM followed by SRS therapy.

The role of Gamma Knife radiosurgery in the management of skull base chordoma.

Objective: Chordoma is a slow-growing and locally aggressive cancer, which arises from the remnants of the primitive notochord. The first line treatment for the skull base chordoma is neurosurgery. Gamma Knife radiosurgery (GKS) is often be chosen especially in the setting of residual or recurrent chordomas. The purpose of this study is to evaluate the prognosis of patients with skull base chordoma who underwent GKS. Methods: The present study was a retrospective analysis of 53 patients with skull base chordomas who underwent GKS. Univariate Cox and Kaplan-Meier survival analysis were performed to analyze the relationship between the tumor control time and the clinical characteristics. Results: The 1-, 2-, 3-, and 5-year progression free survival (PFS) rates were 87, 71, 51, and 18%, respectively. After performing the univariate analysis, the clinical characteristics were not found to be significantly associated with the time of PFS; however, surgical history, peripheral dose, and tumor volume did have tendencies to predict the prognosis. Conclusion: GKS provided a safe and relatively effective treatment for residual or recurrent chordomas after surgical resection. A higher tumor control rate depends on two approaches, an appropriate dose of radiation for the tumor and the accurate identification of the tumor margins.

Stereotactic Radiosurgery With vs. Without Prior Embolization for Brain Arteriovenous Malformations: A Propensity Score Matching Analysis.

Objective: Whether partial embolization could facilitate the post-stereotactic radiosurgery (SRS) obliteration for brain arteriovenous malformations (bAVMs) remains controversial. We performed this study to compare the outcomes of SRS with and without prior embolization for bAVMs. Methods: We retrospectively reviewed the Beijing Tiantan AVMs prospective registration research database from September 2011 to October 2014. Patients were categorized into two groups, combined upfront embolization and SRS (Em+SRS group) and SRS alone (SRS group), and we performed a propensity score matching analysis based on pre-embolization baseline characteristics; the matched groups each comprised 76 patients. Results: The obliteration rate was similar between SRS and Em+SRS (44.7 vs. 31.6%; OR, 1.754; 95% CI, 0.905-3.401; p = 0.096). However, the SRS group was superior to the Em+SRS group in terms of cumulative obliteration rate at a follow-up of 5 years (HR,1.778; 95% CI, 1.017-3.110; p = 0.033). The secondary outcomes, including functional state, post-SRS hemorrhage, all-cause mortality, and edema or cyst formation were similar between the matched cohorts. In the ruptured subgroup, the SRS group could achieve higher obliteration rate than Em+SRS group (56.5 vs. 31.9%; OR, 2.773; 95% CI, 1.190-6.464; p = 0.018). The cumulative obliteration rate at 5 years was also higher in the SRS group (64.5 vs. 41.3%; HR, 2.012; 95% CI, 1.037-3.903; p = 0.038), and the secondary outcomes were also similar between the matched cohorts. Conclusion: Although there was no significant difference in the overall obliteration rate between the two strategies, this study suggested that pre-SRS embolization may have a negative effect on post-SRS obliteration. Furthermore, the obliteration rates of the SRS only strategy was significantly higher than that of the Em+SRS strategy in the ruptured cohort, while no such phenomenon was found in the unruptured cohort.