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     

Curcumin,Quercetin, Catechins and Metabolic Diseases: The Role of Gut Microbiota

Polyphenols (PPs) are the naturally occurring bioactive components in fruits and vegetables, and they are the most abundant antioxidant in the human diet. Studies are suggesting that ingestion of PPs might be helpful to ameliorate metabolic syndromes that may contribute in the prevention of several chronic disorders like diabetes, obesity, hypertension, and colon cancer. PPs have structural diversity which impacts their bioavailability as they accumulate in the large intestine and are extensively metabolized through gut microbiota (GM). Intestinal microbiota transforms PPs into their metabolites to make them bioactive. Interestingly, not only GM act on PPs to metabolize them but PPs also modulate the composition of GM. Thus, change in GM from pathogenic to beneficial ones may be helpful to ameliorate gut health and associated diseases. However, to overcome the low bioavailability of PPs, various approaches have been developed to improve their solubility and transportation through the gut. In this review, we present evidence supporting the structural changes that occur after metabolic reactions in PPs (curcumin, quercetin, and catechins) and their effect on GM composition that leads to improving overall gut health and helping to ameliorate metabolic disorders.     

Peroral Endoscopic Myotomy Is a Safe and Feasible Option in Management of Esophageal Diverticula: Systematic Review and Meta-Analysis

Digestive Diseases and Sciences - Esophageal diverticula can cause significant symptoms and affect the quality of life. There has been recent interest in the use of peroral endoscopic myotomy in...     

Frailty assessment and impact of frailty on outcomes after transcatheter aortic valve replacement

Introduction: Certain frail patients fail to achieve adequate functional or mortality benefit despite successful transcatheter aortic valve replacement (TAVR). Therefore, frailty assessment methods are becoming an important tool to identify and intervene on this high-risk patient subset for improving clinical outcomes.

Areas covered: The authors provide an overview of frailty and frailty assessment tools being used in clinical practice and discuss the impact of frailty on the cardiac patients, particularly among the TAVR population.

Expert commentary: Available evidence suggests that frailty assessment is critical for identifying patients at high risk of morbidity and mortality after TAVR procedures. However, there is lack of consensus for the best methodology to determine frailty and its optimal management in TAVR populations. Although, physical exercise is a commonly employed intervention to reduce frailty, a greater attention towards improving nutrition may convey more benefit than either intervention alone. Ongoing studies are investigating the benefits of a multicomponent approach to improve clinical outcomes in frail patients undergoing TAVR.     

Novel CD3Z and CD3E Deficiency in Two Unrelated Females

Journal of Clinical Immunology -     

Soluble Fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus

OBJECTIVE: Placental synthesis of soluble Fms-like tyrosine kinase (sFlt-1) is responsible for the increased level of serum sFlt-1 in preeclampsia. sFlt-1 binds to the receptor-binding domain of placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), acting as an endogenous inhibitor of VEGF and PlGF signaling in endothelial cells. It has been hypothesized that increased circulating sFlt-1 contributes to the endothelial dysfunction, hypertension, and proteinuria of preeclampsia. We examined the association of sFlt-1 and preeclampsia in pregnancies in patients with systemic lupus erythematosus (SLE). METHODS: A case-control study was performed using stored serum samples. Cases were SLE pregnancies with later preeclampsia and controls were SLE pregnancies without later preeclampsia. RESULTS: The 52 SLE pregnancies occurred from 1998 to 2001. Nine (17%) pregnancies met the definition of preeclampsia and an additional 9 (17%) met the definition of superimposed preeclampsia. sFlt-1 concentration was significantly higher in SLE pregnancies with preeclampsia (1768 +/- 196 pg/ml) than in those without (1177 +/- 143 pg/ml) (p = 0.0185). CONCLUSION: Our study shows for the first time that sFlt-1 is associated with preeclampsia in patients with SLE, as previously shown in the general pregnancy population. This suggests that SLE pregnancies at risk for preeclampsia can be identified early in the pregnancy by sFlt-1, thus identifying them for high-risk obstetric referral and appropriate monitoring.     

The need for a paradigm shift in adherence research: The case of ADHD

Nonadherence to long-term medications attenuates optimum health outcomes. There is an abundance of research on measuring and identifying factors affecting medication adherence in a range of chronic medical conditions. However, there is a lack of standardisation in adherence research, namely in the methods and measures used. In the case of attention deficit hyperactivity disorder, this lack of standardisation makes it difficult to compare and combine findings and to draw meaningful conclusions. Standardisation should commence with a universally accepted categorisation or taxonomy of adherence which takes into consideration the dynamic nature of medication-taking. This should then be followed by the use of valid and reliable measures of adherence which can accurately quantify adherence at any of its phases, and provide useful information which can be utilised in planning targeted interventions to improve adherence throughout the patient medication-taking journey.