Haroutounian, Simon

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.

Summary Patients with obstructive sleep apnoea are at increased risk of adverse postoperative outcomes, such as cardiac and respiratory complications. It has been hypothesised that obstructive sleep apnoea also increases the risk for postoperative delirium and acute postoperative pain. We conducted a retrospective, observational study investigating the relationship of obstructive sleep apnoea with postoperative delirium and acute postoperative pain severity. Patients were classified as being at high risk for obstructive sleep apnoea if they had been diagnosed with this condition, or if they were positive for more than four factors using the ‘ STOP ‐ BANG ’ screening tool. Adjusted logistic regression was used to investigate the association between obstructive sleep apnoea and postoperative delirium, and multivariable linear regression to study the relationship between obstructive sleep apnoea and postoperative pain severity. The incidence of postoperative delirium was 307 in 1441 patients (21.3%; 95% CI 19.2–23.5%). In unadjusted analysis, high risk for obstructive sleep apnoea was associated with delirium, with an odds ratio (95% CI ) of 1.77 (1.22–2.57; p = 0.003). After adjustment for pre‐specified variables, the association was not statistically significant with odds ratio 1.34 (0.80–2.23; p = 0.27). The mean ( SD ) maximum pain (resting or provoked) reported for the entire cohort was 63.8 (27.9) mm on a 0–100 mm visual analogue scale. High risk for obstructive sleep apnoea was not associated with postoperative pain severity (β‐coefficient 2.82; 95% CI , −2.34–7.97; p = 0.28). These findings suggest that obstructive sleep apnoea is unlikely to be a strong risk factor for postoperative delirium or acute postoperative pain severity.