The matrix metalloproteinases (MMPs) are a family of structurally and functionally related proteinases, initially characterized by their ability to degrade the extracellular matrix (ECM) [1]. Nowadays, at least 20 enzymes that share considerable homology within their major domains (signal peptide, propeptide, catalytic, hinge and hemopexin-like domains) were included in MMPs family [2]. Most of MMPs are synthesised and secreted as partially activated latent forms, requiring, for full activation, removal of the entire propeptide domain by proteinases including other MMPs AbstractThe goal of our study was to analyse the prognostic values for some matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in breast cancer. We evaluated the activity and the expression levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in malignant versus benign fresh breast tumor extracts. For this purpose, gelatinzymography, immunoblotting and ELISA were used to analyse the activity and expression of MMPs and TIMPs. We found that MMP-9 expression level and activity are increased in malignant tumors. In addition, MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio values obtained by us were significantly different in malignant tumors compared to benign tumors. We suggest that the abnormal MMP-9/TIMP-1 balance plays a role in the configuration of breast invasive carcinoma of no special type and also in tumor growth, while altered MMP-2/TIMP-2 ratio value could be associated with lymph node invasion and used as a prognostic marker in correlation with Nottingham Prognostic Index. Finally, we showed that in malignant tumors high expression of estrogen receptors is associated with enhanced activity of MMP-2 and increased bcl-2 levels, while high expression of progesterone receptors is correlated with low TIMP-1 protein levels.

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Immunotherapy is part of the new treatments that significantly improved the prognostic of metastatic melanoma patients. The article reviews briefly the old immunotherapeutic approaches e.g., interferon-ᾳ2 and interleukin-2, and focuses on immune checkpoint inhibitors such as anti-CTLA-4 inhibitors and anti-PD-1 inhibitors in monotherapy or in combination (dual immune blockade). We detailed the results from CheckMate and KEYNOTTE clinical trials that lead to US Food and Drug Administration and European Medicines Agency approvals of the new agents for the treatment of advanced melanoma. The chapter concentrates on the algorithms for BRAF wild-type and BRAF mutated metastatic melanoma treatments, according to American (NCCN) and European (ESMO) guidelines. We underlined the first line, second line, and subsequent lines of treatment for both melanoma subtypes and for particular cases, such as in-transit metastasis or brain metastasis. A special attention was paid to treatment options for early and late disease progression (primary and acquired resistance after adjuvant therapy). Unfortunately, the new immune agents produce a higher toxicity rate, mainly immune adverse events. Also, these drugs can interact with the gut microbiome and with antibiotics, decreasing the efficacy of immune therapy. Finally, we review the new directions for immune therapy e.g., new immune combinations, the association of immune and targeted therapies, and adoptive cellular therapy with tumor-infiltrating lymphocytes, interleukin-2, and anti-PD-1.

e17597 Background: Homologous recombination deficiency (HRD) is a tumor characteristic that can be assessed via different biomarkers such as individual mutations in BRCA1 and BRCA2 genes, and/or other HRR genes and genomic instability. We assessed a combined HRD score in three measures; BRCAs mutations, HRR mutation (HRRm) status, and genomic instability scoring via a specific bioinformatic algorithm of the testing panel to establish clinical validation. Methods: We tested 157 ovarian cancer patients’ FFPE samples to define HRD score, BRCA1/2 mutation and other HRRm status, to camper the responses to PARP inhibitors. For the HRD scoring, all the samples that were previously tested with alternative HRD tests and the cases had an indication of PARPi also tested via HRDInfo (CE-IVD) Panel for clinical diagnostics in this study. The PPA, NPA and OPA have been measured according to the FDA regulations of overall agreement for a follow-on CDx to show clinical evidence. Results: Depending on the three levels of testing strategy, BRCA1-2 mutation status in relation to the clinical response for PARPi has the lowest positive percent agreement (PPA) with 63.41% while HRD score has the highest with 97.62% that is higher than the any alternative HRD tests. All the PPA, NPA and OPA measures showed in the Figure for BRCA1-2 status and Genomic Instability stand alone and all BRCA1-2 plus other HRR genes plus Genomic Instability Status (GIS) to define HRD scoring. Conclusions: Even though the testing rate of HRD tests are still low all around the world and limited to specific cancers, there is an increasing requirement for different types of cancers. However, most alternative HRD tests have high overall concordance but fail to reach FDA CDx test requirements. Thus, this study showing the clinical evidence in the treatment of PARPi response data together with high PPA, NPA and OPA measures of HRDInfo panel and its bioinformatics algorithm. [Table: see text]

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One-way sensitivity analyses were performed against all probability, utility, and cost values incorporated into this cost-effectiveness model. Results: In this analysis, AA provides substantial saving with $13,322 per patient versus ENZA. The main drivers of the model are drug costs, health utility values, and efficacy (OS and rPFS). The robustness of the results was supported by sensitivity analyses. ConClusions: Given similar OS benefits, AA is cost saving compared with ENZA for the treatment of patients with mCPRC post-docetaxel based on US data.