Porocarcinoma coexisting at a site of Bowen disease in a 63‐year‐old woman

Porocarcinoma is an unusual, locally aggressive and potentially fatal neoplasm. Several cutaneous malignancies have been described in association with porocarcinoma, including squamous cell carcinoma, basal cell carcinoma and tricholemmal carcinoma. Previous reports have indicated that the occurrence of malignant tumours in combination with porocarcinoma is extremely rare, in particular with regard to Bowen disease (BD). We report an uncommon case of porocarcinoma occurring synchronously in a single BD lesion in a 63‐year‐old woman with multiple BD lesions. The clinical and histological findings confirmed this diagnosis.     

Sensitivity of the environmental costs of air pollution caused by SOx,NOx, and PM from power plants applied to the power mix configuration in South Korea

In the 6th Basic Plan for Long-Term Electricity Supply and Demand (6th BPE) for Korea, for the first time, the environmental costs of air pollution caused by oxides of sulfur (SOx), oxides of nitrogen (NOx), and particulate matters (PM) from power plants were estimated and included. However, several deficiencies in evaluating the environmental costs were found. In this study, (1) the validity of the environmental costs used in the 6th BPE was assessed, (2) a systematic approach was suggested and used to improve the environmental costs estimation, and (3) the sensitivity of the cost of generating electricity to the environmental costs by fuel type with the proposed approach was discussed. We found that the applied environmental costs used in the 6th BPE did not fully include the demographic characteristics of Korea. By applying more realistic parameter values, it was found that the newly estimated environmental cost was about 23 times higher than the cost estimated in the original 6th BPE for coal-fired power plants and about 1.5 times higher for liquefied natural gas (LNG)-fired power plants, suggesting that LNG-fired power plants are more economical if using more realistic environmental costs. Thus, it is critical to check the validity of parameter values when calculating environmental costs.     

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).

Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.

Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).

Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).

Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.

Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED.     

Evaluating the inhibitory potential of Withania somnifera on platelet aggregation and inflammation enzymes: An in vitro and in silico study

Context Withania somnifera (L.) Dunal is traditionally used for treating various ailments, but lacks scientific evaluation.

Objective This study evaluates Withania somnifera (WS) for its effect on platelet activity and inflammatory enzymes.

Materials and methods Aqueous and ethanolic (1:1) leaf extracts were subjected to in vitro indirect haemolytic activity using Naja naja venom, human platelet aggregation was quantified for lipid peroxidation using arachidonic acid (AA) as agonist and 5-lipoxygenase (5-LOX) levels were determined using standard spectrometric assays. Further, molecular docking was performed by the ligand fit method using molegro software package (Molegro ApS, Aarhus, Denmark).

Results The study found that aqueous and ethanol extracts have very negligible effect (15%) with an IC₅₀ value of 13.8?mg/mL on PLA₂ from Naja naja venom. Further, extracts of WS also had very little effect (18%) with an IC₅₀ value of 16.6?mg/mL on malondialdehyde (MDA) formation. However, a 65% inhibition of 5-LOX with an IC₅₀ value of 0.92?mg/mL was observed in 1:1 ethanol extracts. The same was evident from SAR model with the active ingredient withaferin A binding predominantly on Phe 77, Tyr 98, Arg 99, Asp 164, Leu 168, Ser 382, Arg 395, Tyr 396 and Tyr 614 with an atomic contact energy value of??128.96 compared to standard phenidone (?103.61). Thus, the current study validates the application of WS for inflammatory diseases.

Conclusion This study reveals the inhibitory potential of W. somnifera on inflammatory enzymes and platelet aggregation. Thus, WS can serve as a newer, safer and affordable medicine for inflammatory diseases.     

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