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Cryptococcosis is an important systemic mycosis and the third most prevalent disease in human immunodeficiency virus (HIV)-positive individuals. The incidence of cryptococcosis is high among the 25 million people with HIV/acquired immunodeficiency syndrome (AIDS), with recent estimates indicating that there are one million cases of cryptococcal meningitis globally per year in AIDS patients. In Cryptococcus neoformans , resistance to azoles may be associated with alterations in the target enzyme encoded by the gene ERG11, lanosterol 14α-demethylase. These alterations are obtained through mutations, or by overexpressing the gene encoding. In addition, C. gattii and C. neoformans present a heteroresistance phenotype, which may be related to increased virulence. Other species beyond C. neoformans and C. gattii , such as C. laurentii , have been diagnosed mainly in patients with immunosuppression. Infections of C. albidus have been isolated in cats and marine mammals. Recent evidence suggests that the majority of infections produced by this pathogen are associated with biofilm growth, which is also related with increased resistance to antifungal agents. Therefore, there is a great need to search for alternative antifungal agents for these fungi. The search for new molecules is currently occurring from nanoparticle drugs of plant peptide origin. This article presents a brief review of the literature regarding the epidemiology of cryptococcosis, as well as fungal resistance and new alternatives for treatment.

This work aimed to evaluate the activity of 3'-hydroxychalcone against Cryptococcus gattii in planktonic and biofilm forms and their toxicity using alternative animal models. Minimum inhibitory concentration and minimum fungicide concentration were determined. Biofilm formation and the susceptibility tests were performed by the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-5-[carbonyl(phenylamino)]-2H-tetrazolium hydroxide assay. Toxicity and efficacy were checked in Danio rerio and Galleria mellonella models. The compound 3'-hydroxychalcone showed fungicidal activity against C. gattii in both planktonic and biofilm forms. The toxicity in zebrafish embryos revealed a low lethal concentration. In G. mellonella, the compound did not show antifungal activity and larvae toxicity. Because of the activity of 3'-hydroxychalcone against C. gattii in vitro, molecular modifications should be made to improve efficacy and to reduce toxicity in vivo. [Formula: see text].

Dermatophytosis and superficial mycosis are a major global public health problem that affects 20-25% of the world's population. The increase in fungal resistance to the commercially available antifungal agents, in conjunction with the limited spectrum of action of such drugs, emphasises the need to develop new antifungal agents. Natural products are attractive prototypes for antifungal agents due to their broad spectrum of biological activities. This study aimed to verify the antifungal activity of protocatechuic acid, 3,4- diacetoxybenzoic, and fourteen alkyl protocatechuates (3,4- dihydroxybenzoates) against Trichophyton rubrum and Trichophyton mentagrophytes and to further assess their activities when combined with fluconazole. Susceptibility and synergism assays were conducted as described in M38-A2 (CLSI), with modifications. Three strains of Trichophyton rubrum and three strains of Trichophyton mentagrophytes were used in this work. The pentyl, hexyl, heptyl, octyl, nonyl, and decyl protocatechuates showed great fungicidal effects, with minimum inhibitory concentration (MIC) values ranging from 0.97 to 7.8 mg/L. Heptyl showed a synergistic activity (FIC index = 0.49 ), reducing the MIC of fluconazole by fourfold. All substances tested were safe, especially the hexyl, heptyl, octyl, and nonyl compounds, all of which showed a high selectivity index, particularly in combination with fluconazole. These ester associations with fluconazole may represent a promising source of prototypes in the search for anti-Trichophyton therapeutic agents.

This work aims to demonstrate that the gallic acid structure modification to the decyl gallate (G14) compound contributed to increase the antifungal activity against several species of pathogenic fungi, mainly, Candida spp. Cryptococcus spp. Paracoccidioides spp. and Histoplasma capsulatum, according to standardized microdilution method described by Clinical Laboratory Standard Institute (CLSI) documents. Moreover this compound has a particularly good selectivity index value, which makes it an excellent candidate for broad-spectrum antifungal prototype and encourages the continuation of subsequent studies for the discovery of its mechanism of action.

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR , ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg ( n  = 312) or placebo ( n  = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P  = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies. Results from EMPOWER-Lung 3 demonstrate increased overall survival with cemiplimab plus platinum-doublet chemotherapy compared to cemiplimab as first-line treatment in patients with advanced non-small cell lung cancer, irrespective of PD-L1 expression.

We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%. In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0–1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing. Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9–not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2–17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42–0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1–8·8) with cemiplimab versus 5·7 months (4·5–6·2) with chemotherapy (HR 0·54 [0·43–0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3–4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy. Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population. Regeneron Pharmaceuticals and Sanofi.

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi.

Background:Mepolizumab (MEPO) proved its efficacy in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) in the randomised controlled MIRRA trial. The ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire is a novel, disease-specific tool, validated with the aim of assessing the impact of the disease and its treatment on the patients’ perspectives.Objectives:To prospectively evaluate the impact and the rapidity of the effect of MEPO on the AAV-PRO score and patient global assessment (PtGA) in a multicentre cohort of patients with EGPA.Methods:Patients with EGPA satisfying the 2022 ACR/EULAR and/or MIRRA trial classification criteria and initiating treatment with MEPO were included. PtGA and AAV-PRO score were prospectively evaluated at MEPO initiation and after 7, 14, 30, 90 and 180 days of treatment. Predictors of improved AAV-PRO response during treatment with MEPO were also investigated.Results:Seventy patients were included in the study: female 54.3%, mean age at diagnosis 48.7±12.6 years, 20% ANCA-positive. Sixty-three patients (90%) had a history of relapsing disease. Forty-seven (67.1%) and 23 (32.9%) patients received MEPO 100 mg and 300 mg/4 weeks, respectively, with the main indication being refractory asthma and/or rhinosinusitis. Prednisone (PDN)-equivalent mean dose was 10.8±9.2 mg/day. At MEPO initiation, mean PtGA, AAV-PRO organ-specific symptoms, systemic symptoms, treatment side effects, social and emotional impact, concerns about the future and physical function domain 0-100 score were 59.1±21.2, 30.9±17.8, 25.5±18.6, 18.8±18.1, 32.6±21.9, 37.7±22.1 and 28.2±21.2, respectively. After 7 days, a statistically significant reduction of PtGA [ratio 0.87 (95% CI 0.87—0.95); Table 1] was observed. At 14 days, all AAV-PRO domains, except treatment side effects, showed a statistically significant improvement compared to baseline. Conversely, no relevant amelioration of the AAV-PRO domains was demonstrated between 30 and 180 days of follow-up (Figure 1). Previous history of vasculitic relapse, BVAS ≤3, C-reactive protein ≤5 mg/L and PDN-equivalent dose ≤10 mg/day at MEPO initiation were the main predictors of a better response of the AAV-PRO questionnaire during follow-up. MEPO 300 mg/4 weeks positively influenced organ-specific symptoms compared to MEPO 100 mg/4 weeks, although with a less significant improvement of the treatment side effects domain. Conversely, age, educational level and ANCA status at baseline had no impact on the AAV-PRO domains.Conclusion:MEPO allows a quick and remarkable improvement of several aspects of health-related quality of life in patients with refractory EGPA.Table 1. Comparison, at different timepoints, of the AAV-PRO domains 0-100 score, after log-normalization and adjustment for sex and age.OSS: organ-specific symptoms; SS: systemic symptoms; TSA: treatment side effects; SEI: social and emotional impact; CAF: concerns about the future; PF: physical function; PtGA: patient global assessment; 95% CI: 95% confidence interval.Figure 1.Temporal trend of the AAV-PRO specific domains 0-100 score during 6-month treatment with mepolizumab.OSS: organ-specific symptoms; SS: systemic symptoms; TSA: treatment side effects; SEI: social and emotional impact; CAF: concerns about the future; PF: physical function.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Paolo Delvino: None declared, Luca Quartuccio: None declared, Joanna C Robson: None declared, Federico Alberici: None declared, Diego Bagnasco: None declared, Alvise Berti: None declared, Marco Caminati: None declared, Marta Camoni: None declared, Maria C. Cid Lecturing fees from GSK, AbbVie, and CSL-Vifor; participation in advisory boards for GSK, CSL-Vifor, AbbVie, and Astrazeneca, Consulting fees from GSK, AbbVie, CSL- Vifor, and AstraZeneca; royalties from UpToDate, Research grant and meeting travel support from Kiniksa Pharmaceuticals Corp, Edoardo Conticini: None declared, Giulia Costanzo: None declared, Claire de Moreuil: None declared, Stefano Del Giacco: None declared, Georgina Espigol-Frigole Speaker fees from VIFOR and GSK, Consulting fees from VIFOR and GSK, Grant research support from GSK, Virginia V. Ferretti: None declared, Franco Franceschini: None declared, Luca Iorio: None declared, Anna Kernder: None declared, Catherine Klersy: None declared, Alberto Lo Gullo: None declared, Laura Losappio: None declared, Elena Manna: None declared, Matteo Maule: None declared, Carlomaurizio Montecucco: None declared, Simone Negrini: None declared, Roberto Padoan: None declared, Francesca Regola: None declared, Luisa Ricciardi: None declared, Jan Schroeder: None declared, Benjamin Terrier: None declared, Paola Toniati: None declared, Elena Treppo: None declared, Maria Letizia Urban: None declared, Augusto Vaglio: None declared, Giacomo Emmi: None declared, Sara Monti: None declared.

Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications.

Background Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null. Methods Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization. Results By conventional histology, dysplasia was classified as adenomatous/intestinal ( n  = 42; 64 %) and foveolar or pyloric/gastric ( n  = 24; 36 %) and graded as low grade ( n  = 37; 56 %) or high grade ( n  = 29; 44 %). Immunophenotypic classification showed intestinal ( n  = 22; 33.3 %), gastric ( n  = 25; 37.9 %), hybrid ( n  = 17; 25.8 %), or null ( n  = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia ( p  = 0.001), high expression of CDX2 ( p  = 0.015), TP53 ( p  = 0.034), synaptophysin ( p  = 0.003), and chromogranin ( p  < 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia ( p  = 0.001), high Ki-67 proliferative index ( p  = 0.05), and coexistence of intramucosal carcinoma ( p  = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. Conclusions Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma.