Inflammatory juvenile conjunctival nevi (IJCN) is a rare type of nevus and its clinical presentation overlaps with that of malignant conjunctival melanoma. It is a benign lesion that has been described to progress to melanoma in some cases. IJCN may clinically mimic melanoma due to its rapid growth features and atypical histology. Thus, its accurate diagnosis by histopathology is a prerequisite for proper management. Here, we present a case of conjunctival lesion mimicking melanoma clinically.

Equine melanomas are a common neoplasm in gray horses. However, scientific knowledge about their progression over time is quite scarce. Some owners and veterinarians still believe that early intervention is not necessary, stating that tumors evolve very slowly and intervention could worsen the animal\'s condition. This work aims to identify clinical and histological differences that may exist between equine melanomas with different excision intervals (time between tumor detection and surgical excision). A total of 42 tumors (13 benign and 29 malignant) from 34 horses were included in this study. There was a statistically significant association between excision interval and tumor size (p = 0.038), with tumors excised later being significantly larger than the ones excised sooner. The excision interval was also statistically associated with the number of tumors (p = 0.011), since the horses that carried a tumor for longer seemed to be prone to have multiple tumors. Furthermore, there was an association between excision interval and malignancy (p = 0.035), with tumor excised later being fives times more likely to be malignant. This study provides evidence of delayed excision\'s effect on the progression of equine melanomas. Additionally, it reinforces the importance of the early excision of these tumors.

Eumelanin, a macromolecule widespread in all the living world and long appreciated for its protective action against harmful UV radiation, is considered the beneficial component of the melanin family (ευ means good in ancient Greek). This initially limited picture has been rather recently extended and now includes a variety of key functions performed by eumelanin in order to support life also under extreme conditions. A lot of still unexplained aspects characterize this molecule that, in an evolutionary context, survived natural selection. This paper aims to emphasize the unique characteristics and the consequent unusual behaviors of a molecule that still holds the main chemical/physical features detected in fossils dating to the late Carboniferous. In this context, attention is drawn to the duality of roles played by eumelanin, which occasionally reverses its functional processes, switching from an anti-oxidant to a pro-oxidant behavior and implementing therefore harmful effects.

An mRNA with unmodified nucleosides induces type I interferons (IFN-I) through the stimulation of innate immune sensors. Whether IFN-I induced by mRNA vaccine is crucial for anti-tumor immune response remains to be elucidated. In this study, we investigated the immunogenicity and anti-tumor responses of mRNA encoding tumor antigens with different degrees of N1-methylpseudouridine (m1Ψ) modification in B16 melanoma model. Our results demonstrated that ovalbumin (OVA) encoding mRNA formulated in a lipid nanoparticle (OVA-LNP) induced substantial IFN-I production and the maturation of dendritic cells (DCs) with negative correlation with increasing percentages of m1Ψ modification. In B16-OVA murine melanoma model, unmodified OVA-LNP significantly reduced tumor growth and prolonged survival, compared to OVA-LNP with m1Ψ modification. This robust anti-tumor effect correlated with the increase in intratumoral CD40+ DCs and the frequency of granzyme B+/IFN-γ+/TNF-α+ polyfunctional OVA peptide-specific CD8+ T cells. Blocking type I IFN receptor completely reversed the anti-tumor immunity of unmodified mRNA-OVA reflected in a significant decrease in OVA-specific IFN-γ secreting T cells and enrichment of PD-1+ tumor-infiltrating T cells. The robust anti-tumor effect of unmodified OVA-LNP was also observed in the lung metastatic tumor model. Finally, this mRNA vaccine was tested using B16 melanoma neoantigens (Pbk-Actn4) which resulted in delayed tumor growth. Taken together, our findings demonstrated that an unmodified mRNA vaccine induces IFN-I production or the downstream signaling cascades which plays a crucial role in inducing robust anti-tumor T cell response for controlling tumor growth and metastasis.

T cell immunoglobulin and mucin domain-containing-3 (TIM-3) is an immune checkpoint expressed mainly on CD4+ and CD8+ T cells. In addition to negatively regulating inflammatory T cell function, TIM-3 is a promising immunotherapy target. Herein, the aim is to develop an immuno-positron emission tomography (immunoPET) probe for noninvasively characterizing TIM-3 expression. Flow cytometry is used to detect the expression levels of TIM-3 in B16F10 cells. RMT3-23, a rat antimouse TIM-3-specific monoclonal antibody, is radiolabeled with 64Cu and the performance of 64Cu-NOTA-RMT3-23 is interrogated by immunoPET in murine melanoma models before and after radiation therapies. Biodistribution and immunofluorescent staining studies are carried out after the immunoPET imaging studies. TIM-3 is negatively expressed in B16F10 cells, and its expression is not induced by radiation therapies. ImmunoPET imaging with 64Cu-NOTA-RMT3-23 precisely tracks the unique distribution of TIM-3-positive lymphocytes in immunocompetent melanoma models, and tumor uptake of the radiotracer is not affected by either single-dose or fractionated radiation therapies. The 64Cu-NOTA-RMT3-23 immunoPET imaging results are further mirrored by the immunofluorescent staining studies. These results demonstrate the feasibility of 64Cu-NOTA-RMT3-23 immunoPET in tracking TIM-3 and highlight a new opportunity to optimize TIM-3-targeted immunotherapies with this novel imaging strategy.

Uveal melanoma (UM) is an aggressive and deadly neoplasm. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes in UM, enabling the identification of key cellular processes and signalling pathways. Still, there is no effective treatment for the metastatic disease. Intratumoural heterogeneity (ITH) is thought to be one of the leading determinants of metastasis, therapeutic resistance and recurrence. Crucially, tumours are complex ecosystems, where cancer cells, and diverse cell types from their microenvironment engage in dynamic spatiotemporal crosstalk that allows cancer progression, adaptation and evolution. This highlights the urgent need to gain insight into ITH in UM and its intersection with the microenvironment to overcome treatment failure. Here we provide an overview of the studies and technologies to study ITH in human UMs and tumour micro-environmental composition. We discuss how to incorporate ITH into clinical consideration for the purpose of advocating for new clinical management. We focus on the application of single-cell transcriptomic analysis and propose that understanding the driving forces and functional consequences of the observed tumour heterogeneity holds promise for changing the treatment paradigm of metastatic UMs, surmounting resistance and improving patient prognosis.

As an analytic tool in medicine, deep learning has gained great attention and opened new ways for disease diagnosis. Recent studies validate the effectiveness of deep learning algorithms for binary classification of skin lesions (i.e., melanomas and nevi classes) with dermoscopic images. Nonetheless, those binary classification methods cannot be applied to the general clinical situation of skin cancer screening in which multi-class classification must be taken into account. The main objective of this research is to develop, implement, and calibrate an advanced deep learning model in the context of automated multi-class classification of skin lesions. The proposed Deep Convolutional Neural Network (DCNN) model is carefully designed with several layers, and multiple filter sizes, but fewer filters and parameters to improve efficacy and performance. Dermoscopic images are acquired from the International Skin Imaging Collaboration databases (ISIC-17, ISIC-18, and ISIC-19) for experiments. The experimental results of the proposed DCNN approach are presented in terms of precision, sensitivity, specificity, and other metrics. Specifically, it attains 94 % precision, 93 % sensitivity, and 91 % specificity in ISIC-17. It is demonstrated by the experimental results that this proposed DCNN approach outperforms state-of-the-art algorithms, exhibiting 0.964 area under the receiver operating characteristics (AUROC) in ISIC-17 for the classification of skin lesions and can be used to assist dermatologists in classifying skin lesions. As a result, this proposed approach provides a novel and feasible way for automating and expediting the skin lesion classification task as well as saving effort, time, and human life.

Human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule involved in inducing tolerance at the feto-maternal interface and in escape of immune response by tumor cells. The aim of the study is to review the published literature on the expression of HLA-G in malignant melanomas and its clinicopathological and prognostic correlates.
A systematic search was carried out in electronic databases. Studies dealing with HLA-G expression in surgically-removed human samples were retrieved and analyzed.
Of 1737 retrieved articles, 16 were included. The main themes regarded HLA-G expression in malignant melanocytic lesions, assessed by immunohistochemistry (IHC), soluble or molecular techniques, and its relationship with clinicopathological features, such as tumor thickness and malignant behavior. Overall significant HLA-G expression was found in 460/843 tumors (55%), and specifically in 251/556 melanomas (45%) evaluated with IHC, in 208/250 cases (83%) examined with soluble methods and in 13/23 melanoma lesions (57%) tested with polymerase chain reaction. Despite the correlation with parameters indicating an aggressive behavior, no studies demonstrated any prognostic value of HLA-G expression. Furthermore, uveal melanomas were constantly negative for this biomarker.
Overall, published data indicate that while HLA-G is involved in the interactions between melanomas and the immune system, it is unlikely to be the only factor to play such a role, therefore making it difficult to designate it as a prognostically relevant molecule. Evidence further suggests that HLA-G is not implicated in the immunobiology of uveal melanomas.

Melanoma constitutes one of the most sinister and troublesome malignancies encountered by humanity. Generally, the diagnosis of advanced melanoma connotes a grave prognosis, prompting a sense of looming threat of death, however, the early-stage detected disease responds well to robust treatment resulting in reasonable survivorship. Scalp melanomas are even more troublesome, because they typically exhibit more aggressive biologic behavior and are often diagnosed at a late stage. This review tries to comprehensively highlight the various diagnostic, therapeutic, and outcome aspects of scalp melanomas. The literature research includes peer-reviewed articles (clinical trials or scientific reviews). Studies were identified by searching electronic databases (MEDLINE and PubMed) till May 2020 and reference lists of respective articles. Only articles published in English language were included.

Rationale: Mutations in KIT, a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for KIT-mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing melanomas are urgently needed. Methods: A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KIT V560D, KIT K642E and KIT D816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors. Results: Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the KIT D816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KIT WT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have KIT mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.