Matrix Metalloproteinases in Melanoma with and without Regression

Cutaneous melanoma is an aggressive tumor with increasing incidence worldwide. Recent development of promising treatments based on immune checkpoints blockade in cancer immunotherapy or signal transduction inhibitors (B-Raf enzyme inhibitor and MEK inhibitor) requires identification of new biomarkers predictive of either prognosis and/or therapeutic response. Dynamic interaction between melanoma and normal host cells influences tumor progression; proteins regulating connections between melanoma cells and extracellular matrix facilitate tumor invasion and dissemination. We discuss the various functions of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in melanoma and their possible role as prognostic and/or predictive biomarkers. We also studied the correlation with regression of expression of several MMPs and TIMPs in melanoma; regressed and nonregressed components are in fact different tumor subclones; in some cases of melanoma with regression (with a specific morphology), the biologic aggressiveness of the tumor and implicitly the overall prognosis may be more favorable than that of melanoma without regression thus offering the possibility of a supplemental stratification of these patients beyond AJCC staging

CEACAM1: Expression and Role in Melanocyte Transformation

Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination

A New Artificial Intelligence-Based Method for Identifying Mycobacterium Tuberculosis in Ziehl–Neelsen Stain on Tissue

Mycobacteria identification is crucial to diagnose tuberculosis. Since the bacillus is very small, finding it in Ziehl–Neelsen (ZN)-stained slides is a long task requiring significant pathologist’s effort. We developed an automated (AI-based) method of identification of mycobacteria. We prepared a training dataset of over 260,000 positive and over 700,000,000 negative patches annotated on scans of 510 whole slide images (WSI) of ZN-stained slides (110 positive and 400 negative). Several image augmentation techniques coupled with different custom computer vision architectures were used. WSIs automatic analysis was followed by a report indicating areas more likely to present mycobacteria. Our model performs AI-based diagnosis (the final decision of the diagnosis of WSI belongs to the pathologist). The results were validated internally on a dataset of 286,000 patches and tested in pathology laboratory settings on 60 ZN slides (23 positive and 37 negative). We compared the pathologists’ results obtained by separately evaluating slides and WSIs with the results given by a pathologist aided by automatic analysis of WSIs. Our architecture showed 0.977 area under the receiver operating characteristic curve. The clinical test presented 98.33% accuracy, 95.65% sensitivity, and 100% specificity for the AI-assisted method, outperforming any other AI-based proposed methods for AFB detection

Immune Parameters in The Prognosis and Therapy Monitoring of Cutaneous Melanoma Patients: Experience, Role, and Limitations

Cutaneous melanoma is an immune-dependent aggressive tumour. Up to our knowledge, there are no reports regarding immune parameters monitoring in longitudinal followup of melanoma patients. We report a followup for 36 months of the immune parameters of patients diagnosed in stages I–IV. The circulatory immune parameters comprised presurgery and postsurgery immune circulating peripheral cells and circulating intercommunicating cytokines. Based on our analysis, the prototype of the intratumor inflammatory infiltrate in a melanoma with good prognosis is composed of numerous T cells CD3+, few or even absent B cells CD20+, few or absent plasma cells CD138+, and present Langerhans cells CD1a+ or langerin+. Regarding circulatory immune cells, a marker that correlates with stage is CD4+/CD8+ ratio, and its decrease clearly indicates a worse prognosis of the disease. Moreover, even in advanced stages, patients that have an increased overall survival rate prove the increase of this ratio. The decrease in the circulating B lymphocytes with stage is balanced by an increase in circulating NK cells, a phenomenon observed in stage III. Out of all the tested cytokines in the followup, IL-6 level correlated with the patient’s survival, while in our study, IL-8, IL-10, and IL-12 did not correlate statistically in a significant way with overall survival, or relapse-free survival