O-013 The SMART registry: final results on the utility of the penumbra SMART COIL system for treatment of intracranial aneurysms and malformations

IntroductionThe Penumbra SMART COIL® System includes a novel generation of embolic coils comprising complex and WAVE shape properties with varying levels of softness to promote dense packing and durable long-term occlusion. We present the final analysis of 997 patients at 68 U.S./Canada sites with up to 1-yr follow-up in the SMART registry to assess the utility of the SMART COIL System in the treatment of intracranial aneurysms and other malformations.Materials and MethodsThe SMART registry is a prospective, multi-center registry assessing the embolization of neurovascular lesions using the Penumbra SMART COIL System. Procedures must employ ≥75% of SMART, PC400, or POD coils to meet inclusion criteria. SMART registry endpoints included retreatment rates through 1-yr (±6-mo) follow-up, procedural device-related serious adverse events (SAE), and the ability to achieve adequate occlusion at immediate post-procedure.ResultsThis analysis of 997 patients (72.1% female; mean age 59.6±13.0 yr) included cerebral aneurysms (91.0%, 907/997); arteriovenous malformations (1.1%); fistulae (4.1%); and other lesions (3.8%). Aneurysms, of which 31.8% were ruptured, were small (≤10 mm) in 85.3% (774/907) of patients, large (>10 mm to 25 mm) in 14.4% (131/907), and giant (>25 mm) in 0.2% (2/907); 63.5% (555/874) of patients had wide-neck aneurysms (dome-to-neck ratio <2 or neck width ≥4 mm).For all lesions, median coil deployment time, defined as the time from the first coil deployed until the last coil detached, was 16.0 min (IQR 8.0–32.0), and median time of fluoroscopic exposure was 37.0 min (IQR 24.0–56.0). Stent-assisted coiling was performed in 5.7% of patients, and balloon-assisted coiling was performed in 18.7% of patients. Median packing density (calculated for aneurysms only) was 29.1% [IQR 21.0–38.8].For aneurysms, Raymond Occlusion Class (RROC) I and II was achieved in 79.7% (719/902) of cases at immediate post-procedure and in 90.1% (643/714) at 1-yr follow-up, with a recanalization rate of 12.8% (91/710) and a retreatment rate of 7.1% (52/733). In multivariate models, a large or giant aneurysm size (odds ratio [OR]=2.45, p=0.0030), balloon-assisted coiling (OR=1.84, p=0.0195), ruptured aneurysm status (OR=3.91, p<0.0001), and post-procedural RROC III (OR=1.91, p=0.0180), were predictors of incomplete occlusion (RROC III) at 1-yr follow-up. Large or giant aneurysms (OR=2.05, p=0.0426), smoking (OR=0.5, p=0.0186), and balloon-assisted coiling (OR=2.21, p=0.0111) were also predictive of retreatment through 1-yr follow-up.For non-aneurysm lesions, complete angiographic occlusion was achieved in 85.2% (23/27) of lesions post-procedure, with a recanalization rate of 6.1% (3/49) and a retreatment rate of 1.9% (1/53) at 1-yr follow-up.Overall, procedural device-related serious adverse events (SAE) were observed in 2.6% (26/997) of subjects.ConclusionThe final results of the SMART Registry, a prospective registry with 997 subjects, demonstrate that the SMART COIL System achieves safe and adequate embolization in a wide variety of neurovascular lesions with low retreatment rates over 1 yr. Large aneurysm size and balloon-assisted coiling were predictive of incomplete occlusion at 1-yr and retreatment through 1-yr follow-up.Disclosures A. Spiotta: None. M. Park: None. R. Bellon: None. B. Bohnstedt: None. C. Schirmer: None. R. DeLeacy: None. D. Fiorella: None. B. Woodward: None. B. Baxter: None. S. Kale: None. O. Zaidat: None. P. Sunenshine: None. A. Yoo: None. M. Kabbani: None. K. Liu: None. R. Starke: None. A. Reeves: None. K. Snyder: None. T. Sivapatham: None. T. Dumont: None

Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling

Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAFV600E, the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAFV600E-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAFV600E-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.Oncogene advance online publication, 17 August 2015; doi:10.1038/onc.2015.282

The SMART Registry: Long-Term Results on the Utility of the Penumbra SMART COIL System for Treatment of Intracranial Aneurysms and Other Malformations

Introduction: Penumbra SMART COIL® (SMART) System is a novel generation embolic coil with varying stiffness. The study purpose was to report real-world usage of the SMART System in patients with intracranial aneurysms (ICA) and non-aneurysm vascular lesions. Materials and Methods: The SMART Registry is a post-market, prospective, multicenter registry requiring ≥75% Penumbra Coils, including SMART, PC400, and/or POD coils. The primary efficacy endpoint was retreatment rate at 1-year and the primary safety endpoint was the procedural device-related serious adverse event rate. Results: Between June 2016 and August 2018, 995 patients (mean age 59.6 years, 72.1% female) were enrolled at 68 sites in the U.S. and Canada. Target lesions were intracranial aneurysms in 91.0% of patients; 63.5% were wide-neck and 31.8% were ruptured. Adjunctive devices were used in 55.2% of patients. Mean packing density was 32.3%. Procedural device-related serious adverse events occurred in 2.6% of patients. The rate of immediate post-procedure adequate occlusion was 97.1% in aneurysms and the rate of complete occlusion was 85.2% in non-aneurysms. At 1-year, the retreatment rate was 6.8%, Raymond Roy Occlusion Classification (RROC) I or II was 90.0% for aneurysms, and Modified Rankin Scale (mRS) 0-2 was achieved in 83.1% of all patients. Predictors of 1-year for RROC III or retreatment (incomplete occlusion) were rupture status ( P < 0.0001), balloon-assisted coiling ( P = 0.0354), aneurysm size ( P = 0.0071), and RROC III immediate post-procedure ( P = 0.0086) in a model that also included bifurcation aneurysm ( P = 0.7788). Predictors of aneurysm retreatment at 1-year was rupture status ( P < 0.0001). Conclusions: Lesions treated with SMART System coils achieved low long-term retreatment rates. Clinical Trial Registration: https://www.clinicaltrials.gov/ , identifier NCT02729740

助成研究報告

Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAFV600E, the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAFV600E-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAFV600E-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.Oncogene advance online publication, 17 August 2015; doi:10.1038/onc.2015.282