A novel predictor of ischemic complications in the treatment of ruptured middle cerebral artery aneurysms: Neck-branching angle.

Objective: The risk factors of procedural cerebral ischemia (CI) in ruptured middle cerebral artery (MCA) aneurysms are unclear. This study proposed the neck-branching angle (NBA), a simple quantitative indicator of the aneurysm neck and branch vessels, and analyzed its usefulness as a predictor of procedural CI in ruptured MCA aneurysms. Methods: We retrospectively analyzed 128 patients with ruptured saccular MCA aneurysms who underwent surgical or endovascular treatment between January 2014 and June 2021. We defined the NBA as the angle formed by the MCA aneurysm neck and M2 superior or inferior branch vessel line. The superior and inferior NBA were measured on admission via three-dimensional computed tomography angiography on admission. We divided the patients into clipping (106 patients) and coiling (22 patients) groups according to the treatment. Risk factors associated with procedural CI were analyzed in each group. Results: Both groups showed that an enlarged superior NBA was a significant risk factor for procedural CI (clipping, P < 0.0005; coiling group, P = 0.007). The receiver operating characteristic curve showed the closed thresholds of the superior NBA with procedural CI in both groups (clipping group, 128.5°, sensitivity and specificity of 0.667 and 0.848, respectively; coiling group, 130.9°, sensitivity and specificity of 1 and 0.889, respectively). Conclusion: The NBA can estimate the procedural risk of ruptured MCA aneurysms. In addition, an enlarged superior NBA is a risk factor for procedural CI in both clipping and coiling techniques.

ST2825, independent of MyD88, induces reactive oxygen species-dependent apoptosis in multiple myeloma cells.

Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF-κB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-l-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM.

Brain-derived endothelial cells are neuroprotective in a chronic cerebral hypoperfusion mouse model.

Whether organ-specific regeneration is induced by organ-specific endothelial cells (ECs) remains unelucidated. The formation of white matter lesions due to chronic cerebral hypoperfusion causes cognitive decline, depression, motor dysfunction, and even acute ischemic stroke. Vascular ECs are an important target for treating chronic cerebral hypoperfusion. Brain-derived ECs transplanted into a mouse chronic cerebral hypoperfusion model showed excellent angiogenic potential. They were also associated with reducing both white matter lesions and brain dysfunction possibly due to the high expression of neuroprotective humoral factors. The in vitro coculture of brain cells with ECs from several diverse organs suggested the function of brain-derived endothelium is affected within a brain environment due to netrin-1 and Unc 5B systems. We found brain CD157-positive ECs were more proliferative and beneficial in a mouse model of chronic cerebral hypoperfusion than CD157-negative ECs upon inoculation. We propose novel methods to improve the symptoms of chronic cerebral hypoperfusion using CD157-positive ECs.

Gap junction beta-4 accelerates cell cycle progression and metastasis through MET-AKT activation in pancreatic cancer.

Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta-4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G0 /G1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT-2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET-AKT activities. Such data suggest that targeting the GJB4-MET axis could represent a promising new therapeutic strategy for pancreatic cancer.

Detailed Anatomy of Bridging Veins Around the Foramen Magnum: a Multicenter Study Using Three-dimensional Angiography.

BACKGROUND AND PURPOSE: There has been limited literature regarding the bridging veins (BVs) of the medulla oblongata around the foramen magnum (FM). The present study aims to analyze the normal angioarchitecture of the BVs around the FM using slab MIP images of three-dimensional (3D) angiography. METHODS: We collected 3D angiography data of posterior fossa veins and analyzed the BVs around the FM using slab MIP images. We analyzed the course, outlet, and number of BVs around the FM. We also examined the detection rate and mean diameter of each BV. RESULTS: Of 57 patients, 55 patients (96%) had any BV. The median number of BVs was two (range: 0-5). The BVs originate from the perimedullary veins and run anterolaterally to join the anterior condylar vein (ACV), inferior petrosal sinus, sigmoid sinus, or jugular bulb, inferolaterally to join the suboccipital cavernous sinus (SCS), laterally or posterolaterally to join the marginal sinus (MS), and posteriorly to join the MS or occipital sinus. We classified BVs into five subtypes according to the draining location: ACV, jugular foramen (JF), MS, SCS, and cerebellomedullary cistern (CMC). ACV, JF, MS, SCS, and CMC BVs were detected in 11 (19%), 18 (32%), 32 (56%), 20 (35%), and 16 (28%) patients, respectively. The mean diameter of the BVs other than CMC was 0.6 mm, and that of CMC BV was 0.8 mm. CONCLUSION: Using venous data from 3D angiography, we detected FM BVs in most cases, and the BVs were connected in various directions.

Clinical characterization of patients with gBRCA1/2 mutation-positive unresectable pancreatic cancer: a multicenter prospective study.

BACKGROUND: Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan. METHODS & RESULTS: In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0-9.2). CONCLUSIONS: The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies.An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting.

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

LMNA::NTRK1 Fusion-positive Leiomyosarcoma: Discrepancy between DNA-based Comprehensive Genomic Profiling and RNA Sequencing.

A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne® CDx (F1). F1 identified anout-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

Detailed Clinical Characteristics, Interventions, and Long-Term Outcomes of Patients With Gastric Cancer Who Received the Best Supportive Care Without Any Anticancer Treatment.

Background: Due to the lack of studies, the long-term prognoses of unfit patients with gastric cancer (GC) who did not receive any aggressive cancer treatment (best supportive care [BSC] cases) remain unclear, especially for those with potentially curable GC. We conducted this observational study to capture the real-world data of characteristics and outcomes for BSC cases. Method: Consecutive clinical records of patients with GC diagnosed at Steel Memorial Muroran Hospital from January 2017 to December 2021 were analyzed. Result: Of 481 patients diagnosed with GC, 91 (18.9%) were BSC cases. The median overall survival (OS) was 12.4, 8.3, and 2.5 months for clinical stage (cStage) I, II-III, and IV, respectively. Patients with potentially curable GC (cStage I-III) had significantly longer OS than those with incurable disease (cStage IV), with a hazard ratio for death of 0.29 (95% confidence interval: 0.18-0.47). Conclusion: Our report provides useful information for decision-making for unfit patients with GC in daily clinical practice.

Targeting STEAP1 as an anticancer strategy.

Although the six-transmembrane epithelial antigen of prostate 1 (STEAP1) was first identified in advanced prostate cancer, its overexpression is recognized in multiple types of cancer and associated with a poor prognosis. STEAP1 is now drawing attention as a promising therapeutic target because of its tumor specificity and membrane-bound localization. The clinical efficacy of an antibody-drug conjugate targeting STEAP1 in metastatic, castration-resistant, prostate cancer was demonstrated in a phase 1 trial. Furthermore, growing evidence suggests that STEAP1 is an attractive target for immunotherapies such as chimeric antigen receptor-T cell therapy. In this review, we summarize the oncogenic functions of STEAP1 by cancer type. This review also provides new insights into the development of new anticancer strategies targeting STEAP1.

Silicate Microfiber Scaffolds Support the Formation and Expansion of the Cortical Neuronal Layer of Cerebral Organoids With a Sheet-Like Configuration.

Cerebral organoids (COs) are derived from human-induced pluripotent stem cells in vitro and mimic the features of the human fetal brain. The development of COs is largely dependent on "self-organization" mechanisms, in which differentiating cells committed to cortical cells autonomously organize into the cerebral cortex-like tissue. However, extrinsic manipulation of their morphology, including size and thickness, remains challenging. In this study, we discovered that silicate microfiber scaffolds could support the formation of cortical neuronal layers and successfully generated cortical neuronal layers, which are 9 times thicker than conventional COs, in 70 days. These cortical neurons in the silicate microfiber layer were differentiated in a fetal brain-like lamination pattern. While these cellular characteristics such as cortical neurons and neural stem/progenitor cells were like those of conventional COs, the cortical neuronal layers were greatly thickened in sheet-like configuration. Moreover, the cortical neurons in the scaffolds showed spontaneous electrical activity. We concluded that silicate microfiber scaffolds support the formation of the cortical neuronal layers of COs without disturbing self-organization-driven corticogenesis. The extrinsic manipulation of the formation of the cortical neuronal layers of COs may be useful for the research of developmental mechanisms or pathogenesis of the human cerebral cortex, particularly for the development of regenerative therapy and bioengineering.

Pemphigus vulgaris as an immune-related adverse event in recurrent metastatic esophageal squamous cell carcinoma treated with ipilimumab plus nivolumab: a case report and literature review.

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs.

Safety and Efficacy of Prasugrel Administration in Emergent Endovascular Treatment for Intracranial Atherosclerotic Disease.

Objective: Intracranial atherosclerosis disease (ICAD) is one of the most common causes of acute ischemic stroke. In endovascular treatment (EVT) for acute large vessel occlusion stroke-related ICAD, reocclusion of the recanalized artery due to in situ thrombosis is problematic. In this study, the safety and efficacy of prasugrel administration to avoid reocclusion of emergent EVT for ICAD was investigated. Methods: All consecutive emergent EVTs for ICAD between September 2019 and December 2022 were included in this study. The procedures were divided into two groups as receiving periprocedural prasugrel (PSG group) or not (non-PSG group). Target vessel patency on follow-up, postprocedural intracranial hemorrhage (ICH), and clinical outcome were compared between PSG and non-PSG groups. Results: A total of 27 procedures were included in this analysis. Nineteen target vessels were patent on follow-up and eight were non-patent. Fifteen patients received prasugrel (18.75 mg: 11 cases, 11.25 mg: 4 cases), and twelve patients did not receive prasugrel. The target vessel patency rate was better in the PSG group vs. non-PSG group (100% vs. 33.3%, respectively; p = 0.0002). The postprocedural ICH rate was not different between the groups (PSG: 40.0% vs. non-PSG: 25.0%; p = 0.68), and all ICHs were asymptomatic. Good clinical outcome (modified Rankin Scale score of 0 to 3 at discharge) was more frequent in the PSG group than that in the non-PSG group (66.7% vs. 16.7%, respectively; p = 0.019). Conclusion: Prasugrel administration was significantly associated with target vessel patency and good clinical outcome after emergent EVT for ICAD without increasing the symptomatic ICH rate. Prasugrel administration might be safe and effective to avoid reocclusion during and after emergent EVT for ICAD.

Percutaneous Transluminal Angioplasty and Stenting for Progressive Intracranial Carotid Artery Stenosis Secondary to Invasive Sphenoid Sinus Aspergillosis: A Case Report.

We report a case of invasive sphenoid sinus aspergillosis with progressive internal carotid artery (ICA) stenosis and contralateral carotid occlusion that was successfully treated with percutaneous transluminal angioplasty and stenting (PTAS). A 70-year-old man presented with right-sided visual disturbance, ptosis, and left hemiparesis. Magnetic resonance imaging of the head revealed a space-occupying lesion within the sphenoid sinus with infiltration of the bilateral cavernous sinuses, right ICA occlusion, and multiple watershed cerebral infarcts involving the right cerebral hemisphere. The patient was diagnosed with invasive sinus aspergillosis based on transnasal biopsy findings. Despite intensive antifungal therapy using voriconazole, rapidly progressive aspergillosis led to a new stenotic lesion in the left ICA, which increased the risk of bilateral cerebral hypoperfusion. We performed successful PTAS to prevent critical ischemic events. Finally, aspergillosis was controlled with voriconazole treatment, and the patient was discharged. He showed a favorable outcome, with a patent left ICA observed at a 3-year follow-up. PTAS may be feasible in patients with ICA stenosis and invasive sinus aspergillosis.

[Liver metastasis from alpha-fetoprotein-producing gastric cancer 27 years postoperation:a case report].

A 75-year-old man with a history of distal gastrectomy for gastric cancer at 48 years of age underwent abdominal computed tomography, which revealed a left hepatic lobe tumor alongside direct gastric invasion. His blood test results revealed significant increase in serum alpha-fetoprotein (AFP) levels (32240.3ng/mL). A gastroscopy revealed that the histopathological findings of the biopsy specimens of the gastric invasion area were identical to those observed in the surgical specimens of gastric cancer, which was diagnosed 27 years earlier. The evaluation of the biopsy and surgical specimens revealed AFP positivity, which confirmed the diagnosis of the late recurrence of AFP-positive gastric cancer. Herein, we presented a rare clinical case of this malignancy. Additionally, a close, long-term postoperative follow-up is warranted in patients with AFP-producing gastric cancer.

Multiple Myeloma with Hyperammonemia Treated with Novel Agents: A Case Series of Three Patients.

Multiple myeloma (MM) is a cancer characterized by the expansion of plasma cells in the bone marrow. Survival times of patients with MM have increased due to the development of novel therapeutic agents. We herein highlight three MM cases that had a poor prognosis despite treatment with novel therapeutic agents. Of note, all patients presented with hyperammonemia that led to a consciousness disorder. The outcome for patients with MM showing high levels of serum ammonia continues to be poor, even with the use of novel therapies. For such patients showing a consciousness disorder, hyperammonemia should be considered as a possible cause.

Achievement of a durable response with eribulin for relapsed cardiac metastasis of uterine leiomyosarcoma after surgery: a case report and literature review.

BACKGROUND: Uterine leiomyosarcoma (U-LMS) is an aggressive malignancy linked to a high risk of metastasis to distant major organs. Although cardiac metastasis of U-LMS is extremely rare, it is often associated with life-threatening conditions, leading to dismal prognosis. Currently, there is no established therapy for patients with unresectable/relapsed cardiac metastasis of U-LMS. In this article, we report a case of locally relapsed cardiac metastasis of U-LMS, which occurred 3 years after surgical resection, successfully treated with eribulin. CASE DESCRIPTION: A 69-year-old female with cardiac symptoms (e.g., dyspnea, tachycardia, and easy fatigability) was sequentially treated with doxorubicin plus ifosfamide, gemcitabine plus docetaxel, and pazopanib. However, cardiac metastasis continued to grow despite treatment. Hence, eribulin was administered as fourth-line therapy. Exceptionally, eribulin markedly improved cardiac symptoms, and the patient achieved a durable response for 17 months without the development of severe adverse events. Moreover, the volume of the metastatic cardiac tumor was decreased by 70%. Despite the poor prognosis of this condition, the patient survived for 8 years from the diagnosis of cardiac metastasis due to surgery and the continuous administration of chemotherapies. CONCLUSIONS: Eribulin may be an effective and accessible treatment option for cardiac metastasis of U-LMS in patients with life-threatening conditions for whom surgery is not indicated. Additionally, the expression levels of phosphorylated AKT (p-AKT) may be a predictive biomarker for the sensitivity of patients with U-LMS to treatment with eribulin.

Sustained lower bilirubin-binding affinity of albumin in extremely preterm infants.

BACKGROUND: Elevated albumin-free or unbound bilirubin (UB) levels beyond the first week of life have been associated with the development of bilirubin encephalopathy in preterm infants. However, the mechanism(s) that induces this prolonged unbound bilirubinemia has remained unknown. We hypothesized that it may due to a sustained lower bilirubin-binding affinity of albumin in extremely premature infants. METHODS: Twenty-two very preterm infants born at 28-31 weeks' gestational age (GA) (VPT Group) and 21 extremely preterm infants born at 22-27 weeks' GA (EPT Group) were retrospectively studied. On days 14, 21, and 28, bilirubin-binding affinity of albumin was assessed by calculating of the UB/total bilirubin ratio, bilirubin-albumin molar ratio (BAMR), and binding affinity (Ka). RESULTS: On days 14, 21, and 28, significantly higher UB/total bilirubin ratios were found in the EPT than in the VPT Group. Although BAMRs were comparable, significantly lower Ka values on days 14, 21, and 28 were observed in the EPT than those in the VPT Group (56.1 vs. 70.9 L/µmol, p < 0.001; 55.2 vs. 74.7 L/µmol, p < 0.001; 53.0 vs. 86.5 L/µmol, p < 0.001, respectively). CONCLUSIONS: EPT infants have a sustained lower bilirubin-binding affinity of albumin beyond the first week of life. IMPACT: Bilirubin encephalopathy is still reported in extremely preterm (EPT) infants. EPT infants often have prolonged unbound bilirubinemia beyond the first week of life. Sustained lower bilirubin-binding affinity of albumin, regardless of the bilirubin-albumin molar ratio (BAMR), is observed in EPT infants. BAMRs should not be used as a surrogate marker of unbound bilirubinemia, especially in EPT infants at a later postnatal period.

Association of Gut Microbiome with Early Brain Injury After Subarachnoid Hemorrhage: an Experimental Study.

The occurrence of early brain injury (EBI) following subarachnoid hemorrhage (SAH) is crucial in the prognosis of SAH; however, no effective treatment for EBI has been developed. Gut microbiome (GM) composition influences the outcome of various diseases, including ischemic stroke. Here, we evaluated whether prior GM alteration could prevent EBI following SAH. We altered the GM of 7-week-old male rats by administering antibiotic-containing water for 2 weeks and performing fecal microbiome transplantation after antibiotic induction. Composition of the GM was profiled using 16S rRNA. We induced SAH by injecting blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as neurological score, brain water content, Evans blue extravasation, and neuronal injury. Additionally, we studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR, and flow cytometry. EBI was significantly averted by alterations in GM using antibiotics. The altered GM significantly prevented neutrophil infiltration into the brain among inflammatory cells, and this anti-inflammatory effect was observed immediately following SAH onset. The altered GM also prevented neutrophil extracellular trap formation in the brain and blood, indicating the systemic protective effect. The cause of the protective effect was attributed to a significant decrease in aged neutrophils (CXCR4high CD62Llow) by the altered GM. These protective effects against EBI disappeared when the altered GM was recolonized with normal flora. Our findings demonstrated that EBI following SAH is associated with GM, which regulated neutrophil infiltration.

Effect of the RNF213 p.R4810K Variant on the Progression of Intracranial Artery Stenosis: A 15-Year Follow-up Study.

Background and Objectives: Intracranial artery stenosis is the predominant etiology of ischemic stroke in the Asian population. Furthermore, the presence of the RNF213 p.R4810K variant, which is a susceptibility gene for moyamoya disease, increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Accordingly, we hypothesized that this genetic variant may affect the long-term outcome of intracranial artery stenosis in the East Asian population. We thus aimed to examine the effect of this variant on the long-term progression and prognosis of intracranial artery stenosis. Methods: Using a prospective database, we identified adult patients with intracranial artery stenosis who underwent periodic MRI examinations for >5 years. We evaluated stenosis progression using a validated visual grading system. We excluded patients diagnosed with moyamoya disease at the time of initial MRI. Genotyping of RNF213 p.R4810K was performed at the end of the follow-up period. Results: Among 52 eligible patients, 22 (42%) were carriers of the RNF213 p.R4810K variant. The median follow-up duration was 10.3 years. During the follow-up period, progression of intracranial artery stenosis was observed in 64% variant carriers and 27% noncarriers. There was a significant association of the variant with time to progression of intracranial artery stenosis (hazard ratio [HR] 3.31, 95% CI 1.38-7.90, p = 0.007), and time to the composite endpoint of symptomatic stroke and transient ischemic attack (HR 3.70, 95% CI 1.15-11.86, p = 0.028), but not to symptomatic stroke alone (HR 2.18, 95% CI 0.62-7.74, p = 0.23). Two variant carriers with progression were newly diagnosed with moyamoya disease. Discussion: Our findings indicated that the RNF213 p.R4810K variant increases the risk of intracranial artery stenosis progression.