Coil embolization for ruptured and unruptured very small intracranial aneurysms: A retrospective review of a 10-year single-center experience.

Because of the risk of intraoperative rupture and technical difficulties, coil embolization of very small aneurysms (VSIAs) with a diameter of ≤3 mm is challenging. Herein, we reviewed our treatment strategies and outcomes in performing coil embolization for VSIAs compared to those for larger sized intracranial aneurysms (IAs) with 4 to 4.5 mm. We retrospectively reviewed the data on ruptured and unruptured VSIAs and larger-sized IAs treated with coiling from January 2012 to June 2021. Saccular IAs treated with coil embolization and followed up for at least 6 months with imaging studies were included in the study. Fifty-eight VSIAs (27 subarachnoid hemorrhages [SAH group] and 31 unruptured hemorrhages [URA group]) were identified. The wide-necked VSIAs were significantly more common in the URA group (90.3% vs 63.0%, P = .013). Procedural complications occurred in 8 cases (13.8%): intra-procedural rupture (n = 3), coil prolapse (n = 3), and thromboembolic events (n = 2). Complications were more frequent in the SAH group (P = .020). SAH was an independent risk factor for procedural complications (odds ratio, 11.293 [95% confidence interval: 1.173-108.684], P = .036), and the outcomes were affected by SAH presentation (P = .007) and poor clinical status of SAH (P = .001). When compared with larger IAs (n = 57), there were no significant differences in treatment outcomes, procedural complications, and clinical outcomes. VSIAs ≤ 3 mm in diameter were successfully treated with coil embolization, with reasonable procedure-related complications and treatment outcomes. The safety and efficacy of coil embolization for VSIAs were comparable to those of 4 to 4.5 mm sized IAs in this single-center cohort.

Downregulation of androgen receptors by NaAsO2 via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

BACKGROUND: Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO2 on AR signaling in LNCaP and 22Rv1 CRPC cells. METHODS: We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: NaAsO2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO2 on AR stabilization. NaAsO2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. CONCLUSIONS: Here, we show that NaAsO2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO2 could be a novel therapeutics for prostate cancer.

Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration-resistant prostate cancer.

BACKGROUND: PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co-administration of inhibitors of both pathways, GSK2126458 as a dual PI3K/mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase anti-tumor efficacy. METHODS: PC3, DU145, LNCaP, and CRPC patient-derived cells were used to assess apoptosis upon exposure to the drug combination. The human DU145 and PC3 tumor xenograft mouse model was employed to evaluate in vivo efficacy. CellTiter Glo® luminescent assay, annexin V-FITC apoptosis detection, cell cycle analysis, Western blotting and immunohistochemistry were conducted. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: The combination of GSK2126458 and AZD6244 inhibited the growth of DU145 and PC3 prostate cancer cells in vitro and in vivo. GSK2126458 decreased phospho-AKT while increasing phospho-ERK and AZD6244 decreased phospho-ERK efficiently while increasing phospho-AKT. The combination of GSK2126458 and AZD6244 decreased both phospho-AKT and phospho-ERK effectively in vitro and in vivo. The combination treatment synergistically induced annexin V-positive cells, sub-G1 cells, and cleavage of caspase-9, caspase-3 and poly-ADP ribose polymerase (PARP) in DU145 cells in vitro. Moreover, the combination decreased the level of Ki-67, and increased TUNEL-positive cells and cleaved caspase-3 in DU145 xenograft tumors implanted in mice. In addition, this combination treatment inhibited both the PI3K and MEK pathway primary in cultures from CRPC patients harboring PTEN loss, leading to synergistic anti-tumor effect. CONCLUSIONS: The combination of GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways simultaneously and is an effective strategy for the treatment of CRPCs.