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     

Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.     

Congenital diaphragmatic defects that present late.

Twenty two patients (age range: 1 month to 11 years) were treated for congenital diaphragmatic defects (excluding hiatus hernia) in the six year period 1983-8. Presenting features were failure to thrive (n = 7), abdominal pain and vomiting (n = 4), chronic respiratory symptoms (n = 3), and inability to wean from ventilatory support (n = 3). The defect was an incidental finding in five patients. Operative repair was performed with no mortality or serious postoperative morbidity. Dramatic improvement occurred in 15 of the 17 symptomatic patients. Awareness of the differential diagnosis should avoid delay in diagnosis or inappropriate treatment. Surgical correction is strongly recommended in all cases.     

Action of calcitonin gene-related peptide upon bovine vascular endothelial and smooth muscle cells grown in isolation and co-culture.

1. Bovine aortic endothelial cells (BAE) and smooth muscle cells (BASM) were grown separately and in co-culture. 2. Calcitonin gene-related peptide (CGRP) caused dose-dependent activation of adenylate cyclase in each cell type when grown in isolation. The concentration of CGRP causing half-maximal activation in BAE and BASM was 200 nM and 310 nM, respectively. 3. In cells grown in co-culture exposure to bradykinin produced dose-dependent elevations in cyclic GMP content which were maximal 1 min after application of the agonist. 4. CGRP (1 nM-1 microM) did not stimulate a rise in cyclic GMP in co-cultures. 5. Displaceable CGRP binding was identified throughout the wall of the bovine aorta. 6. We conclude that CGRP receptors coupled to adenylate cyclase are present on BAE and BASM, but there is no coupling of these receptors to the release of any agent (such as endothelium-derived relaxing factor) that activates guanylate cyclase.     

Digital radiography of subtle pulmonary abnormalities: an ROC study of the effect of pixel size on observer performance

Forty conventional radiographs with examples of mild interstitial infiltrates and subtle pneumothoraces and 40 normal studies of the chest were selected and digitized, with pixel sizes of 1.0, 0.5, 0.2, and 0.1 mm. Observer performance tests were carried out using receiver operating characteristic analysis. Conventional radiographs and digitized images were compared. The results indicate that, in such cases, diagnostic accuracy increases significantly as the pixel size is reduced, at least to the 0.1-mm level. We conclude that, for digital systems using screen-film or similar image receptors, use of a pixel size substantially larger than 0.1 mm may result in some loss of diagnostic accuracy.