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     

The practical assessment and management of bladder outflow obstruction

The initial management of bladder outflow obstruction typically related to benign prostatic hyperplasia (BPH) falls to a large extent within the remit of general practice. Referral onwards to secondary care typically arises following the failure to respond to conservative measures or when complications have supervened; the most significant of which is urinary retention. In the hospital setting, anaesthesia, constipation and immobility are the common precipitants. What follows is a practical guide to the management of these situations and provides an overview of the conservative, medical, minimally invasive and surgical treatments available.     

Rifampin alone or with trimethoprim for contacts of children with Haemophilus influenzae type b infections.

We carried out a nonrandomized, unblinded study to compare the efficacy of rifampin alone with that of rifampin in combination with trimethoprim in the eradication of the Haemophilus influenzae type b (HIB) carrier state among contacts of patients with invasive HIB infection. The study population comprised 17 index patients admitted to hospital with severe HIB infections and 233 contacts, 43 of whom had nasopharyngeal colonization with HIB of the same biotype as that of the index patient. Rifampin in a daily dose of 20 mg/kg (maximum 600 mg) for 4 days eradicated the carrier state in 86% of cases, as did the combination of rifampin at the same dosage and trimethoprim in a daily dose of 5 mg/kg (maximum 160 mg) for 4 days.     

The effect of optical design on micromanipulator spot size using CO2 laser irradiation

Objective: The study goal was to compare the laser spot size created using reflective and refractive micromanipulators with a CO₂ laser and to determine the sensitivity of spot size to laser power. Study Design and Setting: A CO₂ laser and operating microscope (400-mm focal length) was coupled to either a reflective (Cassegrain-like) or refractive micromanipulator. Laser spot size was determined by measuring the region of ablation created by laser irradiation of wood (dry tongue depressors), exposed photographic film, and agar gel using optical micrometry. Laser power varied from 0.5 to 20 W with pulse durations of 0.1 and 0.5 second. Results: The reflective micromanipulator demonstrated overall smaller spot sizes for a given laser power and lower incremental change in spot size with increasing power. The reflective design demonstrated less sensitivity to increases in laser power. Conclusions: Micromanipulator optical design can result in significant differences in laser spot size. The reflective device used in this study demonstrated less sensitivity to increasing laser power. (Otolaryngol Head Neck Surg 2002;126:593-597.)