Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway.

BACKGROUND: Genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway occur in 82% of patients with acral melanoma (AM), which is the predominant subtype of melanoma in China. We aimed to evaluate the anti-tumour activity of palbociclib, a selective CDK4/6 inhibitor, in patients with advanced AM with CDK4 pathway gene aberrations. METHODS: In this phase II trial, patients with advanced AM with CDK4 or/and CCND1 gain or/and CDKN2A loss were treated with oral palbociclib (125 mg) on days 1-21 of a 28-day cycle. The primary end-point was overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Whole-exome sequencing and multiplex immunohistochemistry of the available formalin-fixed, paraffin-embedded samples of nine patients were analysed to explore the predictive biomarkers of palbociclib response. RESULTS: Fifteen patients were enrolled. Three (20.0%) patients achieved tumour shrinkage at 8 weeks, including one with confirmed partial response. At data cut-off date, treatment was ongoing for one patient. The median PFS was 2.2 mo (range: 1.5-13.3 mo; 95% confidence interval [CI]: 1.9-2.5), and the median OS was 9.5 mo (range: 2.6-14.1 mo, 95% CI: 5.7-13.4). Eight patients died due to disease progression. The most common TRAEs were leukopenia (87%; Grade III/IV, 27%), neutropenia (80%; grade III/IV, 27%), and fatigue (53%; grade III/IV, 7%). Significant JAK2 deletions and SH2B3 amplifications were observed in patients who did not achieve any clinical benefit (CB) with palbociclib treatment. MCM7 amplification or protein expression level was found to be associated with CB. CONCLUSIONS: Palbociclib monotherapy demonstrated preliminary efficacy and an acceptable safety profile in advanced AM patients with CDK4 pathway aberrations. Patients with amplification or high protein levels of MCM7 were more prone to benefit from palbociclib. The JAK-STAT pathway might play a role in the mechanism of action of palbociclib in AM. TRIAL REGISTRATION NUMBER: NCT03454919. THE DATE OF REGISTRATION: March 6, 2018.

Microstructure and Mechanical Properties of Al-12Si Alloys Fabricated by Ultrasonic-Assisted Laser Metal Deposition.

This paper presents a method of ultrasonic-assisted laser metal deposition of Al-12Si alloy. The effects of the ultrasonic power and remelting treatment on the development of porosity, microstructural evolution, and tensile properties of the deposits were investigated. The results suggested that a combination of an ultrasonic vibration and remelting treatment could prolong the existence of the molten pool and the effect of the ultrasound. Therefore, the density of the samples increased from 95.4% to 99.1% compared to the as-prepared samples. The ultrasonic action in the molten pool could not only increase the density of the samples but also refine the grains and improve the tensile properties of the samples. Metallographic observation showed that the maximum size of the primary α-Al dendrites were refined from 277.5 µm to 87.5 µm. The ultimate tensile strength and elongation of the remelting treatment samples with ultrasonic vibration were ~227 ± 3 MPa and 12.2% ± 1.4%, respectively, which were approximately 1.17 and 1.53 times those of the as-prepared samples, respectively. According to the tensile properties and fracture analysis, the density increase dominated the improvement of the mechanical properties.