No clinical difference between TiN-coated versus uncoated cementless CoCrMo mobile-bearing total knee arthroplasty; 10-year follow-up of a randomized controlled trial

Purpose: Improvement of biomechanical properties of cobalt–chromium–molybdenum (CoCrMo) implant surface and reduction of adhesive wear is achieved by titanium–nitride (TiN) coating in vitro. Less pain, higher postoperative outcome scores and a lower revision rate after TKA with a TiN-coated CoCrMo TKA compared with uncoated CoCrMo TKA after 10-year follow-up was hypothesized. Methods: In a double-blinded RCT, 101 patients received a cementless mobile-bearing CoCrMo TKA, either TiN-coated or uncoated. The primary outcome measure was the visual analogue scale (VAS) score for pain and secondary outcome measures were the Knee Society Score (KSS), Oxford Knee Score (OKS), revision rate and adverse events. Patients were assessed at 6 weeks, 6 months, 1 year, 5 years and 10 years, postoperatively. Results: 68 patients (67%) were available for 10-year follow-up. No difference was found in any of the assessed outcome measures with a mean decrease in VAS score (31.6 ± 22.9) and a mean increase in OKS (10.9 ± 8.4), KSS (29.3 ± 31.4), KSSK (26.4 ± 18.2) and KSSF (4.1 ± 22.9). Overall revision rate was 7% (coated 6% vs uncoated 8%) without additional revision procedures between 5 and 10-year follow-up. Conclusions: The in vitro potential benefits of TiN coating did not result in better clinical outcome when compared to an uncoated cementless TKA. Pain, functional outcome and revision rates were comparable after 10-year follow-up. TiN-coated cementless TKA provides comparable good long-term results, similar to uncoated cementless CoCrMo TKA. Level of evidence: Level 1, Therapeutic Study Netherlands Trial Register: NL2887/NTR3033

Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors

Abstract Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor clinical prognosis. Inhibitors of transcriptional CDKs are currently under thorough investigation for application in the treatment of multiple cancer types, including breast cancer. These studies have raised interest in combining these inhibitors, including CDK12/13 inhibitor THZ531, with a variety of other anti-cancer agents. However, the full scope of these potential synergistic interactions of transcriptional CDK inhibitors with kinase inhibitors has not been systematically investigated. Moreover, the mechanisms behind these previously described synergistic interactions remain largely elusive. Methods Kinase inhibitor combination screenings were performed to identify kinase inhibitors that synergize with CDK7 inhibitor THZ1 and CDK12/13 inhibitor THZ531 in TNBC cell lines. CRISPR-Cas9 knockout screening and transcriptomic evaluation of resistant versus sensitive cell lines were performed to identify genes critical for THZ531 resistance. RNA sequencing analysis after treatment with individual and combined synergistic treatments was performed to gain further insights into the mechanism of this synergy. Kinase inhibitor screening in combination with visualization of ABCG2-substrate pheophorbide A was used to identify kinase inhibitors that inhibit ABCG2. Multiple transcriptional CDK inhibitors were evaluated to extend the significance of the found mechanism to other transcriptional CDK inhibitors. Results We show that a very high number of tyrosine kinase inhibitors synergize with the CDK12/13 inhibitor THZ531. Yet, we identified the multidrug transporter ABCG2 as key determinant of THZ531 resistance in TNBC cells. Mechanistically, we demonstrate that most synergistic kinase inhibitors block ABCG2 function, thereby sensitizing cells to transcriptional CDK inhibitors, including THZ531. Accordingly, these kinase inhibitors potentiate the effects of THZ531, disrupting gene expression and increasing intronic polyadenylation. Conclusion Overall, this study demonstrates the critical role of ABCG2 in limiting the efficacy of transcriptional CDK inhibitors and identifies multiple kinase inhibitors that disrupt ABCG2 transporter function and thereby synergize with these CDK inhibitors. These findings therefore further facilitate the development of new (combination) therapies targeting transcriptional CDKs and highlight the importance of evaluating the role of ABC transporters in synergistic drug–drug interactions in general