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     

Stress Testing Versus CT Angiography in Patients With Diabetes and Suspected Coronary Artery Disease

Background

The optimal noninvasive test (NIT) for patients with diabetes and stable symptoms of coronary artery disease (CAD) is unknown.

Rescreening of a group at high risk for colorectal neoplasia using immunochemical tests for faecal occult blood

The results of a screening programme for colorectal neoplasia in a high risk group using an immunochemical test for blood has been reported recently. This test is known as the faecal human haemoglobin (FHH) test. This paper reports the results of rescreening this group after an interval of 1-2 years. The FHH test was compared with a paper disc method. All individuals with positive tests were investigated and those with negative tests were offered investigation. The results confirm the value of the FHH test in screening a high risk group: 19 individuals in 1,153 participants were found to have a significant neoplasm (1.6%). The predictive value of the test for a significant neoplasm was 42%. A false negative rate of 2.6% was found, all lesions being benign. It appears to be more reliable than the paper disc method but the differences do not reach statistical significance. The FHH test is recommended for screening the general population over the age of 40 years, with rescreening annually.     

多发性硬化症的治疗时机窗：单克隆抗体治疗的依据

1991—2002年间采用可长期消耗T淋巴细胞的人单克隆抗体(Cam path-1H)治疗58例多发性硬化症(M S)患者,患者的临床症状和炎性替代标记物得到抑制。在M S的复发-缓解(R R)和继发进展(SP)期,Cam path-1H可降低患者的年复发率(分别由2.2降至0.19和由0.7降至0.001,P<0.001)。7年前使     

The St. George's dementia bed investigation study: a comparison of clinical and pathological diagnosis.

Sixty-four elderly patients who had been admitted to the St. George's Hospital Alzheimer's disease evaluation project during 1981-1989 were followed up to postmortem examination. Comparison between clinical diagnoses and neuropathological diagnoses indicated positive predictive values for the antemortem diagnoses of 50-67%. Existing clinical criteria may not be accurate enough to permit firm antemortem diagnosis of older people for either research or clinical purposes.     

Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values.

Regional cerebral blood flow (CBF) was studied with O(15)-water positron emission tomography and anatomic region-of-interest analysis on co-registered magnetic resonance in patients with idiopathic (n = 12) and secondary (n = 5) normal pressure hydrocephalus (NPH). Mean CBF was compared with values obtained from healthy volunteers (n = 12) and with clinical parameters. Mean CBF was significantly decreased in the cerebrum and cerebellum of patients with NPH. The regional analysis demonstrated that CBF was reduced in the basal ganglia and the thalamus but not in white matter regions. The results suggest that the role of the basal ganglia and thalamus in NPH may be more prominent than currently appreciated. The implications for theories regarding the pathogenesis of NPH are discussed.