Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy.

Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46-72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.

Pediatric tracheostomy: A large single-center experience.

OBJECTIVES: To describe the epidemiology, specifically the indications, complications, and outcomes, of pediatric tracheostomies performed in one tertiary referral unit. METHODS: Single-center retrospective cohort study of pediatric patients undergoing tracheostomy between May 2010 and May 2018 at the Newcastle upon Tyne Hospitals, United Kingdom. RESULTS: One hundred seventy-two pediatric tracheostomies were performed during the study period with a median age of 141 (interquartile range [IQR] 51-484) days. The most common primary indication was long-term ventilation (38.4%, 66 of 172), followed by weaning from ventilation in cardiac patients (22.1%, 38 of 172). Only 5.2% (9 of 172) of our cohort underwent tracheostomy for subglottic stenosis. The vast majority of tracheostomies were performed electively, with just 6.4% (11 of 172) performed as an emergency procedure. Early and late complication rates were 9.8% (15 of 153) and 40.0% (61 of 153), respectively. Tracheostomy decannulation was successful in 44.4% of children (68 of 153). The median duration the tracheostomy was in situ was 397 (IQR 106-708) days. All-cause mortality was 22.1% (38 of 172), with tracheostomy-related mortality at 1.2% (2 of 172). CONCLUSION: We report one of the largest contemporary case series of pediatric tracheostomies. Present-day pediatric tracheostomy is primarily performed as an elective procedure in ventilated children under the age of 1 year. Pediatric tracheostomy should be considered as a long-term intervention in many children. Nevertheless, a large proportion of children are ultimately decannulated. It is important to acknowledge the significant morbidity associated with this intervention and the small-but-present risk of tracheostomy-related mortality. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E375-E380, 2020.