Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

缺血性卒中或短暂性脑缺血发作患者的卒中预防指南

这份新声明旨在为缺血性卒中或短暂性脑缺血发作存活者的缺血性卒中预防提供全面和及时的循证推荐，循证推荐包括对危险因素的控制，动脉粥样硬化性疾病的干预措施，心源性栓塞的抗栓治疗以及非心源性卒中抗血小板药的应用。另外，还为其他多种特殊情况下复发性卒中的预防提供了推荐、包括动脉夹层分离、卵圆孔未闭、高同型半胱氨酸血症、高凝状态、镰状细胞病、脑静脉窦血栓形成、女性卒中（特别是与妊娠和绝经后激素替代治疗相关卒中），脑出血后肮凝药的应用，以及该指南在高危人群中执行和应用的特殊措施。     

Comorbidities of migraine: a user-friendly overview

Comorbidity of migraine is important from a number of different perspectives. Co-occurrence of different diseases may complicate diagnosis as a high degree of symptomatic overlap may occur among conditions associated with migraine. Furthermore, comorbidity has also important implications for treatment. The commonest comorbidities of migraine are represented by psychiatric disorders, epilepsy, tremor, stroke, and cardiovascular abnormalities.     

A randomized controlled trial of electromagnetic therapy in the primary care management of venous leg ulceration

OBJECTIVE: The aim was to establish the potential efficacy, tolerabilityand side-effect profile of electromagnetic therapy as an adjunctto conventional dressings in the treatment of venous leg ulcers. METHOD: A prospective, randomized, double blind controlled clinicaltrial was carried out in a dedicated leg ulcer clinic basedin one urban general practice. Nineteen patients with leg ulcersof confirmed venous aetiology were assessed. The main outcomemeasures were rate and scale of venous leg ulcer healing, changesin patient-reported pain levels, quality of life, degree ofmobility, side effect profile and acceptability to patientsand staff. RESULTS: Sixty-eight per cent of patients attending this dedicated clinicachieved improvements in the size of their ulcer (4, 21%, healedfully) and in reduced pain levels (P < 0.05) during the trial,despite the chronicity of ulcer histories. Patients treatedwith electromagnetic therapy at 800 Hz were found at day 50to have significantly greater healing (P < 0.05) and paincontrol (P < 0.05) than placebo therapy or treatment with600 Hz. All patients reported improved mobility at the end ofthe study. The electromagnetic therapy was well tolerated bypatients, with no differences between groups in reporting adverseevents, and proved acceptable to staff. CONCLUSION: Despite the small numbers in this pilot study, electromagnetictherapy provided significant gains in the healing of venousleg ulcers and reduction in pain. Keywords. Electromagnetic therapy, RCT, leg ulcers, primary care.