RESUMO
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Professional hockey players have a high incidence of lumbar disc herniations (LDH). The purpose of this study was to determine the impact of LDH on the performance and financial earnings of National Hockey League (NHL) players. METHODS: NHL players who sustained a LDH were retrospectively reviewed utilizing an online database and a 2:1 matched control cohort. Player performance and game usage was compared at one- and three-season(s) pre- and post-injury season within the cohorts. Injured and matched players were divided into 3 groups based on the player's adjusted index season salary. RESULTS: A total of 181 players were included, with 62 LDH players matched to 119 healthy controls. Return to play after LDH was 79%. The LDH cohort had fewer seasons played throughout their career compared to the matched group (12.5 ± 4.3 vs 14.2 ± 3.8; P = .031). At 1 season post-index, the LDH cohort had significantly fewer goals per 60 and points per 60 when compared to pre-index. At 3 seasons post-index, the LDH cohort exhibited a significant decline in time-on-ice per game played, goals per 60, and points per 60 compared to pre-index. CONCLUSION: The majority of NHL players who sustained a LDH returned to play (79%) but had shorter careers overall and decreased performance outcomes when compared to matched cohorts at both 1 and 3 seasons post-injury.
RESUMO
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma. Cancer Res; 76(22); 6657-68. ©2016 AACR.
