The Early Impact of the IDEA Collaboration Results: How the Results Changed Prescribing Practice.

Background: Traditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined. Methods: In an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer. Results: The survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease. Conclusion: This survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.

Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.