Transcatheter Aortic Valve Replacement for Failed Surgical or Transcatheter Bioprosthetic Valves: A Comprehensive Review.

Transcatheter aortic valve replacement (TAVR) has proven to be a safe, effective, and less invasive approach to aortic valve replacement in patients with aortic stenosis. In patients who underwent prior aortic valve replacement, transcatheter and surgical bioprosthetic valve dysfunction may occur as a result of structural deterioration or nonstructural causes such as prosthesis-patient mismatch (PPM) and paravalvular regurgitation. Valve-in-Valve (ViV) TAVR is a procedure that is being increasingly utilized for the replacement of failed transcatheter or surgical bioprosthetic aortic valves. Data regarding long-term outcomes are limited due to the recency of the procedure's approval, but available data regarding the short- and long-term outcomes of ViV TAVR are promising. Studies have shown a reduction in perioperative and 30-day mortality with ViV TAVR procedures compared to redo surgical repair of failed bioprosthetic aortic valves, but 1-year and 5-year mortality rates are more controversial and lack sufficient data. Despite the reduction in 30-day mortality, PPM and rates of coronary obstruction are higher in ViV TAVR as compared to both redo surgical valve repair and native TAVR procedures. New transcatheter heart valve designs and new procedural techniques have been developed to reduce the risk of PPM and coronary obstruction. Newer generation valves, new procedural techniques, and increased operator experience with ViV TAVR may improve patient outcomes; however, further studies are needed to better understand the safety, efficacy, and durability of ViV TAVR.

Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.

Genetic Alterations Detected in Cell-Free DNA Are Associated With Enzalutamide and Abiraterone Resistance in Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor (AR) gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate AR gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC. METHODS: Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies-enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n = 2)-and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in AR and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS). RESULTS: Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; P = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; P = .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; P = .004). AR ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; P = .020) were associated with a shorter PFS in multivariable models. AR CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; P = .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; P = .026) were associated with a worse OS in multivariable models. CONCLUSION: These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. AR status associations with outcomes were not robust, and additional validation is needed.