Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis

Background: The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA). Methods: A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted. Results: A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints. Conclusions: This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies

Successful Protein Extraction from Over-Fixed and Long-Term Stored Formalin-Fixed Tissues

One of the major breakthroughs in molecular pathology during the last decade was the successful extraction of full-length proteins from formalin-fixed and paraffin-embedded (FFPE) clinical tissues. However, only limited data are available for the protein extraction efficiency of over-fixed tissues and FFPE blocks that had been stored for more than 15 years in pathology archives. In this study we evaluated the protein extraction efficiency of FFPE tissues which had been formalin-fixed for up to 144 hours and tissue blocks that were stored for 20 years, comparing an established and a new commercial buffer system. Although there is a decrease in protein yield with increasing fixation time, the new buffer system allows a protein recovery of 66% from 144 hours fixed tissues compared to tissues that were fixed for 6 hours. Using the established extraction procedure, less than 50% protein recovery was seen. Similarly, the protein extraction efficiency decreases with longer storage times of the paraffin blocks. Comparing the two buffer systems, we found that 50% more proteins can be extracted from FFPE blocks that were stored for 20 years when the new buffer system is used. Taken together, our data show that the new buffer system is superior compared to the established one. Because tissue fixation times vary in the routine clinical setting and pathology archives contain billions of FFPE tissues blocks, our data are highly relevant for research, diagnosis, and treatment of disease

Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies

Micro-RNAs (miRs) are important regulators of mRNA and protein expression; the ability of miR expression profilings to distinguish different cancer types and classify their sub-types has been well-described. They also represent a novel biological entity with potential value as tumour biomarkers, which can improve diagnosis, prognosis, and monitoring of treatment response for human cancers. This endeavour has been greatly facilitated by the stability of miRs in formalin-fixed paraffin-embedded (FFPE) tissues, and their detection in circulation. This review will summarize some of the key dysregulated miRs described to date in human epithelial malignancies, and their potential value as molecular bio-markers in FFPE tissues and blood samples. There remain many challenges in this domain, however, with the evolution of different platforms, the complexities of normalizing miR profiling data, and the importance of evaluating sufficiently-powered training and validation cohorts. Nonetheless, well-conducted miR profiling studies should contribute important insights into the molecular aberrations driving human cancer development and progression

Cost-effectiveness of quadrivalent versus trivalent influenza vaccine in the United States

BACKGROUND: Currently used trivalent influenza vaccines (TIVs) contain two strains of influenza A and one strain of influenza B. However, co-circulation of two distinct B lineages and difficulties in predicting which lineage will predominate in the next season have led to frequent B-strain mismatches. Newly registered quadrivalent influenza vaccines (QIVs) include two B strains and might therefore provide wider protection. Objectives: To evaluate the cost-effectiveness of using QIV versus TIV for routine influenza vaccination in the United States (US) during the next 20 years. Methods: A dynamic transmission model was used to estimate the additional protection offered by QIV over TIV against symptomatic influenza B disease. Subsequently, we used a decision tree model to determine the costeffectiveness of replacing TIV with QIV from a societal perspective. US data on influenza-related disease outcomes and corresponding costs were derived from published sources (e. g. Molinari et al. 2007). Results: Over 20 years, replacing TIV with QIV is predicted to prevent 13.3 million influenza B cases. According to our model this resulted in a reduction of 113,000 hospitalizations and 13,200 deaths. Moreover, 200,000 quality- adjusted life-years (QALYs), US$3.1 billion in medical costs and US$0.6 billion in indirect costs were saved. The base case estimate of the incremental cost-effectiveness ratio (ICER) was US$29,000 per QALY gained. Economic parameters with highest impact on the ICER were vaccine price, QALY loss due to influenza and probability of hospitalization or death given symptomatic infection. Conclusions: Introducing QIV into the immunization program of the United States would prevent a substantial number of hospitalizations and deaths. Moreover, cost-effectiveness was shown to be favorable when a cost-effectiveness threshold of US$50,000 is applied