bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–07–25
89 papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Nucleotide stress responses in neural crest cell fate and melanoma.
  2. Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells.
  3. UVB Radiation and Selected Tryptophan-Derived AhR Ligands-Potential Biological Interactions in Melanoma Cells.
  4. The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice.
  5. miR-302a-3p suppresses melanoma cell progression via targeting METTL3.
  6. PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN.
  7. Polymorphisms at site 469 of B-RAF protein associated with skin melanoma may be correlated with dabrafenib resistance: An in silico study.
  8. Differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents.
  9. Special Issue "Precision Oncology in Melanoma Progression".
  10. Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo.
  11. Contemporary management of locoregionally advanced melanoma in Australia and New Zealand and the role of adjuvant systemic therapy.
  12. Development and validation of an immune gene set-based prognostic signature in cutaneous melanoma.
  13. Flavonoid Glycosides from Ziziphus jujuba var. inermis (Bunge) Rehder Seeds Inhibit α-Melanocyte-Stimulating Hormone-Mediated Melanogenesis.
  14. Proteomic profiles of melanoma cell-derived exosomes in plasma: discovery of potential biomarkers of melanoma progression.
  15. miR-383-5p inhibits human malignant melanoma cells function via targeting CENPF.
  16. Identification of the m6A RNA Methylation Regulators WTAP as a Novel Prognostic Biomarker and Genomic Alterations in Cutaneous Melanoma.
  17. The immunosuppressive role of Edn3 over-expression in the melanoma microenvironment.
  18. Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma.
  19. Identification of melanoma-specific exosomal miRNAs as the potential biomarker for canine oral melanoma.
  20. CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
  21. Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma.
  22. Retrospective Analysis of Rechallenge with Ipilimumab in Patients with Metastatic Melanoma.
  23. Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.
  24. Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases.
  25. Secondary Glaucoma Associated With Intraocular Metastatic Cutaneous Melanoma.
  26. Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours.
  27. DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma.
  28. Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.
  29. The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2.
  30. Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis.
  31. The Analysis of Inflammation-Related Proteins in a Cargo of Exosomes Derived from the Serum of Uveal Melanoma Patients Reveals Potential Biomarkers of Disease Progression.
  32. Multiple genetically distinct uveal melanomas arise in the same eye of two patients with melanosis oculiUnilateral multifocal uveal melanoma in melanosis oculi.
  33. The Abscopal Effect in the Era of Checkpoint Inhibitors.
  34. SFRP5 inhibits melanin synthesis of melanocytes in vitiligo by suppressing the Wnt/β-catenin signaling.
  35. Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors.
  36. Electrochemotherapy and Other Clinical Applications of Electroporation for the Targeted Therapy of Metastatic Melanoma.
  37. Synergistic effect of cold atmospheric pressure plasma and free or liposomal doxorubicin on melanoma cells.
  38. Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study.
  39. Progression of melanoma is suppressed by targeting all transforming growth factor‑β isoforms with an Fc chimeric receptor.
  40. [The prognostic value of uveal melanoma cell type].
  41. Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
  42. Tumor response evaluation in patients with malignant melanoma undergoing immune checkpoint inhibitor therapy and prognosis prediction using 18F-FDG PET/CT: multicenter study for comparison of EORTC, PERCIST, and imPERCIST.
  43. Current status of intralesional agents in treatment of malignant melanoma.
  44. A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.
  45. Experimental Modeling of Multiple Primary Malignant Processes with One Tumor Suppressed by Another under Conditions of Primary Immunodeficiency.
  46. Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers.
  47. Molecular characterization of fast-growing melanomas.
  48. Profiling Cancer-Associated Fibroblasts in Melanoma.
  49. Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis.
  50. Early detection of metastatic uveal melanoma by the analysis of tumor-specific mutations in cell-free plasma DNA.
  51. Cutaneous Events Associated with Immunotherapy of Melanoma: A Review.
  52. Glucose-Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy.
  53. Prognostic signature and immune efficacy of m1 A-, m5 C- and m6 A-related regulators in cutaneous melanoma.
  54. Surveillance of patients with thin melanoma.
  55. Coronavirus disease 2019 vaccine mimics lymph node metastases in patients undergoing skin cancer follow-up: A monocentre study.
  56. A comparison of immune receptor recombination databases sourced from tumour exome or RNAseq files: Verifications of immunological distinctions between primary and metastatic melanoma.
  57. Clinical Features, Immunopathogenesis, and Therapeutic Strategies in Vitiligo.
  58. Microbeam Radiotherapy-A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma.
  59. Proliferative Clonal T-Cell Infiltrate Mimicking a Cutaneous T-Cell Lymphoma Arising in Active Regression of Melanoma.
  60. Circular RNA circRNA_0082835 promotes progression and lymphatic metastasis of primary melanoma by sponging microRNA miRNA-429.
  61. Immunosuppressive activity is attenuated by Astragalus polysaccharides via remodeling the gut microenvironment in melanoma mice.
  62. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts.
  63. Melanoma and Racial Health Disparities in Black Individuals-Facts, Fallacies, and Fixes.
  64. Identification of the fate and regenerative mechanism of zebrafish melanocyte progenitor cells and melanocytes after laser-induced pigment ablation.
  65. Enhancing the Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Signaling and Arginine Deprivation in Melanoma.
  66. Diffuse Alveolar Hemorrhage: An Unusual Presentation of Recurrent Malignant Melanoma.
  67. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma.
  68. Nonsyndromic Primary Diffuse Leptomeningeal Melanomatosis in a Child.
  69. Apoptosis Induction in Murine Melanoma (B16F10) Cells by Mannosylerythritol Lipids-B; a Glycolipid Biosurfactant with Antitumoral Activities.
  70. Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.
  71. Cell-type-specific meQTLs extend melanoma GWAS annotation beyond eQTLs and inform melanocyte gene-regulatory mechanisms.
  72. Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model.
  73. Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges.
  74. Corrigendum to "Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma".
  75. Effects of COVID-19 restriction measures and clinical resetting on delayed melanoma diagnosis: a single Institution experience.
  76. B16 Melanoma Cancer Cells with Higher Metastatic Potential are More Deformable at a Whole-Cell Level.
  77. Multiple Gastrointestinal Melanoma Causing Small Bowel Intussusception.
  78. Single-Cell Transcriptome Analysis in Melanoma Using Network Embedding.
  79. Desmoplastic Melanoma Masquerading as Neurofibroma.
  80. Compliance with sentinel lymph node biopsy guidelines for invasive melanomas treated with Mohs micrographic surgery.
  81. Selective Apoptotic Effect of Plasma Activated Liquids on Human Cancer Cell Lines.
  82. Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential.
  83. CCL27 Signaling in the Tumor Microenvironment.
  84. 3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms.
  85. Stratum corneum biomarkers after in vivo repeated exposure to sub-erythemal dosages of ultraviolet radiation in unprotected and sunscreen (SPF 50+) protected skin.
  86. Preliminary screening and correlation analysis for lncRNAs related to radiosensitivity in melanoma cells by inhibiting glycolysis.
  87. [The significance of C-KIT gene mutations in the diagnosis and prognosis of malignant tumors].
  88. Synergistic Effect of 300 μm Needle-Depth Fractional Microneedling Radiofrequency on the Treatment of Senescence-Induced Aging Hyperpigmentation of the Skin.
  89. Lactobacillus paracasei HY7015 Promotes Hair Growth in a Telogenic Mouse Model.
  1. Cell Cycle. 2021 Jul 19. 1-13
    Nucleotide stress responses in neural crest cell fate and melanoma.
    Audrey Sporrij, Leonard I Zon.
      Melanoma is the deadliest form of skin cancer. While clinical developments have significantly improved patient prognosis, effective treatment is often obstructed by limited response rates, intrinsic or acquired resistance to therapy, and adverse events. Melanoma initiation and progression are associated with transcriptional reprogramming of melanocytes to a cell state that resembles the lineage from which the cells are specified during development, that is the neural crest. Convergence to a neural crest cell (NCC)-like state revealed the therapeutic potential of targeting developmental pathways for the treatment of melanoma. Neural crest cells have a unique sensitivity to metabolic dysregulation, especially nucleotide depletion. Mutations in the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) particularly affect neural crest-derived tissues and cause Miller syndrome, a genetic disorder characterized by craniofacial malformations in patients. The developmental susceptibility of the neural crest to nucleotide deficiency is conserved in melanoma and provides a metabolic vulnerability that can be exploited for therapeutic purposes. We review the current knowledge on nucleotide stress responses in neural crest and melanoma and discuss how the recent scientific advances that have improved our understanding of transcriptional regulation during nucleotide depletion can impact melanoma treatment.
    Keywords:  DHODH; HEXIM; Neural crest; RNA helicase DDX21; melanoma; nucleotide stress
    DOI:  https://doi.org/10.1080/15384101.2021.1947567
  2. Cancers (Basel). 2021 Jul 15. pii: 3551. [Epub ahead of print]13(14):
    Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells.
    Angela Leo, Erica Pranzini, Laura Pietrovito, Elisa Pardella, Matteo Parri, Paolo Cirri, Gennaro Bruno, Maura Calvani, Silvia Peppicelli, Eugenio Torre, Maiko Sasaki, Lily Yang, Lei Zhu, Paola Chiarugi, Giovanni Raugei, Jack L Arbiser, Maria Letizia Taddei.
      Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination.
    Keywords:  Claisened Hexafluoro; amoeboid motility; melanoma; mitochondria
    DOI:  https://doi.org/10.3390/cancers13143551
  3. Int J Mol Sci. 2021 Jul 13. pii: 7500. [Epub ahead of print]22(14):
    UVB Radiation and Selected Tryptophan-Derived AhR Ligands-Potential Biological Interactions in Melanoma Cells.
    Katarzyna Walczak, Paulina Kazimierczak, Karolina Szalast, Tomasz Plech.
      Excessive UV exposure is considered the major environmental factor in melanoma progression. Human skin is constantly exposed to selected tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, including kynurenine (KYN) and kynurenic acid (KYNA), as they are endogenously produced and present in various tissues and body fluids. Importantly, recent studies confirmed the biological activity of KYN and KYNA toward melanoma cells in vitro. Thus, in this study, the potential biological interactions between UVB and tryptophan metabolites KYN and KYNA were studied in melanoma A375, SK-MEL-3, and RPMI-7951 cells. It was shown that UVB enhanced the antiproliferative activity of KYN and KYNA in melanoma cells. Importantly, selected tryptophan-derived AhR ligands did not affect the invasiveness of A375 and RPMI-7951 cells; however, the stimulatory effect was observed in SK-MEL-3 cells exposed to UVB. Thus, the effect of tryptophan metabolites on metabolic activity, cell cycle regulation, and cell death in SK-MEL-3 cells exposed to UVB was assessed. In conclusion, taking into account that both UVB radiation and tryptophan-derived AhR ligands may have a crucial effect on skin cancer formation and progression, these results may have a significant impact, revealing the potential biological interactions in melanoma cells in vitro.
    Keywords:  UVB; aryl hydrocarbon receptor; kynurenic acid; kynurenine; melanoma; necrosis; proliferation; tryptophan; tumor cell transendothelial cell migration assay
    DOI:  https://doi.org/10.3390/ijms22147500
  4. Front Oncol. 2021 ;11 675296
    The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice.
    Gerardo Ferrara, Giuseppe Argenziano.
      The "multidimensional" World Health Organization (WHO) classification 2018 of melanocytic tumors encompasses nine melanoma pathways (seven of which for cutaneous melanoma) according to a progression model in which morphologically intermediate melanocytic tumors are cosidered as simulators and/or precursors to melanoma. These "intermediates" can be subclassified into: i) a "classical" subgroup (superficial/thin compound: dysplastic nevus), which is placed within the morphologic and molecular progression spectrum of classical (Clark's and McGovern's) melanoma subtypes (superficial spreading and, possibly, nodular); and ii) a "non-classical" subgroup (thick compound/dermal: "melanocytomas") whose genetic pathways diverge from classical melanoma subtypes. Such a progression model is aimed at giving a conceptual framework for a histopathological classification; however, routine clinicopathological practice strongly suggests that most melanomas arise de novo and that the vast majority of nevi are clinically stable or even involuting over time. Clinicopathological correlation can help identify some severely atypical but benign tumors (e.g.: sclerosing nevus with pseudomelanomatous features) as well as some deceptively bland melanomas (e.g.: lentiginous melanoma; nested melanoma), thereby addressing some ambiguous cases to a correct clinical management. The recently available adjuvant therapy regimens for melanoma raise the problem of a careful distinction between severely atypical (high grade) melanocytoma and "classical" melanoma: conventional morphology can guide an algorithmic approach based on an antibody panel (anti-mutated BRAF, BAP1, PRAME, ALK, TRKA, MET, HRAS-WT, ROS; beta catenin; R1alpha; p16; HMB45; Ki67), a first-line molecular study (identification of hot spot mutations of BRAF and NRAS) and an advanced molecular study (sequencing of NF1, KIT, BRAF, MAP2K1, GNAQ, GNA11, PLCB4, CYSLTR2, HRAS; fusions studies of BRAF, RET, MAP3K8, PRKCA); as a final step, next-generation sequencing can identify melanocytic tumors with rare genetic signatures and melanocytic tumors with a high tumor mutation burden which should be definitely ascribed to the category of classical melanoma with the respective therapeutic options.
    Keywords:  clinicopathological correlation; dysplastic nevus; histopathology; immunohistochemistry; melanocytoma; melanoma; molecular biology
    DOI:  https://doi.org/10.3389/fonc.2021.675296
  5. J Chemother. 2021 Jul 21. 1-12
    miR-302a-3p suppresses melanoma cell progression via targeting METTL3.
    Xiao Chang, Yu-Ying Lin, Li-Na Bai, Wei Zhu.
      The miRNA-302 family plays a critical role in carcinogenesis. As an enzyme that regulates the N6-methyladenosine modification, methyltransferase-like 3 (METTL3) plays important roles in the development and progression of various tumours. However, the upstream regulatory mechanisms of METTL3 in melanoma have not yet been fully investigated. Herein, we investigated the functions of miR-302a-3p and its target RNA METTL3 on proliferation, apoptosis, and invasion of melanoma. Quantitative real-time PCR and immunofluorescence staining were used to measure the expression of METTL3 mRNA and protein level after transfection. miR-302a-3p expression was determined by quantitative reverse transcription-PCR. The cell proliferation, cell cycle progression, apoptosis, colony formation, migration, and cell invasion ability were determined using MTT assay, propidium iodide (PI) staining, Annexin V/PI flow cytometry, plate clone assay, and Transwell migration and invasion assays, respectively. Melanoma cell metastasis was also evaluated using an in vivo model. The effect of METTL3 on the phosphorylation of PI3K and AKT was measured with western blot analysis. Our results showed that miR-302a-3p was significantly downregulated in melanoma and exerted a tumour suppressive role against melanoma progression. We identified METTL3 as a direct target of miR-302a-3p in melanoma cells using bioinformatics analysis and luciferase assay. Furthermore, the enforced overexpression of METTL3 promoted the proliferation, cell cycle progression, cell invasion, migration, expression of epithelial-to-mesenchymal transition markers, and the PI3K-AKT signalling pathway as well as suppressed the apoptosis of melanoma cells. Meanwhile, silencing the expression of METTL3 with specific shRNA demonstrated reverse outcomes of the above phenotypes in melanoma cells. By rescue experiments, we found that the restoration of METTL3 expression in miR-302a-3p-overexpressing melanoma cells successfully recovered the miR-302a-3p-mediated melanoma suppression. The in vivo results also showed that miR-302a-3p substantially inhibited melanoma cell growth and metastasis. In summary, this study demonstrated that miR-302a-3p targets METTL3 and plays tumour suppressive roles in the proliferation, apoptosis, invasion, and migration of melanoma cells.
    Keywords:  METTL3; carcinogenesis; m6A; melanoma; miR-302a-3p
    DOI:  https://doi.org/10.1080/1120009X.2021.1953886
  6. NPJ Precis Oncol. 2021 Jul 19. 5(1): 68
    PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN.
    Yifei Qin, Qiang Zuo, Lei Huang, Liping Huang, Glenn Merlino, Yanlin Yu.
      Targeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses.
    DOI:  https://doi.org/10.1038/s41698-021-00207-x
  7. J Biomol Struct Dyn. 2021 Jul 19. 1-16
    Polymorphisms at site 469 of B-RAF protein associated with skin melanoma may be correlated with dabrafenib resistance: An in silico study.
    Samadrita Chatterjee, Rajkumar Chakraborty, Yasha Hasija.
      Melanoma is a type of skin cancer. Numerous genes and their proteins are strongly associated with melanoma susceptibility. This study aims to use an in silico method to identify genetic variants in the melanoma susceptibility gene. The COSMIC database was queried for genes and cross-referenced with three environment-gene interaction databases (EGP, SeattleSNPs and CTD) to identify shared genes. The majority of approved skin melanoma drugs were found to act on the protein serine/threonine-protein kinase (B-RAF) encoded by the BRAF gene, which was also present in all three referenced databases. Comprehensive computational analysis was performed to predict deleterious genetic variants associated with skin melanoma, and the nsSNPs G469V and G469E were prioritized based on their predicted deleterious effects. Molecular dynamic simulation analysis of the B-RAF protein mutants G469V and G469E reveals that variations in the amino acid conformation at the drug binding site result in inconsistency in drug interaction. Additionally, this analysis showed that the G469V and G469E mutants have lower binding energy for dabrafenib than the wild type. The population with the highest frequency of each deleterious and pathogenic variant has been determined. The study's findings would support the development of more effective treatment strategies for skin melanoma. Communicated by Ramaswamy H. Sarma.
    Keywords:  B-RAF mutants; G469E; G469V; Skin melanoma; dabrafenib
    DOI:  https://doi.org/10.1080/07391102.2021.1950571
  8. Eur J Pediatr. 2021 Jul 17.
    Differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents.
    Fortes Cristina, Mastroeni Simona, Capuano Maria, Ricozzi Ilaria, Bono Riccardo, Ricci Francesco, Pagnanelli Gianluca, Nudo Maurizio.
      It is not known if children and adolescents with atypical Spitz tumour and cutaneous melanoma differ in terms of etiological factors. The aim of this study was to explain differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour. In the context of a study on melanocytic lesions, all subjects aged under 20 years with either cutaneous melanoma or atypical Spitz tumour were included (N = 105). Information on socio-demographic characteristics, individual and environmental factors were collected for both mother and child. The Fisher's exact test and the Mann-Whitney U test were used for categorical variables and continuous variables respectively. A multivariate logistic model was used to explain differences in outcome by differences in explanatory variables. In comparison to patients with cutaneous melanoma, patients with atypical Spitz tumour had less freckles (p = 0.020), lower number of common nevi (p = 0.002), and lower body mass index (p = 0.001) and experienced less sunburns episodes (p = 0.008). However, in the multivariate analysis, only a low number of common nevi remained statistically significant. Children and adolescents with cutaneous melanoma have a high number of nevi in comparison to the same-age group with atypical Spitz tumour.Conclusion: The results of this study suggest that the only difference in individual and environmental risk factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents is the number of nevi. What is Known: •Atypical Spitz tumours and cutaneous melanoma in children and adolescents are clinically similar, but compared with melanoma, they have a good overall prognosis. •Risk factors for cutaneous melanoma in children and adolescents are similar to the ones found in adults in the literature What is New: •Differences in individual and environmental risk factors for atypical Spitz tumour in children and adolescents are described for the first time in this study. •Individual and environmental factors for atypical Spitz tumour in children and adolescents are comparable to cutaneous melanoma, except for the presence of low number of nevi.
    Keywords:  Adolescents; Atypical Spitz tumour; Children; Cutaneous melanoma; Individual and environmental factors
    DOI:  https://doi.org/10.1007/s00431-021-04204-x
  9. Int J Mol Sci. 2021 Jul 20. pii: 7723. [Epub ahead of print]22(14):
    Special Issue "Precision Oncology in Melanoma Progression".
    Simona D'Aguanno.
      Melanoma represents the most malignant type of skin cancer, with increasing incidence worldwide [...].
    DOI:  https://doi.org/10.3390/ijms22147723
  10. Sci Rep. 2021 Jul 19. 11(1): 14644
    Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo.
    Yona Goldshmit, Rita Perelroizen, Alex Yakovchuk, Evgeni Banyas, Lior Mayo, Sari David, Amit Benbenishty, Pablo Blinder, Moshe Shalom, Angela Ruban.
      Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma.
    DOI:  https://doi.org/10.1038/s41598-021-94183-8
  11. ANZ J Surg. 2021 Aug;91 Suppl 2 3-13
    Contemporary management of locoregionally advanced melanoma in Australia and New Zealand and the role of adjuvant systemic therapy.
    B Mark Smithers, Robyn P M Saw, David E Gyorki, Richard C W Martin, Victoria Atkinson, Andrew Haydon, Rachel Roberts-Thomson, John F Thompson.
      Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long-term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post-surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high-risk primary melanoma and recent advances in adjuvant systemic therapies for high-risk patients.
    Keywords:  adjuvant drug therapy; cutaneous melanoma; immunotherapy; sentinel node biopsy; staging; targeted therapy
    DOI:  https://doi.org/10.1111/ans.17051
  12. Future Oncol. 2021 Jul 22.
    Development and validation of an immune gene set-based prognostic signature in cutaneous melanoma.
    Qi Tian, Huan Gao, Wen Zhao, Yan Zhou, Jin Yang.
      We aimed to fully understand the landscape of the skin cutaneous melanoma (SKCM) microenvironment and develop an immune prognostic signature that can predict the prognosis for SKCM patients. RNA sequencing data and clinical information were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus databases. The immune-prognostic signature was constructed by LASSO Cox regression analysis. We calculated the relative abundance of 29 immune-related gene sets based on the mRNA expression profiles of 314 SKCM patients in the Cancer Genome Atlas training set. Hierarchical clustering was performed to classify SKCM patients into three clusters: immunity-high, -medium and -low. The values of our prognostic model in predicting disease progression, metastasis and immunotherapeutic responses were also validated. In conclusion, the prognostic model demonstrated a powerful ability to distinguish and predict SKCM patients' prognosis.
    Keywords:  GEO; TCGA; cutaneous melanoma; immunotherapeutic response; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.2217/fon-2021-0104
  13. Int J Mol Sci. 2021 Jul 19. pii: 7701. [Epub ahead of print]22(14):
    Flavonoid Glycosides from Ziziphus jujuba var. inermis (Bunge) Rehder Seeds Inhibit α-Melanocyte-Stimulating Hormone-Mediated Melanogenesis.
    Ilandarage Menu Neelaka Molagoda, Kyoung-Tae Lee, Athapaththu Mudiyanselage Gihan Kavinda Athapaththu, Yung-Hyun Choi, Jaeyoung Hwang, Su-Jin Sim, Sanghyuck Kang, Gi-Young Kim.
      Ziziphus jujuba extracts possess a broad spectrum of biological activities, such as antioxidant and anticancer activities in melanoma cancers. Nevertheless, the compounds contain high antioxidant capacities and anticancer activities in melanoma cells, shown to be effective in hyperpigmentation disorders, but whether flavonoid glycosides from Z. jujuba regulate anti-melanogenesis remains unclear. In this study, we evaluated the anti-melanogenic activity of five flavonoid glycosides from Z. jujuba var. inermis (Bunge) Rehder seeds, including jujuboside A (JUA), jujuboside B (JUB), epiceanothic acid (EPA), betulin (BTL), and 6'''-feruloylspinosin (FRS), in B16F10 melanoma cells and zebrafish larvae. According to our results, JUB, EPA, and FRS potently inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and prevented hyperpigmentation in zebrafish larvae. In particular, under α-MSH-stimulated conditions, FRS most significantly inhibited α-MSH-induced intracellular and extracellular melanin content in B16F10 melanoma cells. Additionally, JUB, EPS, and FRS remarkably downregulated melanogenesis in α-MSH-treated zebrafish larvae, with no significant change in heart rate. Neither JUA nor BTA were effective in downregulating melanogenesis in B16F10 melanoma cells and zebrafish larvae. Furthermore, JUB, EPA, and FRS directly inhibited in vitro mushroom tyrosinase enzyme activity. JUB, EPA, and FRS also downregulated cyclic adenosine monophosphate (cAMP) levels and the phosphorylation of cAMP-response element-binding protein (CREB), and subsequent microphthalmia transcription factor (MITF) and tyrosinase expression. In conclusion, this study demonstrated that JUB, EPA, and FRS isolated from Z. jujuba var. inermis (Bunge) Rehder seeds exhibit potent anti-melanogenic properties by inhibition of the cAMP-CERB-MITF axis and consequent tyrosinase activity.
    Keywords:  Ziziphus jujuba var. inermis (Bunge) Rehder; flavonoid glycoside
    DOI:  https://doi.org/10.3390/ijms22147701
  14. Melanoma Res. 2021 Jul 19.
    Proteomic profiles of melanoma cell-derived exosomes in plasma: discovery of potential biomarkers of melanoma progression.
    Sujan Kumar Mondal, Theresa L Whiteside.
      Cancer liquid biopsy encompassing circulating tumor cells (CTC), circulating tumor DNA (ctDNA) and/or tumor-derived exosomes (TEX) emerges as a novel approach to early detection, noninvasive monitoring of responses to therapy and predicting patient survival. TEX are a key component of liquid biopsy because they mimic tumor cells in their proteomic and genetic content. Two recent proteomic analyses of TEX released into plasma by melanoma cells confirms the potential of TEX as diagnostic and prognostic markers in melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000762
  15. Reprod Biol. 2021 Jul 15. pii: S1642-431X(21)00056-5. [Epub ahead of print]21(3): 100535
    miR-383-5p inhibits human malignant melanoma cells function via targeting CENPF.
    Haiting Xu, Xuwei Zhu, Li Shi, Nan Lin, Xiaoyang Li.
      Human malignant melanoma (MM), is a type of skin cancer with high morbidity and mortality. In this study, we investigated the role of miR-383-5p in human MM cells in vitro. miR-383-5p expression was downregulated in MM cell lines compared with the human normal melanocyte cell line, and miR-383-5p overexpression inhibited the proliferation, migration, and invasion of M14 and A375 cells. Furthermore, miR-383-5p was able to effectively bind to the 3'UTR of CENPF mRNA. miR-383-5p expression was negatively correlated with CENPF expression and miR-383-5p overexpression inhibited CENPF protein expression in M14 and A375 cells. The overexpression of CENPF could effectively rescue the inhibitory effect on proliferation and invasion caused by miR-383-5p. Additionally, using publicly available databases, we showed that CENPF expression was upregulated in human MM tissues and could predict the prognosis of MM. In conclusion, miR-383-5p acts as a tumor suppressor in human MM by targeting CENPF, suggesting CENPF as a potential therapeutic target for human MM.
    Keywords:  Apoptosis; CENPF; Human malignant melanoma; Proliferation; miR-383-5p
    DOI:  https://doi.org/10.1016/j.repbio.2021.100535
  16. Front Mol Biosci. 2021 ;8 665222
    Identification of the m6A RNA Methylation Regulators WTAP as a Novel Prognostic Biomarker and Genomic Alterations in Cutaneous Melanoma.
    Zi-Yi Feng, Ting Wang, Xin Su, Shu Guo.
      Background: The purpose of our research was to establish a gene signature and determine the prognostic value of m6A methylation regulators in cutaneous melanoma and WTAP as a protective gene in cutaneous melanoma prognosis, we also evaluated gene mutations in cutaneous melanoma. Methods: We downloaded the RNA-seq transcriptome data and the clinical information for cutaneous melanoma patients from the GTEx and TCGA databases. Consensus clustering analysis was applied to divide the samples into two groups. Then the least absolute shrinkage and selection operator (LASSO) analyses were conducted to construct a risk signature, and we use external and internal datasets to verify its predictive value. We further searched the cBioPortal tools to detect genomic alterations and WTAP mutations. Finally, WTAP was further identified as a prognostic factor, and the related mechanisms mediated by WTAP were predicted by gene set enrichment analysis (GSEA). Experimental validations and have been further carried out. Results: Notably, m6A RNA methylation regulators play significant roles in tumorigenesis and development. In total, we selected three subtypes of cutaneous melanoma according to consensus clustering of the m6A RNA methylation regulators, and the stage of cutaneous melanoma was proven to be related to the subtypes. The Cox regression and LASSO analyses built a risk signature including ELF3, ZC3H13 and WTAP. The prognostic value of the risk signature in internal and external datasets have been proven then. The whole-genome and selected gene WTAP mutations were further explored. WTAP as a single prognostic factor was also explored and found to serve as an independent protective prognostic factor. Conclusions: Our study constructed a stable risk signature composed of m6A RNA methylation regulators in cutaneous melanoma. Moreover, WTAP was identified as a valuable prognostic factor and potential molecular target for cutaneous melanoma treatment.
    Keywords:  WTAP; biomarker; cutaneous melanoma; genomic alterations; m6A regulators; survival analysis
    DOI:  https://doi.org/10.3389/fmolb.2021.665222
  17. Pigment Cell Melanoma Res. 2021 Jul 20.
    The immunosuppressive role of Edn3 over-expression in the melanoma microenvironment.
    Juliano T Freitas, Jesus Lopez, Claudia Llorian, Mariana Boroni, Lidia Kos.
      Endothelins are cytokines expressed in the microenvironment of several tumors. To identify which stromal cells in the melanoma microenvironment respond to endothelin, we injected murine melanoma cell lines B16F10, YUMM1.7and YUMMER1.7 in a transgenic mouse that over-expresses endothelin 3 (Edn3) under the control of the Keratin 5 promoter in the skin (K5-Edn3). All cell lines developed larger tumors in K5-Edn3 mice than in control animals. In YUMM1.7 tumors, the Edn3 receptor, Endothelin receptor b (Ednrb), was expressed in several stromal cell types including immune cells. This result was validated by the identification of Ednrb positive stromal cells in human melanoma from previously published RNA-seq data. Regulatory T cells (Treg) and Dendritic Cells numbers were significantly higher in K5-Edn3 tumors when compared to control tumors. Edn3 increased Treg proliferation in vitro and the expression of FOXP3. YUMM1.7-GFP tumors in K5-Edn3 mice were sensitive to immune checkpoint inhibitor (anti-CTLA-4) as well as to Ednrb blockage (BQ-788). Our results indicate that Ednrb signaling has an important role in the melanoma microenvironment where it mediates immunosuppression resulting in escape from tumor immunity.
    Keywords:  Tregs; endothelin; immunosuppression; melanoma; microenvironment
    DOI:  https://doi.org/10.1111/pcmr.13002
  18. Cancers (Basel). 2021 Jul 17. pii: 3591. [Epub ahead of print]13(14):
    Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma.
    Piotr Rutkowski, Patrick Pauwels, Joseph Kerger, Bart Jacobs, Geert Maertens, Valerie Gadeyne, Anne Thielemans, Katrien de Backer, Bart Neyns.
      Tissue-based tests for BRAFV600 mutation-positive melanoma involve invasive biopsy procedures, and can lead to an erroneous diagnosis when the tumor samples degrade. Herein, we explored a minimally invasive, cell-free deoxyribonucleic acid (cfDNA)-based platform, to retest patients for BRAFV600 mutations. This phase 2 study enrolled adult patients with unresectable/metastatic melanoma. A prescreening testing phase evaluated the concordance between a prior tissue-based BRAFV600 mutation test result and a subsequent plasma cfDNA-based test result. A treatment phase evaluated the patients who were confirmed as BRAFV600 mutation-positive, and were treated with cobimetinib plus vemurafenib. It was found that 35/54 patients (64.8%) with a mutant BRAF status by prior tissue test had a positive BRAFV600 mutation with the cfDNA test. Further, 7/118 patients (5.9%) with a wild-type BRAF status had a positive BRAFV600 mutation cfDNA test; tissue retests on archival samples confirmed BRAFV600 mutation positivity in 5/7 patients (71.4%). One of these patients received BRAF pathway-targeted therapy (cobimetinib plus vemurafenib), and had progression-free survival commensurate with previous experience. In the overall cobimetinib plus vemurafenib-treated population, 29/36 patients (80.6%) had an objective response. The median progression-free survival was 13.6 months (95% confidence interval, 9.5-16.5). Cell-free DNA-based tests may be a fast and convenient option to identify BRAF mutation status in melanoma patients, and help inform treatment decisions.
    Keywords:  BRAFV600 mutations; cell-free DNA; melanoma
    DOI:  https://doi.org/10.3390/cancers13143591
  19. Pigment Cell Melanoma Res. 2021 Jul 17.
    Identification of melanoma-specific exosomal miRNAs as the potential biomarker for canine oral melanoma.
    Al Asmaul Husna, Md Mahfuzur Rahman, Yu-Chang Lai, Hui-Wen Chen, Md Nazmul Hasan, Takayuki Nakagawa, Naoki Miura.
      Considering the importance of the canine cancer model of human disease, as well as the need for strategies for canine cancer management, the properties of exosomes are an emerging topic in canine oncology. In our study, exosomal RNA was isolated and investigated by next-generation sequencing. We identified several differentially expressed microRNAs (miRNAs/miRs) in the exosomes of two melanoma cell lines compared with non-tumor reference exosomes. We explored these potential melanoma-specific exosomal miRNAs further and found that miR-143 and let-7b increased in primary, whereas miR-210, 708, 221, and 222 increased in metastatic site originated melanoma cells. Further analysis showed miR-143 and 221 significantly increased in plasma exosomes of metastatic melanoma patients. Moreover, the sensitivity and specificity are greater than 85% for differentiating the non-metastatic and metastatic patients. Therefore, these miRNAs can be an incredible biomarker candidate to identify metastatic melanoma and facilitate a better prognosis.
    Keywords:  Dog; Exosome; Melanoma; MicroRNA; Next generation sequencing
    DOI:  https://doi.org/10.1111/pcmr.13000
  20. EMBO Rep. 2021 Jul 23. e51683
    CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
    Pietro Berico, Max Cigrang, Guillaume Davidson, Cathy Braun, Jeremy Sandoz, Stephanie Legras, Bujamin Hektor Vokshi, Nevena Slovic, François Peyresaubes, Carlos Mario Gene Robles, Jean-Marc Egly, Emmanuel Compe, Irwin Davidson, Frederic Coin.
      Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.
    Keywords:  CDK7; GATA6; MITF; TFIIH; melanoma
    DOI:  https://doi.org/10.15252/embr.202051683
  21. Melanoma Res. 2021 Jul 19.
    Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma.
    Caroline Torricelli, Juliana Carron, Bruna Fernandes Carvalho, Ligia Traldi Macedo, José Augusto Rinck-Junior, Carmen Silvia Passos Lima, Gustavo Jacob Lourenço.
      Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1β (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients' survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher's exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan-Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III-V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10-8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.
    DOI:  https://doi.org/10.1097/CMR.0000000000000763
  22. J Skin Cancer. 2021 ;2021 5531864
    Retrospective Analysis of Rechallenge with Ipilimumab in Patients with Metastatic Melanoma.
    A A Formozo, J R Gomes, R A Schmerling, A C Buzaid.
       Background: Checkpoint inhibitors are effective in the treatment of several types of cancer, either being used separately or in combination. Ipilimumab pioneered the treatment of metastatic melanoma, and nowadays, it has been used more frequently in combination with anti-PD-1. Since the development of anti-PD1 for melanoma, rechallenge with ipilimumab has not been considered, although its use was considered in early trials.
    Cases: In this study, we analyzed 22 patients with metastatic melanoma who had benefited from the first treatment with ipilimumab, but eventually had progressive disease. They received ipilimumab at the same dose as the first treatment. Most of the patients received the second course after six months or more from the first treatment with ipilimumab. The median progression-free survival (mPFS) of the treatment with ipilimumab was 8.9 months, and the median progression-free survival of the second course was 6.3 months.
    Conclusion: There are limited data on rechallenge with ipilimumab addressing progression-free survival (PFS). In our analysis, twenty-two patients treated with a second course of ipilimumab were analyzed and most of them had a significant benefit. Despite the current alternatives for salvage therapies, rechallenging with ipilimumab might be an alternative to be considered in patients who had initial benefit.
    DOI:  https://doi.org/10.1155/2021/5531864
  23. J Exp Med. 2021 Sep 06. pii: e20210571. [Epub ahead of print]218(9):
    Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.
    Roberto Vendramin, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, Panagiotis Karras, Ewout Demesmaeker, Francesca M Bosisio, Lukas Kucera, Jan Rozman, Ivan Gladwyn-Ng, Lara Rizzotto, Erik Dassi, Stefania Millevoi, Oliver Bechter, Jean-Christophe Marine, Eleonora Leucci.
      The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAFV600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.
    DOI:  https://doi.org/10.1084/jem.20210571
  24. Cancers (Basel). 2021 Jul 08. pii: 3426. [Epub ahead of print]13(14):
    Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases.
    Brett M Szeligo, Abby D Ivey, Brian A Boone.
      Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.
    Keywords:  immunotherapy; isolated hepatic perfusion; melphalan; percutaneous hepatic perfusion; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13143426
  25. Ophthalmol Glaucoma. 2021 Jul 20. pii: S2589-4196(21)00173-3. [Epub ahead of print]
    Secondary Glaucoma Associated With Intraocular Metastatic Cutaneous Melanoma.
    Jason A Greenfield, Megan Rowlands, J William Harbour.
      
    Keywords:  Metastatic cutaneous melanoma; cyclophotocoagulation; pars plana vitrectomy; secondary glaucoma
    DOI:  https://doi.org/10.1016/j.ogla.2021.07.005
  26. Eur J Cancer. 2021 Jul 20. pii: S0959-8049(21)00335-X. [Epub ahead of print]154 227-234
    Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours.
    Titus J Brinker, Lennard Kiehl, Max Schmitt, Tanja B Jutzi, Eva I Krieghoff-Henning, Dieter Krahl, Heinz Kutzner, Patrick Gholam, Sebastian Haferkamp, Joachim Klode, Dirk Schadendorf, Achim Hekler, Stefan Fröhling, Jakob N Kather, Sarah Haggenmüller, Christof von Kalle, Markus Heppt, Franz Hilke, Kamran Ghoreschi, Markus Tiemann, Ulrike Wehkamp, Axel Hauschild, Michael Weichenthal, Jochen S Utikal.
       AIM: Sentinel lymph node status is a central prognostic factor for melanomas. However, the surgical excision involves some risks for affected patients. In this study, we therefore aimed to develop a digital biomarker that can predict lymph node metastasis non-invasively from digitised H&E slides of primary melanoma tumours.
    METHODS: A total of 415 H&E slides from primary melanoma tumours with known sentinel node (SN) status from three German university hospitals and one private pathological practice were digitised (150 SN positive/265 SN negative). Two hundred ninety-one slides were used to train artificial neural networks (ANNs). The remaining 124 slides were used to test the ability of the ANNs to predict sentinel status. ANNs were trained and/or tested on data sets that were matched or not matched between SN-positive and SN-negative cases for patient age, ulceration, and tumour thickness, factors that are known to correlate with lymph node status.
    RESULTS: The best accuracy was achieved by an ANN that was trained and tested on unmatched cases (61.8% ± 0.2%) area under the receiver operating characteristic (AUROC). In contrast, ANNs that were trained and/or tested on matched cases achieved (55.0% ± 3.5%) AUROC or less.
    CONCLUSION: Our results indicate that the image classifier can predict lymph node status to some, albeit so far not clinically relevant, extent. It may do so by mostly detecting equivalents of factors on histological slides that are already known to correlate with lymph node status. Our results provide a basis for future research with larger data cohorts.
    Keywords:  Artificial intelligence; Biomarkers; Histology; Lymph node biopsy; Machine learning; Melanoma; Neural network model; Pathology; Sentinel; Skin cancer
    DOI:  https://doi.org/10.1016/j.ejca.2021.05.026
  27. J Immunother Cancer. 2021 Jul;pii: e002226. [Epub ahead of print]9(7):
    DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma.
    Katharina Filipski, Michael Scherer, Kim N Zeiner, Andreas Bucher, Johannes Kleemann, Philipp Jurmeister, Tabea I Hartung, Markus Meissner, Karl H Plate, Tim R Fenton, Jörn Walter, Sascha Tierling, Bastian Schilling, Pia S Zeiner, Patrick N Harter.
       BACKGROUND: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking.
    METHODS: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP).
    RESULTS: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma.
    CONCLUSIONS: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
    Keywords:  biomarkers; biostatistics; immunotherapy; melanoma; tumor; tumor biomarkers
    DOI:  https://doi.org/10.1136/jitc-2020-002226
  28. Melanoma Res. 2021 Jul 19.
    Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.
    Gina Klee, Jonas Kurzhals, Victoria Hagelstein, Detlef Zillikens, Andreas Recke, Ewan A Langan, Patrick Terheyden.
      Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.
    DOI:  https://doi.org/10.1097/CMR.0000000000000760
  29. Int J Mol Sci. 2021 Jul 13. pii: 7511. [Epub ahead of print]22(14):
    The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2.
    Albina Fejza, Maurizio Polano, Lucrezia Camicia, Evelina Poletto, Greta Carobolante, Giuseppe Toffoli, Maurizio Mongiat, Eva Andreuzzi.
      The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2-/- mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.
    Keywords:  extracellular matrix; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms22147511
  30. Cancers (Basel). 2021 Jul 04. pii: 3359. [Epub ahead of print]13(13):
    Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis.
    Elias A T Koch, Anne Petzold, Anja Wessely, Edgar Dippel, Anja Gesierich, Ralf Gutzmer, Jessica C Hassel, Sebastian Haferkamp, Bettina Hohberger, Katharina C Kähler, Harald Knorr, Nicole Kreuzberg, Ulrike Leiter, Carmen Loquai, Friedegund Meier, Markus Meissner, Peter Mohr, Claudia Pföhler, Farnaz Rahimi, Dirk Schadendorf, Beatrice Schell, Max Schlaak, Patrick Terheyden, Kai-Martin Thoms, Beatrice Schuler-Thurner, Selma Ugurel, Jens Ulrich, Jochen Utikal, Michael Weichenthal, Fabian Ziller, Carola Berking, Markus V Heppt, On Behalf Of The German Dermatologic Cooperative Oncology Group DeCOG Committee Ocular Melanoma.
       BACKGROUND: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB.
    METHODS: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts.
    RESULTS: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts.
    CONCLUSION: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
    Keywords:  CTLA-4; PD-1; immune checkpoint blockade; liver metastasis; treatment resistance; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13133359
  31. Cancers (Basel). 2021 Jul 02. pii: 3334. [Epub ahead of print]13(13):
    The Analysis of Inflammation-Related Proteins in a Cargo of Exosomes Derived from the Serum of Uveal Melanoma Patients Reveals Potential Biomarkers of Disease Progression.
    Joanna Patrycja Wróblewska, Michał Stefan Lach, Katarzyna Kulcenty, Łukasz Galus, Wiktoria Maria Suchorska, Daniel Rösel, Jan Brábek, Andrzej Marszałek.
       BACKGROUND: Uveal melanoma (UM) is the most common intraocular tumour in adults with a poor prognosis and extremely high mortality rate due to the development of metastatic disease. However, despite relatively good knowledge about the histological and genetic risk factors for metastasis development, there is no specific biomarker that would allow early detection of UM progression. Recently, exosomes and their molecular cargo have been widely studied in the search for potential biomarkers in several cancers. The purpose of this study was to analyze the inflammation-related protein cargo of exosomes derived from the serum of primary and metastatic UM patients and healthy donors.
    METHODS: The exosomes were isolated from the serum of primary and metastatic UM patients and healthy donors. Using multiplex immunoassay technology, we analyzed the concentration of 37 inflammation-related proteins in obtained exosomes.
    RESULTS: The analysis of protein cargo showed several molecules related to inflammation, such as interferon-gamma, interleukin 2, 22 and 12(p40), Pentraxin-3, TNFSF13B and TNFSF8 which were significantly enriched in metastatic UM exosomes. We showed a significant correlation between the disease stage and the concentration of these inflammation-related proteins from exosomal cargo.
    CONCLUSIONS: Based on the obtained results, we propose the panel of exosomal proteins for early detection of uveal melanoma progression into metastatic disease.
    Keywords:  biomarkers; exosomes; inflammation-related proteins; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13133334
  32. Am J Ophthalmol. 2021 Jul 17. pii: S0002-9394(21)00366-4. [Epub ahead of print]
    Multiple genetically distinct uveal melanomas arise in the same eye of two patients with melanosis oculiUnilateral multifocal uveal melanoma in melanosis oculi.
    Sushant Wagley, Peter J Belin, James J Dollar, J William Harbour, Amanda C Maltry, Prithvi Mruthyunjaya, Amy C Schefler, Peter H Tang.
       PURPOSE: To determine whether unilateral multifocal uveal melanomas (UM) in the setting of ocular melanosis (melanosis oculi) represent genetically independent tumors.
    DESIGN: Clinical case series.
    METHODS: Two patients with unilateral multifocal UM in the setting of melanosis oculi were included. Tumors were evaluated for gene expression profile (GEP) and next generation sequencing (NGS) for uveal melanoma-associated mutations. Histopathologic analysis of enucleated specimens was also performed when available.
    RESULTS: Patients were both female, ages 73 and 83 years. In Patient #1, the tumors both exhibited Class 2 GEP but each harbored a unique BAP1 mutation. In Patient #2, one tumor was Class 1 and harbored an SF3B1 mutation, whereas the other tumor was Class 2 and harbored a BAP1 mutation.
    CONCLUSIONS: Unilateral multifocal UM in the setting of melanosis oculi can arise due to the development of genetically independent primary tumors, which is detectable based on the mutation profile of each tumor. This is the first report of genetically-confirmed independent primary tumors in the setting of unilateral multifocal UM.
    Keywords:  BAP1; GNAQ; PRAME; SF3B1; Uveal melanoma; cancer; choroidal melanoma; melanoma; oculodermal melanocytosis; tumor
    DOI:  https://doi.org/10.1016/j.ajo.2021.06.037
  33. Int J Mol Sci. 2021 Jul 04. pii: 7204. [Epub ahead of print]22(13):
    The Abscopal Effect in the Era of Checkpoint Inhibitors.
    Ondřej Kodet, Kristýna Němejcova, Karolína Strnadová, Andrea Havlínová, Pavel Dundr, Ivana Krajsová, Jiří Štork, Karel Smetana, Lukáš Lacina.
      Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.
    Keywords:  abscopal effect; anti-CTLA-4; cryotherapy; melanoma; tumor neoantigens; wound healing
    DOI:  https://doi.org/10.3390/ijms22137204
  34. Genes Dis. 2021 Sep;8(5): 677-688
    SFRP5 inhibits melanin synthesis of melanocytes in vitiligo by suppressing the Wnt/β-catenin signaling.
    Dao-Pei Zou, Yang-Mei Chen, Ling-Zhao Zhang, Xiao-Hui Yuan, Yu-Jie Zhang, Adelina Inggawati, Pham Thi Kieu Nguyet, Tian-Wen Gao, Jin Chen.
      Secreted frizzled-related protein 5 (SFRP5) plays a pivotal role in regulating the development of many tissues and organs, however, as an inhibitor of Wnt signaling, the role of SFRP5 in vitiligo remains unknown. Hence, we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo. In this study, we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo. Compared with that in normal epidermal melanocytes (PIG1), the expression of SFRP5 was increased in vitiligo melanocytes (PIG3V). To investigate the effect of SFRP5 on melanin synthesis, PIG1 cells were infected with recombinant SFRP5 adenovirus (AdSFRP5), and PIG3V cells were infected with recombinant siSFRP5 adenovirus (AdsiSFRP5). The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor (MITF) and its target proteins via suppression of the Wnt/β-catenin signaling pathway. Accordingly, SFRP5 silencing increased melanin synthesis and activated the Wnt signaling pathway in PIG3V cells. Moreover, SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor (TCF/LEF) in PIG1 cells. Furthermore, this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the β-catenin agonist, SKL2001. The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model. Hence, our results indicate that SFRP5 can inhibit melanogenesis in melanocytes. Additionally, our findings showed that SFRP5 plays a vital role in the development of vitiligo, and thus may serve as a potential therapeutic target for vitiligo.
    Keywords:  MITF; Melanin synthesis; Melanocytes; SFRP5; Vitiligo; Wnt signaling
    DOI:  https://doi.org/10.1016/j.gendis.2020.06.003
  35. Cancers (Basel). 2021 Jul 20. pii: 3640. [Epub ahead of print]13(14):
    Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors.
    Deirdre Kelly, April A N Rose, Thiago Pimentel Muniz, David Hogg, Marcus O Butler, Samuel D Saibil, Ian King, Zaid Saeed Kamil, Danny Ghazarian, Kendra Ross, Marco Iafolla, Daniel V Araujo, John Waldron, Normand Laperriere, Hatem Krema, Anna Spreafico.
      Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0-17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014-2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan-Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0-1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS-a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.
    Keywords:  CTLA4; PD1; immune checkpoint inhibitor; immunotherapy; predictive score; prognostic; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13143640
  36. Materials (Basel). 2021 Jul 16. pii: 3985. [Epub ahead of print]14(14):
    Electrochemotherapy and Other Clinical Applications of Electroporation for the Targeted Therapy of Metastatic Melanoma.
    Corina Ioana Cucu, Călin Giurcăneanu, Liliana Gabriela Popa, Olguța Anca Orzan, Cristina Beiu, Alina Maria Holban, Alexandru Mihai Grumezescu, Bogdan Mircea Matei, Marius Nicolae Popescu, Constantin Căruntu, Mara Mădălina Mihai.
      Electrochemotherapy (ECT) is an effective bioelectrochemical procedure that uses controlled electrical pulses to facilitate the increase of intracellular concentration of certain substances (electropermeabilization/ reversible electroporation). ECT using antitumor drugs such as bleomycin and cisplatin is a minimally invasive targeted therapy that can be used as an alternative for oncologic patients not eligible for surgery or other standard therapies. Even though ECT is mainly applied as palliative care for metastases, it may also be used for primary tumors that are unresectable due to size and location. Skin neoplasms are the main clinical indication of ECT, the procedure reporting good curative results and high efficiency across all tumor types, including melanoma. In daily practice, there are many cases in which the patient's quality of life can be significantly improved by a safe procedure such as ECT. Its popularity must be increased because it has a safe profile and minor local adverse reactions. The method can be used by dermatologists, oncologists, and surgeons. The aim of this paper is to review recent literature concerning electrochemotherapy and other clinical applications of electroporation for the targeted therapy of metastatic melanoma.
    Keywords:  advanced melanoma; electrochemotherapy; electropermeabilization; electroporation; gene transfer; metastatic melanoma; targeted therapy
    DOI:  https://doi.org/10.3390/ma14143985
  37. Sci Rep. 2021 Jul 20. 11(1): 14788
    Synergistic effect of cold atmospheric pressure plasma and free or liposomal doxorubicin on melanoma cells.
    Konstantina Pefani-Antimisiari, Dimitrios K Athanasopoulos, Antonia Marazioti, Kyriakos Sklias, Maria Rodi, Anne-Lise de Lastic, Athanasia Mouzaki, Panagiotis Svarnas, Sophia G Antimisiaris.
      The aim of the present study was to investigate combined effects of cold atmospheric plasma (CAP) and the chemotherapeutic drug doxorubicin (DOX) on murine and human melanoma cells, and normal cells. In addition to free drug, the combination of CAP with a liposomal drug (DOX-LIP) was also studied for the first time. Thiazolyl blue tetrazolium bromide (MTT) and Trypan Blue exclusion assays were used to evaluate cell viability; the mechanism of cell death was evaluated by flow cytometry. Combined treatment effects on the clonogenic capability of melanoma cells, was also tested with soft agar colony formation assay. Furthermore the effect of CAP on the cellular uptake of DOX or DOX-LIP was examined. Results showed a strong synergistic effect of CAP and DOX or DOX-LIP on selectively decreasing cell viability of melanoma cells. CAP accelerated the apoptotic effect of DOX (or DOX-LIP) and dramatically reduced the aggressiveness of melanoma cells, as the combination treatment significantly decreased their anchorage independent growth. Moreover, CAP did not result in increased cellular uptake of DOX under the present experimental conditions. In conclusion, CAP facilitates DOX cytotoxic effects on melanoma cells, and affects their metastatic potential by reducing their clonogenicity, as shown for the first time.
    DOI:  https://doi.org/10.1038/s41598-021-94130-7
  38. Cancer Manag Res. 2021 ;13 5699-5709
    Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study.
    Johannes Kleemann, Manuel Jäger, Eva Valesky, Stefan Kippenberger, Roland Kaufmann, Markus Meissner.
       Purpose: Rising melanoma incidences lead to an increasing need for individual therapy strategies in old patients. Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, approved for the local treatment of unresectable metastatic melanoma. Since data on the efficacy and safety of geriatric patients are sparse, this study was conducted to gain further real-world experience in the treatment of old and oldest-old patients with T-VEC and to obtain data on therapy costs in this population in Germany.
    Patients and Methods: We performed a retrospective analysis, including all patients with a minimum age of 75 years who were treated with T-VEC from August 2016 to September 2020 in the Skin Cancer Center of the University Hospital Frankfurt, Germany. Patient clinicopathological data, treatment responses, toxicities, treatment-specific data and therapy costs were assessed.
    Results: Twelve patients with a median age of 83 years (75-89 years) at the start of treatment were identified. By the end of the study, three (25%) patients experienced complete remission (CR), four (33%) experienced partial response (PR), two patients (17%) remained at stable disease (SD) and three (25%) patients suffered from progressive disease (PD). Overall response rate was 58.3%, and durable response rate was 41.7%. There were no treatment-related adverse events grade 3 or higher. The median duration of treatment was seventeen weeks (3-57 weeks). Median medication costs in the patients who had completed treatment (n=10) were calculated to be 27,325 Euros in Germany.
    Conclusion: This study provides further evidence for an effective use of T-VEC in old and oldest-old patients. The low rate of adverse events seems to be favorable compared to other systemic melanoma therapies. Furthermore, duration of treatment was short and therapy costs were lower than would have been expected from clinical trial data. Altogether, these data encourage the use of T-VEC in this special patient cohort.
    Keywords:  advanced melanoma; cutaneous oncology; elderly patients; immunotherapy; intralesional therapy; oncolytic virus
    DOI:  https://doi.org/10.2147/CMAR.S286917
  39. Oncol Rep. 2021 Sep;pii: 197. [Epub ahead of print]46(3):
    Progression of melanoma is suppressed by targeting all transforming growth factor‑β isoforms with an Fc chimeric receptor.
    Shingo Kodama, Katarzyna Α Podyma-Inoue, Toshihiro Uchihashi, Kyoko Kurioka, Hitomi Takahashi, Akinari Sugauchi, Kazuki Takahashi, Toshihiro Inubushi, Mikihiko Kogo, Susumu Tanaka, Tetsuro Watabe.
      Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor‑β (TGF‑β) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial‑mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF‑β isoforms, TGF‑β1, TGF‑β2 and TGF‑β3, all of which engage in pro‑tumorigenic activities by activating SMAD signaling pathways. All TGF‑β isoforms activate signaling pathways by binding to their TGF‑β type I (TβRI) and type II (TβRII) receptors. Thus, effective targeting of all TGF‑β isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TβRI and/or TβRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TβRI and TβRII (TβRI‑TβRII‑Fc) effectively trapped all TGF‑β isoforms. Conversely, TβRII‑Fc chimeric receptor, that comprises TβRII only, was able to interact with TGF‑β1 and TGF‑β3 isoforms, but not with TGF‑β2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TβRI‑TβRII‑Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF‑β isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TβRII‑Fc chimeric receptor inhibited the EMT program induced by TGF‑β1 and TGF‑β3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TβRI‑TβRII‑Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF‑β signals that affect various components of the TME may result in the development of effective anti‑melanoma agents.
    Keywords:  EMT; Fc chimeric receptor; TGF‑β; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.3892/or.2021.8148
  40. Arkh Patol. 2021 ;83(4): 14-21
    [The prognostic value of uveal melanoma cell type].
    V A Yarovaya, A V Shatskikh, A R Zaretsky, I A Levashov, D P Volodin, A A Yarovoy.
       OBJECTIVE: To determine the prognostic value of a uveal melanoma (UM) cell type for the development of metastases (MTS).
    SUBJECTS AND METHODS: The investigation enrolled 96 patients (96 eyes) with UM after enucleation. Forty-one patients without signs of MTS were included in this group, who were followed up for more than 36 months (mean, 70.5 months (36 to 105 months)), 55 patients with MTS who were followed up for an average of 21 months (2 to 44 months). The MTS and non-MTS groups were statistically homogeneous in age, gender, tumor size, location, and ciliary body involvement in the process, as well as in extrabulbar growth.
    RESULTS: There were spindle cell, mixed cell, and epithelioid cell UMs in 44, 35, and 21% of patents, respectively. The tumors in patients without MTS were noted to be significantly more likely to have spindle cell-type UM (p<0.0001). Mixed cell and epithelioid cell UMs were more frequently detected in patients with MTS (p<0.0001), which was believed to be due to the presence of epithelioid cells in both cell types. A survival analysis showed that the 3- and 5-year survival rates for patients with spindle cell UM were significantly higher than that for those with epithelioid cell or mixed cell UM (p<0.001); the 3-and 5-year survival rates for spindle cell UM were 78 and 70%, respectively; those for mixed cell UM were 37 and 24%; and those for epithelioid cell UM were 50 and 31%.
    CONCLUSION: The similar survival rates for patients with mixed cell or epithelioid cell type UM could conclude that it is advisable to use the binary principle - the presence or absence of epithelioid cells in the tumor, when assessing a UM cell type as a prognostic factor.
    Keywords:  cell type; metastases; prognosis; survival rate; uveal melanoma
    DOI:  https://doi.org/10.17116/patol20218304114
  41. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00823-8. [Epub ahead of print]36(3): 109410
    Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
    Christopher J Terranova, Ming Tang, Mayinuer Maitituoheti, Ayush T Raman, Archit K Ghosh, Jonathan Schulz, Samir B Amin, Elias Orouji, Katarzyna Tomczak, Sharmistha Sarkar, Junna Oba, Caitlin Creasy, Chang-Jiun Wu, Samia Khan, Rossana Lazcano, Khalida Wani, Anand Singh, Praveen Barrodia, Dongyu Zhao, Kaifu Chen, Lauren E Haydu, Wei-Lien Wang, Alexander J Lazar, Scott E Woodman, Chantale Bernatchez, Kunal Rai.
      The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.
    Keywords:  Polycomb repressive complex 2; bivalent; broad domains; chromatin; epigenetics; melanoma; melanoma therapeutics; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2021.109410
  42. Jpn J Radiol. 2021 Jul 21.
    Tumor response evaluation in patients with malignant melanoma undergoing immune checkpoint inhibitor therapy and prognosis prediction using 18F-FDG PET/CT: multicenter study for comparison of EORTC, PERCIST, and imPERCIST.
    Kazuhiro Kitajima, Tadashi Watabe, Masatoyo Nakajo, Mana Ishibashi, Hiromitsu Daisaki, Fumihiko Soeda, Atsushi Tanemura, Takuro Kanekura, Naoya Yamazaki, Kimiteru Ito.
       OBJECTIVE: In malignant melanoma patients treated with immune checkpoint inhibitor (ICI) therapy, three different FDG-PET criteria, European Organization for Research and Treatment of Cancer (EORTC), PET Response Criteria in Solid Tumors (PERCIST), immunotherapy-modified PERCIST (imPERCIST), were compared regarding response evaluation and prognosis prediction using standardized uptake value (SUV) harmonization of results obtained with various PET/CT scanners installed at different centers.
    MATERIALS AND METHODS: Malignant melanoma patients (n = 27) underwent FDG-PET/CT examinations before and again 3 to 9 months after therapy initiation (nivolumab, n = 21; pembrolizumab, n = 6) with different PET scanners at five hospitals. EORTC, PERCIST, and imPERCIST criteria were used to evaluate therapeutic response, then concordance of the results was assessed using Cohen's κ coefficient. Log-rank and Cox methods were employed to determine progression-free (PFS) and overall (OS) survival.
    RESULTS: Complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) with harmonized EORTC, PERCIST, and imPERCIST was seen in 3/5/4/15, 4/5/3/15, and 4/5/5/13 patients, respectively. Nearly perfect concordance between each pair of criteria was noted (κ = 0.939-0.972). Twenty patients showed progression and 14 died from malignant melanoma after a median 19.2 months. Responders (CMR/PMR) showed significantly longer PFS and OS than non-responders (SMD/PMD) (harmonized EORTC: p < 0.0001 and p = 0.011; harmonized PERCIST: p < 0.0001 and p = 0.0012; harmonized imPERCIST: p < 0.0001 and p = 0.0012, respectively).
    CONCLUSIONS: All harmonized FDG-PET criteria (EORTC, PERCIST, imPERCIST) showed accuracy for response evaluation of ICI therapy and prediction of malignant melanoma patient prognosis. Additional studies to determine their value in larger study populations will be necessary.
    Keywords:  EORTC (European Organization for Research and Treatment of Cancer); FDG (fluorodeoxyglucose); ICI (immune checkpoint inhibitor); Malignant melanoma; PERCIST (Positron Emission Tomography Response Criteria in Solid Tumors); PET/CT (positron emission tomography/computed tomography)
    DOI:  https://doi.org/10.1007/s11604-021-01174-w
  43. Ann Transl Med. 2021 Jun;9(12): 1038
    Current status of intralesional agents in treatment of malignant melanoma.
    Misam Zawit, Umang Swami, Hassan Awada, Joyce Arnouk, Mohammed Milhem, Yousef Zakharia.
      Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved the median overall survival (OS) of metastatic melanoma from 6 months to more than 3 years. However, still about half of the patients die due to uncontrolled disease. Therefore, multiple strategies are currently being investigated to improve outcomes. One such strategy is intralesional/intratumoral (IT) therapies which can either directly kill the tumor cells or make the tumor more immunogenic to be recognized by the immune system. Talimogene laherparepvec (T-VEC), an oncolytic virus, is the first FDA approved IT therapy. This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.
    Keywords:  Melanoma; intralesional; intratumoral; talimogene laherparepvec (T-VEC)
    DOI:  https://doi.org/10.21037/atm-21-491
  44. Int J Mol Sci. 2021 Jul 02. pii: 7165. [Epub ahead of print]22(13):
    A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.
    Siras Hakobyan, Henry Loeffler-Wirth, Arsen Arakelyan, Hans Binder, Manfred Kunz.
      Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (n = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (RAB6B), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (MSR1), Collagen Type XI Alpha 2 Chain (COLL11A2), and LY6/PLAUR Domain Containing 1 (LYPD1). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (CHEK1) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (SF3A3, SF3B3), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.
    Keywords:  melanoma; splicing; transcriptome; tumor progression
    DOI:  https://doi.org/10.3390/ijms22137165
  45. Bull Exp Biol Med. 2021 Jul 24.
    Experimental Modeling of Multiple Primary Malignant Processes with One Tumor Suppressed by Another under Conditions of Primary Immunodeficiency.
    E M Frantsiyants, I V Kaplieva, L K Trepitaki, E I Surikova, V A Bandovkina, I V Neskubina, I М Коtievа, K А Shumarin.
      The phenomenon of multiple primary malignant tumors (MPMT) is characterized by the presence of several primary neoplasms in the same patient. An experimental model of MPMT with one dominating tumor was developed. Female BALB/c nude mice received simultaneous subcutaneous inoculation of Guerin's carcinoma (5×105 tumor cells in 0.5 ml saline) and B16/F10 melanoma (0.5 ml suspension diluted 1:20 with saline). Control females received transplantation of either melanoma or carcinoma alone in the same doses and volumes. In animals with MPMT model, tumors appeared 3-fold faster than after isolated transplantation of melanoma or Guerin's carcinoma and were larger by 7.5 and 2.2 times, respectively; the survival of mice with MPMT was lower. Guerin's carcinoma in the MPMT model metastasized to melanoma and almost completely suppressed its growth. Thus, a MPMT model was created with carcinoma suppressing the malignant growth of melanoma.
    Keywords:  female BALB/c nude mice; multiple primary malignant tumors; murine B16/F10 melanoma; rat Guerin’s carcinoma
    DOI:  https://doi.org/10.1007/s10517-021-05229-w
  46. Cancers (Basel). 2021 Jul 14. pii: 3520. [Epub ahead of print]13(14):
    Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers.
    Geeng-Fu Jang, Jack S Crabb, Bo Hu, Belinda Willard, Helen Kalirai, Arun D Singh, Sarah E Coupland, John W Crabb.
      Uveal melanoma metastases are lethal and remain incurable. A quantitative proteomic analysis of 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM) was pursued for insights into UM metastasis and protein biomarkers. The metastatic status of the pUM specimens was defined based on clinical data, survival histories, prognostic analyses, and liver histopathology. LC MS/MS iTRAQ technology, the Mascot search engine, and the UniProt human database were used to identify and quantify pUM proteins relative to the normal choroid excised from UM donor eyes. The determined proteomes of all 100 tumors were very similar, encompassing a total of 3935 pUM proteins. Proteins differentially expressed (DE) between metastasizing and non-metastasizing pUM (n = 402) were employed in bioinformatic analyses that predicted significant differences in the immune system between metastasizing and non-metastasizing pUM. The immune proteins (n = 778) identified in this study support the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM, and suggest CDH1, HLA-DPA1, and several DE immune kinases and phosphatases as possible candidates for immune therapy checkpoint blockade. Prediction modeling identified 32 proteins capable of predicting metastasizing versus non-metastasizing pUM with 93% discriminatory accuracy, supporting the potential for protein-based prognostic methods for detecting UM metastasis.
    Keywords:  bioinformatics; iTRAQ; immune profiling; metastasis; prediction modeling; quantitative proteomics; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13143520
  47. J Am Acad Dermatol. 2021 Jul 16. pii: S0190-9622(21)02101-0. [Epub ahead of print]
    Molecular characterization of fast-growing melanomas.
    Caroline Gaudy-Marqueste, Nicolas Macagno, Anderson Loundou, Eric Pellegrino, L'houcine Ouafik, Timothy Budden, Piyushkumar Mundra, Gabriela Gremel, Victoria Akhras, Lijing Lin, Martin Cook, Rajiv Kumar, Jean-Jacques Grob, Eduardo Nagore, Richard Marais, Amaya Virós.
       BACKGROUND: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM), and its potential to stratify patients at high risk of death, has not been comprehensively studied.
    OBJECTIVE: To investigate the epidemiological, clinical and mutational profile of primary cutaneous melanomas with a thickness ≥ 1mm, stratified by rate of growth (ROG).
    METHODS: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin embedded primary melanoma samples. Comparison of FGMM (ROG >0.5mm/month) and non-FGMM (ROG≤0.5 mm/month).
    RESULTS: Two hundred patients were enrolled among which 70 were FGMM. The relapse free survival was lower in the FGMM group (p=0.014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than non-FGMM (p=0.033). Ulceration (p=0.032), thickness (p=0.006), lower sun exposure (p=0.049), and FGFR2 mutations (p=0.037) were significantly associated with fast growth.
    LIMITATIONS: Single-center study, cohort size, potential memory bias, number of investigated genes.
    CONCLUSION: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness and FGFR2 mutations associate with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM which are probably good candidates for adjuvant therapies.
    Keywords:  FGFR2 mutations; Melanoma; fast growth melanoma; mutations of poor prognosis
    DOI:  https://doi.org/10.1016/j.jaad.2021.07.011
  48. Int J Mol Sci. 2021 Jul 06. pii: 7255. [Epub ahead of print]22(14):
    Profiling Cancer-Associated Fibroblasts in Melanoma.
    Federica Papaccio, Daniela Kovacs, Barbara Bellei, Silvia Caputo, Emilia Migliano, Carlo Cota, Mauro Picardo.
      Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.
    Keywords:  CAF; inflammation; melanoma; stroma; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms22147255
  49. Int J Mol Sci. 2021 Jul 09. pii: 7406. [Epub ahead of print]22(14):
    Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis.
    Ana Amor López, Marina S Mazariegos, Alessandra Capuano, Pilar Ximénez-Embún, Marta Hergueta-Redondo, Juan Ángel Recio, Eva Muñoz, Fátima Al-Shahrour, Javier Muñoz, Diego Megías, Roberto Doliana, Paola Spessotto, Héctor Peinado.
      Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.
    Keywords:  EMILIN-1; melanoma; metastasis; small extracellular vesicles
    DOI:  https://doi.org/10.3390/ijms22147406
  50. Cancer Med. 2021 Jul 21.
    Early detection of metastatic uveal melanoma by the analysis of tumor-specific mutations in cell-free plasma DNA.
    Claudia H D Le Guin, Norbert Bornfeld, Nikolaos E Bechrakis, Leyla Jabbarli, Heike Richly, Dietmar R Lohmann, Michael Zeschnigk.
       BACKGROUND: Eye salvaging therapy of malignant melanomas of the uvea can preserve the eye in most cases, but still about half of patients die from metastatic disease. Previous analyses of cell-free DNA from plasma had shown detectable levels of tumor-specific GNAQ/GNA11 mutations in patients with the clinical diagnosis of progressive disease. However, data on the time span that elapses from the detection of ctDNA in plasma to the clinical detection of metastases (diagnostic lead time) are missing.
    METHODS: We examined 135 patients with uveal melanoma. Cell-free DNA was isolated from a total of 807 blood samples which were taken over a period of up to 41 months and analyzed for the presence of GNAQ/GNA11 mutations by deep amplicon sequencing.
    RESULTS: Twenty-one of the 135 patients developed metastases or recurrence. A ctDNA signal was identified in the plasma of 17 of the 21 patients. In 10 patients, this ctDNA signal preceded the clinical diagnosis of metastasis by 2-10 months. In 10 other patients, a ctDNA signal was only detected in samples obtained shortly before or after radiotherapy. The presence of a ctDNA signal in 16 of the remaining 125 patients was linked to clinical manifestation of metastases (n = 14) or tumor recurrence (n = 2) with a sensitivity and specificity of 80% and 96%, respectively.
    CONCLUSION: Detection of ctDNA in plasma can provide a diagnostic lead time over the clinical diagnosis of metastases or tumor recurrence. Longer lead times are to be expected if intervals between sampling are shortened.
    Keywords:  GNAQ/GNA11; cell-free DNA; cell-free tumor DNA; deep amplicon sequencing; oncogenic mutations; uveal melanoma
    DOI:  https://doi.org/10.1002/cam4.4153
  51. J Clin Med. 2021 Jul 08. pii: 3047. [Epub ahead of print]10(14):
    Cutaneous Events Associated with Immunotherapy of Melanoma: A Review.
    Lorenza Burzi, Aurora Maria Alessandrini, Pietro Quaglino, Bianca Maria Piraccini, Emi Dika, Simone Ribero.
      Immunotherapy with checkpoint inhibitors significantly improves the outcome for stage III and IV melanoma. Cutaneous adverse events during treatment are often reported. We herein aim to review the principal pigmentation changes induced by immune check-point inhibitors: the appearance of vitiligo, the Sutton phenomenon, melanosis and hair and nail toxicities.
    Keywords:  alopecia; halo nevus; immunotherapy; melanoma; melanosis; pigmentation disorders; poliosis; vitiligo
    DOI:  https://doi.org/10.3390/jcm10143047
  52. J Med Chem. 2021 Jul 20.
    Glucose-Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy.
    Xinxin Zhao, Peng Zhang, Yaqi Li, Saizhi Wu, Fengjiao Li, Ying Wang, Songping Liang, Xiao He, Youlin Zeng, Zhonghua Liu.
      Glycosylation and fatty acid modification are promising strategies to improve peptide performance. We previously studied glycosylation and fatty acid modification of the anticancer peptide R-lycosin-I. In this study, we further investigated the co-modification of fatty acids and monosaccharides in R-lycosin-I. A glucose derivative was covalently coupled to the ε-amino group of the Lys residues of the lipopeptide R-C12, which was derived from R-lycosin-I modified with dodecanoic acid, and obtained seven glycolipid peptides. They exhibited different cytotoxicity profiles, which may be related to the changes in physicochemical properties and binding ability to glucose transporter 1 (GLUT1). Among them, R-C12-4 exhibited the highest cytotoxicity and improved selectivity. A further study demonstrated that R-C12-4 showed significant cytotoxicity and antimetastasis activity in murine melanoma cells, melanoma spheroids, and animal models. Our results indicated that the glucose derivative modification position plays important roles in glucose-lipopeptide conjugates, and R-C12-4 might be a promising lead for developing anticancer drugs.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c00805
  53. J Cell Mol Med. 2021 Jul 21.
    Prognostic signature and immune efficacy of m1 A-, m5 C- and m6 A-related regulators in cutaneous melanoma.
    Xian Rui Wu, Zheng Chen, Yang Liu, Zi Zi Chen, Fengjie Tang, Zhi Zhao Chen, Jing Jing Li, Jun Lin Liao, Ke Cao, Xiang Chen, Jianda Zhou.
      Cutaneous melanoma (CM) is an aggressive cancer; given that initial and specific signs are lacking, diagnosis is often late and the prognosis is poor. RNA modification has been widely studied in tumour progression. Nevertheless, little progress has been made in the signature of N1 -methyladenosine (m1 A), 5-methylcytosine (m5 C), N6 -methyladenosine (m6 A)-related regulators and the tumour microenvironment (TME) cell infiltration in CM. Our study identified the characteristics of m1 A-, m5 C- and m6 A-related regulators based on 468 CM samples from the public database. Using univariate, multivariate and LASSO Cox regression analysis, a risk model of regulators was established and validated by a nomogram on independent prognostic factors. The gene set variation analysis (GSVA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) clarified the involved functional pathways. A combined single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT approach revealed TME of regulator-related prognostic signature. The nine-gene signature stratified the patients into distinct risk subgroups for personalized prognostic assessment. Additionally, functional enrichment, immune infiltration and immunotherapy response analysis indicated that the high-risk group was correlated with T-cell suppression, while the low-risk group was more sensitive to immunotherapy. The findings presented here contribute to our understanding of the TME molecular heterogeneity in CM. Nine m1 A-, m5 C- and m6 A-related regulators may also be promising biomarkers for future research.
    Keywords:  cutaneous melanoma; immunotherapy; m1A; m5C; m6A; prognosis; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.16800
  54. Australas J Dermatol. 2021 Jul 22.
    Surveillance of patients with thin melanoma.
    Simone Ribero, Anne E Cust.
      
    DOI:  https://doi.org/10.1111/ajd.13670
  55. Eur J Cancer. 2021 Jun 26. pii: S0959-8049(21)00398-1. [Epub ahead of print]154 167-174
    Coronavirus disease 2019 vaccine mimics lymph node metastases in patients undergoing skin cancer follow-up: A monocentre study.
    Jan-Malte Placke, Henning Reis, Eva Hadaschik, Alexander Roesch, Dirk Schadendorf, Ingo Stoffels, Joachim Klode.
       INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has changed the lives of people around the world. Fortunately, sufficient vaccines are now available. Local reactions with ipsilateral lymphadenopathy are among the most common side effects. We investigated the impact of lymphadenopathy after COVID-19 vaccination on the value of ultrasound in tumour patients.
    PATIENTS AND METHODS: Patients with melanoma or Merkel cell carcinoma were included who underwent lymph node excision and received COVID-19 vaccination within 6 weeks before surgery. The consistency of the preoperative ultrasound findings with the histopathologic findings was investigated.
    RESULTS: Eight patients were included (two Merkel cell carcinoma and six melanoma patients) who underwent lymph node excision between 16th April 2021 and 19th May 2021 and had previously received COVID-19 vaccination. In three of the eight patients (one Merkel cell carcinoma and two melanoma patients), lymph node metastases were erroneously diagnosed preoperatively during tumour follow-up with physical examination, ultrasound, and or fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). In these three patients, the suspected lymph node metastases were located in the left axilla after COVID-19 vaccination in the left upper arm, which resulted in selective lymph node removal in two patients and complete lymphadenectomy in one patient.
    CONCLUSION: COVID-19 vaccine-associated lymphadenopathy is expected to be observed much more frequently in the near future because of increasing vaccination rates. This cause of lymphadenopathy, which may in ultrasound as well as in FDG PET/CT resemble lymph node metastases, must be considered, especially in oncologic patients undergoing tumour follow-up. In addition, COVID-19 vaccination should be given as far away as possible from an underlying primary on the contralateral side to avoid oncologic misdiagnosis followed by malpractice.
    Keywords:  COVID-19 vaccine; Lymphadenopathy; Melanoma; Merkel cell carcinoma; Ultrasound
    DOI:  https://doi.org/10.1016/j.ejca.2021.06.023
  56. Int J Immunogenet. 2021 Jul 23.
    A comparison of immune receptor recombination databases sourced from tumour exome or RNAseq files: Verifications of immunological distinctions between primary and metastatic melanoma.
    Dhruv N Patel, Michelle Yeagley, Juan F Arturo, Shayan Falasiri, Boris I Chobrutskiy, Etienne C Gozlan, George Blanck.
      It became apparent several years ago that RNAseq and exome files prepared from tissue could be mined for adaptive immune receptor (IR) recombinations, which has given extra value to datasets originally intended for gene expression or mutation studies. For example, recovery of IR recombination reads from tumour specimen genomics files can correlate with survival rates. In particular, many benchmarking processes have been applied to the two sets of the IR recombination reads obtained from the cancer genome atlas files, but these two sets have never been directly compared. Here we show that both sets largely agree regarding several parameters. For example, recovery of TRB recombination reads from both WXS and RNAseq files representing metastatic melanoma was associated with a better outcome (p < .0004 in both cases); and T-cell receptor recombination read recovery, for both genomics file types, associated very strongly with T-cell gene expression markers. However, the use of CDR3 chemical features for survival distinctions was not consistent. This topic, and the surprising result that both datasets indicated that primary melanoma with recovery of IR recombination reads, in stark contrast to metastatic melanoma, represents a worse outcome, are discussed.
    Keywords:  V(D)J recombinations; exome and RNAseq files; immune receptor recombinations; sequencing reads; the cancer genome atlas
    DOI:  https://doi.org/10.1111/iji.12550
  57. Clin Rev Allergy Immunol. 2021 Jul 20.
    Clinical Features, Immunopathogenesis, and Therapeutic Strategies in Vitiligo.
    Yinghan Wang, Shuli Li, Chunying Li.
      Vitiligo is an autoimmune disease of the skin characterized by epidermal melanocyte loss resulting in white patches, with an approximate prevalence of 0.5-2% worldwide. Several precipitating factors by chemical exposure and skin injury present commonly in patients with vitiligo. Although the diagnosis appears to be straightforward for the distinct clinical phenotype and specific histological features, vitiligo provides many challenges including chronicity, treatment resistance, frequent relapse, associated profound psychosocial effect, and negative impact on quality of life. Multiple mechanisms are involved in melanocyte disappearance, including genetics, environmental factors, and immune-mediated inflammation. Compelling evidence supports the melanocyte intrinsic abnormalities with poor adaptation to stressors leading to instability and release of danger signals, which will activate dendritic cells, natural killer cells, and innate lymphoid cells to initiate innate immunity, ultimately resulting in T-cell mediated adaptive immune response and melanocyte destruction. Importantly, the cross- talk between keratinocytes, melanocytes, and immune cells, such as interferon (IFN)-γ signaling pathway, builds inflammatory loops that give rise to the disease deterioration. Improved understanding of the immune pathogenesis of vitiligo has led to the development of new therapeutic options including Janus kinase (JAK) inhibitors targeting IFN-γ signaling pathways, which can effectively reverse depigmentation. Furthermore, definition of treatment goals and integration of comorbid diseases into vitiligo management have revolutionized the way vitiligo is treated. In this review, we highlight recent developments in vitiligo clinical aspects and immune pathogenesis. Our key objective is to raise awareness of the complexity of this disease, the potential of prospective therapy strategies, and the need for early and comprehensive management.
    Keywords:  Autoimmunity; Immunopathology; Repigmentation; Stress; Therapy; Vitiligo
    DOI:  https://doi.org/10.1007/s12016-021-08868-z
  58. Int J Mol Sci. 2021 Jul 20. pii: 7755. [Epub ahead of print]22(14):
    Microbeam Radiotherapy-A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma.
    Verdiana Trappetti, Jennifer M Fazzari, Cristian Fernandez-Palomo, Maximilian Scheidegger, Vladislav Volarevic, Olga A Martin, Valentin G Djonov.
      Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an 'MRT-induced immune effect'. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.
    Keywords:  immune response; melanoma; microbeam radiotherapy; oncology; radiotherapy; spatial fractionation; synchrotron
    DOI:  https://doi.org/10.3390/ijms22147755
  59. Am J Dermatopathol. 2021 Jul 20.
    Proliferative Clonal T-Cell Infiltrate Mimicking a Cutaneous T-Cell Lymphoma Arising in Active Regression of Melanoma.
    Andrew Siref, Sumire Kitahara, Bonnie Balzer.
       ABSTRACT: Complete melanoma regression is an uncommon phenomenon involving a complex interplay of the tumor microenvironment and host immune response. We report a case of an 84-year-old woman with a history of colon and breast cancers who presented with a right forearm tumor, which was found to be a nodular melanoma; focal features of regression were noted in the biopsy. Approximately 6 weeks later, surgical resection of the site revealed no gross evidence of tumor, and histologic sections showed an extensive lymphoid infiltrate with prominent epidermotropism. Rare residual melanoma cells were present in the dermis, best visualized on immunohistochemical stains. T cells predominated in the infiltrate with an inverted CD4:CD8 ratio at approximately 1:2. There was no appreciable loss of pan[FIGURE DASH]T-cell antigens. T-cell receptor beta and gamma gene rearrangements were performed by polymerase chain reaction and demonstrated clonality in each assay. Although a synchronous cutaneous T-cell lymphoma was considered, the overall clinicopathologic features are more in line with an exaggerated host immune response leading to near complete regression of the tumor.
    DOI:  https://doi.org/10.1097/DAD.0000000000002025
  60. Bioengineered. 2021 Dec;12(1): 4159-4173
    Circular RNA circRNA_0082835 promotes progression and lymphatic metastasis of primary melanoma by sponging microRNA miRNA-429.
    Yute Sun, Zuoqiong Hou, Binlin Luo, Chujun Li, Jinfang Liu, Jianlan Liu, Jian Tang, Gang Yao.
      To identify how circular RNA circRNA_0082835 impacts melanoma cells and lymphatic metastasis to observe whether it exerts effects through its action mechanism of sponging microRNA miR-429. Clinical baseline information was collected, and clinical samples were used for detection on circRNA_0082835 and EZH2. The expression of circRNA_0082835, EZH2, and miR-429 was detected by quantitative real-time PCR (RT-qPCR). Cell proliferation was tested with cell counting kit-8 (CCK-8). Flow cytometry was applied to examination of cell cycle levels. Cell invasion and migration were observed by transwell and wound healing. The expression of Wnt/β-catenin pathway, cell cycle and epithelial-mesenchymal transition (EMT) marker proteins was analyzed by western blot. Dual-luciferase determined the binding of miR-429 and circ_0082835. As a result, the expression of circRNA_0082835 was increased and that of miR-429 was decreased with the increase in lymphatic metastasis level. CircRNA_0082835 expression was downregulated by circ_0082835 interference, upregulated by EZH2 interference and also downregulated after transfection of both shRNA-circ_0082835 and shRNA-EZH2. Inhibiting circ_0082835 and EZH2 suppressed the proliferation, invasion and migration, regulated the cell cycle levels, inhibited Wnt/β-catenin and attenuated EMT in melanoma cells. Inhibition of circ_0082835 and/or EZH2 elevated miR-429 expression. The binding among miR-429 and circ_0082835 was verified. MiR-429 inhibitor reversed the effect of circ_0082835 interference while having no significant impact on EZH2. In conclusion, circRNA_0082835 sponges miR-429 to affect the anti-tumor effect of miR-429 in primary melanoma and lymphatic metastasis.
    Keywords:  CircRNA_0082835; EZH2; Wnt/β-catenin; miR-429; primary melanoma
    DOI:  https://doi.org/10.1080/21655979.2021.1953822
  61. Cancer Sci. 2021 Jul 21.
    Immunosuppressive activity is attenuated by Astragalus polysaccharides via remodeling the gut microenvironment in melanoma mice.
    Guiqing Ding, Qianyi Gong, Jinyun Ma, Xiaojun Liu, Yuanhua Wang, Xiaodong Cheng.
      Astragalus polysaccharides (APS), which is the main effective component of Astragalus membranaceus, can inhibit tumor growth, but the underlying mechanisms are still unclear. Previous studies suggested that APS is a kind of herbal polysaccharide that can regulate the gut microenvironment, including the gut microbiota and fecal metabolites. In this work, our results showed that APS could control tumor growth in melanoma-bearing mice. It could reduce the number of myeloid-derived suppressor cells (MDSCs), as well as the expression of MDSCs related molecule Arg-1 and cytokines IL-10 and TGF-β, so that CD8+ T cells could kill tumor cells more effectively. However, while APS was administrated with antibiotic cocktail (ABX), MDSCs could not be reduced, and the growth rate of tumor was accelerated. Consistent with the changes in MDSCs, the serum level of IL-6, IL-1β was the lowest in the APS group. Meanwhile, we found that fecal suspension from mice in APS group could also reduce the number of MDSCs in tumor tissues. These results revealed that APS regulated the immune function in tumor-bearing mice via remodeling the gut microbiota. Next, we focused on the results of 16S rRNA, and it showed that APS significantly regulated the abundance of microorganisms such as Bifidobacterium_pseudolongum, Lactobacillus_johnsonii and Lactobacillus. According to the Spearman analysis, the changes of abundance of these microorganisms were related to the increase of metabolites like glutamate and creatine, which could control tumor growth. Taken together, this study demonstrates that APS attenuates the immunosuppressive activity of MDSCs in melanoma-bearing mice by remodeling the gut microbiota and fecal metabolites, and our findings will provide a new therapeutic strategy to control tumor growth.
    Keywords:   Astragalus polysaccharides ; Gut microenvironment; Immunosuppressive activity; Melanoma; Myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1111/cas.15078
  62. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00835-4. [Epub ahead of print]36(3): 109422
    Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts.
    Anthony B Rodriguez, J David Peske, Amber N Woods, Katie M Leick, Ileana S Mauldin, Max O Meneveau, Samuel J Young, Robin S Lindsay, Marit M Melssen, Salwador Cyranowski, Geoffrey Parriott, Mark R Conaway, Yang-Xin Fu, Craig L Slingluff, Victor H Engelhard.
      Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-α1β2. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy.
    Keywords:  B lymphocytes; B16 melanoma; CD8 T lymphocytes; cancer-associated fibroblasts; checkpoint blockade immunotherapy; lymphoid tissue inducer cell; lymphoid tissue organizer cell; lymphotoxin-β receptor; tertiary lymphoid structure; tumor necrosis factor receptor
    DOI:  https://doi.org/10.1016/j.celrep.2021.109422
  63. JAMA Dermatol. 2021 Jul 21.
    Melanoma and Racial Health Disparities in Black Individuals-Facts, Fallacies, and Fixes.
    Michael A Marchetti, Adewole S Adamson, Allan C Halpern.
      
    DOI:  https://doi.org/10.1001/jamadermatol.2021.2215
  64. Lasers Surg Med. 2021 Jul 23.
    Identification of the fate and regenerative mechanism of zebrafish melanocyte progenitor cells and melanocytes after laser-induced pigment ablation.
    Ji Hyun Park, Soonil Koun, Ko Eun Kim, Il-Hwan Kim.
       BACKGROUND AND OBJECTIVES: Lasers are known to be the most effective treatment modality for pigmentary skin diseases. However, melanocytes and melanin pigment often recur or leave post-inflammatory hyperpigmentation after the laser procedure. Studies have reported on the role of progenitor cells in pigment cell regeneration, which can be constantly replenished through mitosis. However, the response of unpigmented melanocyte progenitor cells to laser treatment is poorly understood. In this study, we used adult zebrafish skin as the melanocyte regenerative system and examined the response of melanocyte progenitor cells to laser photothermolysis.
    MATERIALS AND METHODS: The two groups of adult zebrafish were irradiated with 1064 nm wavelength laser system of Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with 0.3 or 0.7 J·cm-2 . We compared the regeneration of pigment at different energy levels by measuring new melanocyte counts and pigment area. We traced and quantitatively compared the melanocyte lineage cells by immunohistochemical staining using specific markers such as sox10, mitfa, and dct during the regeneration process. Three repetitive laser ablations were also held to test the postinflammatory hyperpigmentation.
    RESULTS: After the laser ablation of melanocytes, most of the new melanocytes appeared between Days 5 and 10. In high-energy irradiation of 0.7 J·cm-2 , the unpigmented mitfa-expressing cells showed significant decrease (p < 0.05) and showed delay in the differentiation process of melanocyte lineage cells. After repeated laser irradiation, hyperpigmentation did not appear and the final recovery ratio of the pigmented area was 87.5% and 75.3% at the 0.3 and 0.7 J·cm-2 energy levels, respectively.
    CONCLUSION: We suggest that laser treatment overcoming the recurrence should be planned based on the adequate energy level targeting the melanocyte progenitor cells. High-energy irradiation may induce apoptosis of progenitor cells and delay their process of differentiation. Short-term repetitive sessions of laser therapy can reduce the pigmentation in the long-term observation.
    Keywords:  laser; melanocyte; postinflammatory hyperpigmentation; progenitor cell
    DOI:  https://doi.org/10.1002/lsm.23458
  65. Int J Mol Sci. 2021 Jul 16. pii: 7628. [Epub ahead of print]22(14):
    Enhancing the Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Signaling and Arginine Deprivation in Melanoma.
    Chunjing Wu, Min You, Dao Nguyen, Medhi Wangpaichitr, Ying-Ying Li, Lynn G Feun, Macus T Kuo, Niramol Savaraj.
      Melanoma as a very aggressive type of cancer is still in urgent need of improved treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and arginine deiminase (ADI-PEG20) are two of many suggested drugs for treating melanoma. Both have shown anti-tumor activities without harming normal cells. However, resistance to both drugs has also been noted. Studies on the mechanism of action of and resistance to these drugs provide multiple targets that can be utilized to increase the efficacy and overcome the resistance. As a result, combination strategies have been proposed for these drug candidates with various other agents, and achieved enhanced or synergistic anti-tumor effect. The combination of TRAIL and ADI-PEG20 as one example can greatly enhance the cytotoxicity to melanoma cells including those resistant to the single component of this combination. It is found that combination treatment generally can alter the expression of the components of cell signaling in melanoma cells to favor cell death. In this paper, the signaling of TRAIL and ADI-PEG20-induced arginine deprivation including the main mechanism of resistance to these drugs and exemplary combination strategies is discussed. Finally, factors hampering the clinical application of both drugs, current and future development to overcome these hurdles are briefly discussed.
    Keywords:  ADI-PEG20; TRAIL; apoptosis; arginine deprivation therapy; autophagy; melanoma; rhArg
    DOI:  https://doi.org/10.3390/ijms22147628
  66. Cureus. 2021 Jul;13(7): e16324
    Diffuse Alveolar Hemorrhage: An Unusual Presentation of Recurrent Malignant Melanoma.
    Patrick R McKillion, Sanjeev Shrestha, Andrew R Medvec, Amirahwaty Abdullah.
      Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by bleeding into the alveolar spaces of the lungs, secondary to disruption of the alveolar-capillary basement membrane. While numerous disease processes have been associated with DAH including certain malignancies, to the best of our knowledge, recurrent malignant melanoma has not been previously described in the literature as a cause of DAH. Here, we present a case of a 73-year-old female with a history of malignant melanoma of the left shoulder status post wide local incision two years prior, who presented with complaints of progressive shortness of breath without productive cough or hemoptysis. On examination, she was hypoxemic and required high-flow nasal cannula initiation. Initial investigation revealed a hemoglobin of 4.6 g/dL. Computed tomography of the chest with contrast revealed multiple areas of rounded infiltrates with air bronchograms, mediastinal adenopathy, and a right pleural effusion. Diagnostic bronchoscopy revealed findings of recent bleeding throughout the tracheobronchial tree with progressively bloody bronchoalveolar lavage (BAL) suggestive of DAH. BAL cytology was positive for malignant melanoma. After a comprehensive workup that excluded the common causes of DAH, we present the first case of DAH caused by recurrent malignant melanoma.
    Keywords:  bronchoalveolar lavage; bronchoscopy; diffuse alveolar hemorrhage; malignancy; melanoma
    DOI:  https://doi.org/10.7759/cureus.16324
  67. Nature. 2021 Jul 21.
    Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma.
    Giacomo Oliveira, Kari Stromhaug, Susan Klaeger, Tomasz Kula, Dennie T Frederick, Phuong M Le, Juliet Forman, Teddy Huang, Shuqiang Li, Wandi Zhang, Qikai Xu, Nicoletta Cieri, Karl R Clauser, Sachet A Shukla, Donna Neuberg, Sune Justesen, Gavin MacBeath, Steven A Carr, Edward F Fritsch, Nir Hacohen, Moshe Sade-Feldman, Kenneth J Livak, Genevieve M Boland, Patrick A Ott, Derin B Keskin, Catherine J Wu.
      Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.
    DOI:  https://doi.org/10.1038/s41586-021-03704-y
  68. Iran J Child Neurol. 2021 ;15(3): 153-157
    Nonsyndromic Primary Diffuse Leptomeningeal Melanomatosis in a Child.
    Salim Tavana Rad, Farah Ashrafzadeh, Hassan Golmakani, Babak Ganjeifar.
       INTRODUCTION: In this study, we present a case of primary diffuse leptomeningeal melanomatosis (PDLM), without neurocutaneous melanosis syndrome. A female patient (age: 14 years) presented with headache, nausea, vomiting, vertigo, diplopia, and lower limb weakness. The magnetic resonance imaging (MRI) showed leptomeningeal isointensity on T1- and T2-weighted images and hyperintensity on fluid attenuation inversion recovery (FLAIR) sequences. Definitive histological examination showed a densely cellular tumor, characterized by irregular clusters of large pleomorphic cells and melanin in tumor cells. Adjuvant therapy was refused by the parents, and the patient died within six months. Primary diffuse leptomeningeal melanomatosis is recognized as an uncommon and malignant melanoma affecting the central nervous system. In case comorbidities are not diagnosed in patients with unusual symptoms of meningitis, diagnostic methods such as cerebrospinal fluid analysis and central nervous system biopsy can be helpful in identifying other underlying conditions.
    Keywords:  Central nervous system; Child; Melanoma; Spine
    DOI:  https://doi.org/10.22037/ijcn.v15i2.20159
  69. Appl Biochem Biotechnol. 2021 Jul 24.
    Apoptosis Induction in Murine Melanoma (B16F10) Cells by Mannosylerythritol Lipids-B; a Glycolipid Biosurfactant with Antitumoral Activities.
    P E Feuser, A L S Coelho, M E de Melo, R Scussel, B A M Carciofi, R A Machado-de-Ávila, D de Oliveira, C J de Andrade.
      Mannosylerythritol lipids have drawn attention to cosmetic and pharmaceutical industries due to their non-toxicity and excellent biological interactions with human skin, particularly with the deepest epidermal layer. Lamellar liquid crystal structure, formed by MEL-B, is an interesting feature due to its similarity to the stratum corneum molecular arrangement and cell signaling events involved in the deregulation of the cancerous cell membrane. Thus, this work aimed to evaluate the cytotoxicity of commercial mannosylerythritol lipids-B in murine melanoma, fibroblast, and human erythrocytes cells. Cytotoxic effect was more pronounced on the tumor cells from 20 µg/mL, reducing cell viability by 65%, whereas fibroblast and human erythrocytes cells were more resistant to glycolipid treatment. Fluorescence microscopy and flow cytometer proved that mannosylerythritol lipids-B is an apoptosis inducer in tumor cells related to reactive oxygen species generation.
    DOI:  https://doi.org/10.1007/s12010-021-03620-x
  70. PLoS One. 2021 ;16(7): e0254772
    Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.
    Birgit Sadoghi, Karin Schmid-Zalaudek, Iris Zalaudek, Regina Fink-Puches, Anna Niederkorn, Ingrid Wolf, Peter Rohrer, Erika Richtig.
       BACKGROUND: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated.
    METHODS: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts.
    RESULTS: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively).
    CONCLUSION: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas.
    DOI:  https://doi.org/10.1371/journal.pone.0254772
  71. Am J Hum Genet. 2021 Jul 15. pii: S0002-9297(21)00266-4. [Epub ahead of print]
    Cell-type-specific meQTLs extend melanoma GWAS annotation beyond eQTLs and inform melanocyte gene-regulatory mechanisms.
    Tongwu Zhang, Jiyeon Choi, Ramile Dilshat, Berglind Ósk Einarsdóttir, Michael A Kovacs, Mai Xu, Michael Malasky, Salma Chowdhury, Kristine Jones, D Timothy Bishop, Alisa M Goldstein, Mark M Iles, Maria Teresa Landi, Matthew H Law, Jianxin Shi, Eiríkur Steingrímsson, Kevin M Brown.
      Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.
    Keywords:  DNA methylation; GWAS; IRF4; MWAS; QTL; colocalization; genome-wide association study; mediation analysis; melanocyte; melanoma; methylome-wide association study; quantitative trait loci; trans-QTL
    DOI:  https://doi.org/10.1016/j.ajhg.2021.06.018
  72. Front Oncol. 2021 ;11 701968
    Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model.
    Falih M Gorgun, Steven G Widen, Douglas S Tyler, Ella W Englander.
      Sequencing data from different types of cancers including melanomas demonstrate that tumors with high mutational loads are more likely to respond to immune checkpoint blockade (ICB) therapies. We have previously shown that low-dose intratumoral injection of the chemotherapeutic DNA damaging drug cisplatin activates intrinsic mutagenic DNA damage tolerance pathway, and when combined with ICB regimen leads to tumor regression in the mouse YUMM1.7 melanoma model. We now report that tumors generated with an in vitro cisplatin-mutagenized YUMM1.7 clone (YUMM1.7-CM) regress in response to ICB, while an identical ICB regimen alone fails to suppress growth of tumors generated with the parental YUMM1.7 cells. Regressing YUMM1.7-CM tumors show greater infiltration of CD8 T lymphocytes, higher granzyme B expression, and higher tumoral cell death. Similarly, ex-vivo, immune cells isolated from YUMM1.7-CM tumors-draining lymph nodes (TDLNs) co-incubated with cultured YUMM1.7-CM cells, eliminate the tumor cells more efficiently than immune cells isolated from TDLNs of YUMM1.7 tumor-bearing mice. Collectively, our findings show that in vitro induced cisplatin mutations potentiate the antitumor immune response and ICB efficacy, akin to tumor regression achieved in the parental YUMM1.7 model by ICB administered in conjunction with intratumoral cisplatin injection. Hence, our data uphold the role of tumoral mutation burden in improving immune surveillance and response to ICB, suggesting a path for expanding the range of patients benefiting from ICB therapy.
    Keywords:  CD8 T lymphocyte; cisplatin; immune checkpoint blockade; lymph node; melanoma; mutagenesis; tumor regression
    DOI:  https://doi.org/10.3389/fonc.2021.701968
  73. Cell Mol Life Sci. 2021 Jul 18.
    Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges.
    Marketa Kaucka, Bara Szarowska, Michaela Kavkova, Maria Eleni Kastriti, Polina Kameneva, Inga Schmidt, Lucie Peskova, Alberto Joven Araus, Andras Simon, Jozef Kaiser, Igor Adameyko.
      Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.
    Keywords:  Endothelin 3 and endothelin receptor B; Extracutaneous pigment cell; Glial precursor; Hypopigmentation-associated deafness; Peripheral nerves; Targeted recruitment
    DOI:  https://doi.org/10.1007/s00018-021-03885-9
  74. Exp Cell Res. 2021 Jul 14. pii: S0014-4827(21)00265-2. [Epub ahead of print] 112733
    Corrigendum to "Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma".
    Zhaozhou Ren, Feifei Ni, Tao Zhang, Xiangnan Yuan, Jianjun Li, Wan'an Xiao.
      
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112733
  75. Ital J Dermatol Venerol. 2021 Jul 20.
    Effects of COVID-19 restriction measures and clinical resetting on delayed melanoma diagnosis: a single Institution experience.
    Giuseppe Lo Bello, Giacomo M Pini, Guido Ferguglia, Roberto Regazzini, Amelia Locatelli, Carlo Patriarca.
      
    DOI:  https://doi.org/10.23736/S2784-8671.21.07052-3
  76. Cell Mol Bioeng. 2021 Aug;14(4): 309-320
    B16 Melanoma Cancer Cells with Higher Metastatic Potential are More Deformable at a Whole-Cell Level.
    Yoshihiro Ujihara, Daichi Ono, Koki Nishitsuji, Megumi Ito, Shukei Sugita, Masanori Nakamura.
       Introduction: Metastasis is a process in which cancer cells spread from the primary focus site to various other organ sites. Many studies have suggested that reduced stiffness would facilitate passing through extracellular matrix when cancer cells instigate a metastatic process. Here we investigated the compressive properties of melanoma cancer cells with different metastatic potentials at the whole-cell level. Differences in their compressive properties were analyzed by examining actin filament structure and actin-related gene expression.
    Methods: Compressive tests were carried out for two metastatic B16 melanoma variants (B16-F1 and B16-F10) to characterize global compressive properties of cancer cells. RNA-seq analysis and fluorescence microscopic imaging were performed to clarify contribution of actin filaments to the global compressive properties.
    Results: RNA-seq analysis and fluorescence microscopic imaging revealed the undeveloped structure of actin filaments in B16-F10 cells. The Young's modulus of B16-F10 cells was significantly lower than that of B16-F1 cells. Disruption of the actin filaments in B16-F1 cells reduced the Young's modulus to the same level as that of B16-F10 cells, while the Young's modulus in B16-F10 cells remained the same regardless of the disruption.
    Conclusions: In B16 melanoma cancer cell lines, cells with higher metastatic potential were more deformable at the whole-cell level with undeveloped actin filament structure, even when highly deformed. These results imply that invasive cancer cells may gain the ability to inhibit actin filament development.
    Supplementary Information: The online version contains supplementary material available at (10.1007/s12195-021-00677-w).
    Keywords:  Actin filaments; Compression test; Mechanical property; Metastatic potential; Whole-cell level; Young’s modulus
    DOI:  https://doi.org/10.1007/s12195-021-00677-w
  77. Ann Coloproctol. 2021 Jul 21.
    Multiple Gastrointestinal Melanoma Causing Small Bowel Intussusception.
    Jian Yang Eng, Salehah Tahkin, Huzairi Yaacob, Nor Hayati Yunus, Ahmad Shan Wani Mohamed Sidek, Michael Pak-Kai Wong.
      A 61-year-old gentleman presented with small bowel intussusception from small bowel melanoma intussusceptum. He complains of intermittent abdominal distension but no history of intestinal obstruction. Apart from this, he was also symptomatic anemia which required repeated transfusion for the past few months. The contrast-enhanced computed tomography of the abdomen shows an omental mass with small bowel intussusception. He then underwent an exploratory laparotomy with segmental resection of the affected segment. Histopathological examination confirmed primary gastrointestinal melanoma. Multiple small bowel malignant melanoma is a rare disease. It remains a controversial diagnosis as it may be a primary or metastasis from an unidentified or regressed primary cutaneous melanoma. Prompt surgical intervention enables us to obtain tissue diagnosis, prevent complete intestinal obstruction and strategize the goals of treatment for the patient.
    Keywords:  Acute abdomen; Intestinal obstruction; Intussusception; Melanoma
    DOI:  https://doi.org/10.3393/ac.2021.00143.0020
  78. Front Genet. 2021 ;12 700036
    Single-Cell Transcriptome Analysis in Melanoma Using Network Embedding.
    Liming Wang, Fangfang Liu, Longting Du, Guimin Qin.
      Single-cell sequencing technology provides insights into the pathology of complex diseases like cancer. Here, we proposed a novel computational framework to explore the molecular mechanisms of cancer called melanoma. We first constructed a disease-specific cell-cell interaction network after data preprocessing and dimensionality reduction. Second, the features of cells in the cell-cell interaction network were learned by node2vec which is a graph embedding technology proposed previously. Then, consensus clusters were identified by considering different clustering algorithms. Finally, cell markers and cancer-related genes were further analyzed by integrating gene regulation pairs. We exploited our model on two independent datasets, which showed interesting results that the differences between clusters obtained by consensus clustering based on network embedding (CCNE) were observed obviously through visualization. For the KEGG pathway analysis of clusters, we found that all clusters are extremely related to MicroRNAs in cancer and HTLV-I infection, and the hub genes in cluster specific regulatory networks, i.e., ETS1, TP53, E2F1, and GATA3 are highly associated with melanoma. Furthermore, our method can also be extended to other scRNA-seq data.
    Keywords:  cell type; gene regulatory network; melanoma; network embedding; single cell
    DOI:  https://doi.org/10.3389/fgene.2021.700036
  79. Cutis. 2021 May;107(5): 258-260
    Desmoplastic Melanoma Masquerading as Neurofibroma.
    Evan Stokar, Carlos Rodriguez, Jerry Feldman.
      Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major diagnostic challenges. It can mimic both benign or other malignant tumors and may be easily confused by clinicians and pathologists. We report a patient who presented with a pink-colored papule on the left lateral neck. Histopathology revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma at low power. However, higher-power evaluation and the use of immunohistochemical staining confirmed the diagnosis of DMM.We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor. Advancing age, male gender, and head and neck location are associated with an increased risk of DMM-specific death. It is important that new or changing lesions in the correct cohort and location are biopsied promptly.
    DOI:  https://doi.org/10.12788/cutis.0241
  80. Cancer. 2021 Jul 22.
    Compliance with sentinel lymph node biopsy guidelines for invasive melanomas treated with Mohs micrographic surgery.
    Kelly M MacArthur, Brian C Baumann, Joseph F Sobanko, Jeremy R Etzkorn, Thuzar M Shin, H William Higgins, Cerrene N Giordano, Stacy L McMurray, Aimee Krausz, Jason G Newman, Karthik Rajasekaran, Steven B Cannady, Robert M Brody, Giorgos C Karakousis, John T Miura, Justine V Cohen, Ravi K Amaravadi, Tara C Mitchell, Lynn M Schuchter, Christopher J Miller.
       BACKGROUND: Sentinel lymph node biopsy (SLNB) has not been studied for invasive melanomas treated with Mohs micrographic surgery using frozen-section MART-1 immunohistochemical stains (MMS-IHC). The primary objective of this study was to assess the accuracy and compliance with National Comprehensive Cancer Network (NCCN) guidelines for SLNB in a cohort of patients who had invasive melanoma treated with MMS-IHC.
    METHODS: This retrospective cohort study included all patients who had primary, invasive, cutaneous melanomas treated with MMS-IHC at a single academic center between March 2006 and April 2018. The primary outcomes were the rates of documenting discussion and performing SLNB in patients who were eligible based on NCCN guidelines. Secondary outcomes were the rate of identifying the sentinel lymph node and the percentage of positive lymph nodes.
    RESULTS: In total, 667 primary, invasive, cutaneous melanomas (American Joint Committee on Cancer T1a-T4b) were treated with MMS-IHC. The median patient age was 69 years (range, 25-101 years). Ninety-two percent of tumors were located on specialty sites (head and/or neck, hands and/or feet, pretibial leg). Discussion of SLNB was documented for 162 of 176 (92%) SLNB-eligible patients, including 127 of 127 (100%) who had melanomas with a Breslow depth >1 mm. SLNB was performed in 109 of 176 (62%) SLNB-eligible patients, including 102 of 158 melanomas (65%) that met NCCN criteria to discuss and offer SLNB and 7 of 18 melanomas (39%) that met criteria to discuss and consider SLNB. The sentinel lymph node was successfully identified in 98 of 109 patients (90%) and was positive in 6 of those 98 patients (6%).
    CONCLUSIONS: Combining SLNB and MMS-IHC allows full pathologic staging and confirmation of clear microscopic margins before reconstruction of specialty site invasive melanomas. SLNB can be performed accurately and in compliance with consensus guidelines in patients with melanoma using MMS-IHC.
    Keywords:  Mohs micrographic surgery; National Comprehensive Cancer Network (NCCN) guidelines; melanoma; sentinel lymph node biopsy; specialty sites
    DOI:  https://doi.org/10.1002/cncr.33651
  81. Molecules. 2021 Jul 13. pii: 4254. [Epub ahead of print]26(14):
    Selective Apoptotic Effect of Plasma Activated Liquids on Human Cancer Cell Lines.
    Dominika Sersenová, Zdenko Machala, Vanda Repiská, Helena Gbelcová.
      Plasma medicine is a new field focusing on biomedical and clinical applications of cold gas plasmas, including their anticancer effects. Cold plasmas can be applied directly or indirectly as plasma-activated liquids (PAL). The effects of plasma-activated cell growth medium (PAM) and plasma-activated phosphate buffered saline (PAPBS) were tested, using a plasma pen generating streamer corona discharge in ambient air, on different cancer cell lines (melanoma A375, glioblastoma LN229 and pancreatic cancer MiaPaCa-2) and normal cells (human dermal fibroblasts HDFa). The viability reduction and apoptosis induction were detected in all cancer cells after incubation in PAL. In melanoma cells we focused on detailed insights to the apoptotic pathways. The anticancer effects depend on the plasma treatment time or PAL concentration. The first 30 min of incubation in PAL were enough to start processes leading to cell death. In fibroblasts, no apoptosis induction was observed, and only PAPBS, activated for a longer time, slightly decreased their viability. Effects of PAM and PAPBS on cancer cells showed selectivity compared to normal fibroblasts, depending on correctly chosen activation time and PAL concentration, which is very promising for potential clinical applications. This selectivity effect of PAL is conceivably induced by plasma-generated hydrogen peroxide.
    Keywords:  cancer cell; cold plasma; fibroblast; melanoma; plasma-activated liquid
    DOI:  https://doi.org/10.3390/molecules26144254
  82. Front Immunol. 2021 ;12 682492
    Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential.
    Espen Basmo Ellingsen, Sara M Mangsbo, Eivind Hovig, Gustav Gaudernack.
      Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.
    Keywords:  cancer; cancer vaccine; hTERT; immune response; immuno-oncology; immunotherapy; melanoma; telomerase
    DOI:  https://doi.org/10.3389/fimmu.2021.682492
  83. Adv Exp Med Biol. 2021 ;1302 113-132
    CCL27 Signaling in the Tumor Microenvironment.
    Miguel Martínez-Rodríguez, Carlos Monteagudo.
      Chemokines are a group of small proteins which play an important role in leukocyte migration and invasion. They are also involved in the cellular proliferation and migration of tumor cells.Chemokine CCL27 (cutaneous T cell-attracting chemokine, CTACK) is mainly expressed by keratinocytes of the normal epidermis. It is well known that this chemokine plays an important role in several inflammatory diseases of the skin, such as atopic dermatitis, contact dermatitis, and psoriasis. Moreover, several studies have shown an association between CCL27 expression and a variety of neoplasms including skin cancer.In this chapter, we address the role of chemokine CCL27 in the tumor microenvironment in the most relevant cancers of the skin and other anatomical locations. We also make a brief comment on future perspectives and the potential relation of CCL27 with different immunotherapeutic modalities.
    Keywords:  Angiogenesis; Breast cancer; CCL27; CCR10; Chemokine receptors; Chemokines; Colorectal cancer; Glioblastoma; Immunotherapy; Melanoma, mycosis fungoides; Metastasis; Pericytes; Skin cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-030-62658-7_9
  84. J Pharmacol Sci. 2021 Sep;pii: S1347-8613(21)00059-1. [Epub ahead of print]147(1): 156-167
    3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms.
    Milica Kosic, Verica Paunovic, Biljana Ristic, Aleksandar Mircic, Mihajlo Bosnjak, Danijela Stevanovic, Tamara Kravic-Stevovic, Vladimir Trajkovic, Ljubica Harhaji-Trajkovic.
      We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone. 2DG/rotenone reduced ATP levels and increased mitochondrial superoxide production, causing mitochondrial swelling and necrotic death in various cancer cell lines. 2DG/rotenone failed to increase proautophagic beclin-1 and autophagic flux in melanoma cells despite the activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). 3MA, but not autophagy inhibition with other PI3K and lysosomal inhibitors, attenuated 2DG/rotenone-induced mitochondrial damage, oxidative stress, ATP depletion, and cell death, while antioxidant treatment mimicked its protective action. The protection was not mediated by autophagy upregulation via class I PI3K/Akt inhibition, as it was preserved in cells with genetically inhibited autophagy. 3MA increased AMPK and mTORC1 activation in energy-stressed cells, but neither AMPK nor mTORC1 inhibition reduced its cytoprotective effect. 3MA reduced JNK activation, and JNK pharmacological/genetic suppression mimicked its mitochondria-preserving and cytoprotective activity. Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.
    Keywords:  3-Methyladenine; Autophagy; Glycolysis; Mitochondria; Necrosis
    DOI:  https://doi.org/10.1016/j.jphs.2021.06.003
  85. Photodermatol Photoimmunol Photomed. 2021 Jul 18.
    Stratum corneum biomarkers after in vivo repeated exposure to sub-erythemal dosages of ultraviolet radiation in unprotected and sunscreen (SPF 50+) protected skin.
    Anne Josephine Keurentjes, Ivone Jakasa, Arjan van Dijk, Edith van Putten, Richard Brans, Swen Malte John, Thomas Rustemeyer, Henk van der Molen, Sanja Kezic.
       BACKGROUND: There is a need for non-invasive biomarkers to assess in vivo efficacy of protective measures aiming at reducing ultraviolet radiation (UVR) exposure. Stratum corneum (SC) biomarkers showed to be promising markers for internal UVR dose and immune response.
    PURPOSE: To establish a dose-response relationship for SC biomarkers and explore their suitability for in vivo assessment of the blocking effect of two sunscreens with a high sun protection factor (SPF) (50+).
    METHODS: Twelve volunteers were exposed to a broad-spectrum UVB (280-320 nm), five times a week, during one week. Unprotected back skin was irradiated with 0.24, 0.48, 0.72 and 1.44 standard erythema dose (SED) and sunscreen-protected skin with 3.6 SED. SC samples for determination of the relative amount of cis-urocanic acid (cUCA) and thirteen immunological makers including cytokines and matrix metalloproteinases (MMP) were collected after each irradiation.
    RESULTS: cUCA sharply increased after the first irradiation in a dose-dependent fashion. However, it levelled-off after subsequent exposures and reached a plateau for the highest UV-dose after the third irradiation. None of the immunological markers showed dose-dependency. However, MMP-9, IL-1β and CCL27 increased gradually from baseline during repetitive exposures to the highest UV-dose. Assessed from cUCA, both sunscreens blocked >98% of the applied UV-dose.
    CONCLUSIONS: cUCA is a sensitive, non-invasive marker of the internal UVR dose enabling in vivo assessment of the blocking effect of high SPF sunscreens in the UVB-region. Immunological SC markers show low sensitivity in detecting immune response at sub-erythemal UVR dosages, suggesting they might be suitable only at higher and/or repetitive UVR exposure.
    Keywords:  biomarkers; skin cancer; stratum corneum; sunscreen; urocanic acid
    DOI:  https://doi.org/10.1111/phpp.12717
  86. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Jun 28. pii: 1672-7347(2021)06-0565-10. [Epub ahead of print]46(6): 565-574
    Preliminary screening and correlation analysis for lncRNAs related to radiosensitivity in melanoma cells by inhibiting glycolysis.
    Qi Wang, Chenghui Huang, Yi Hu, Wenguang Yan, Lian Gong.
       OBJECTIVES: To screen the expression profiles of lncRNA and mRNA related to the radiosensitivity of melanoma cells by inhibiting glycolysis through microarray technology.
    METHODS: WM35 melanoma cells were treated with different concentrations (1.25, 2.50, 5.00, 10.00 mmol/L) of 2-deoxy-D-glucose (2-DG) and different doses (0, 2, 4, 6, 8 Gy) of X-ray irradiation. MTT assay was used to detect the proliferation ability of NC-0 Gy group (negative control group), NC-4 Gy group (only 4 Gy X-ray irradiation), 2-DG group (only 2.50 mmol/L DG treatment), and 2-DG-4 Gy group (2.50 mmol/L 2-DG treatment, 4 Gy X-ray irradiation). Microarray chip was used to detect the changes in the expression profiles of lncRNA and mRNA in the NC-4 Gy group and the 2-DG-4 Gy group. Real-time RT-PCR was used to quantitatively detect the top 5 upregulated and the top 5 downregulated expression lncRNA. CNC analysis was used to predict potential target genes for the 10 most significantly expressed lncRNAs, after which the co-expression network of lncRNA and co-regulated mRNA were constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to predict the functional distribution of differentially expressed lncRNA. Real-time RT-PCR was used to quantitatively detect the top 5 upregulated and the top 5 downregulated expression lncRNAs.
    RESULTS: After 48 and 96 h, the cell proliferation of WM35 treated with 2-DG was significantly inhibited in a dose-dependent manner (all P<0.05). The cell proliferation of WM35 was inhibited by a high dose of X-ray irradiation, resulting in the death of mass cells. The cell proliferation activity of WM35 after 4 Gy X-ray irradiation descended 61% compared to the negative control group. Microarray analysis showed that there were 1 206 lncRNAs and 543 differentially expressed mRNAs between the NC-4 Gy group and the 2-DG-4 Gy group, while real-time RT-PCR showed basically consistent changes in lncRNA and mRNA microarray. Further CNC analysis showed that these 10 lncRNAs had a positive or negative correlation with 333 target genes. GO analysis was mainly concentrated in DNA binding, DNA damage repair, cell cycle arrest, and oxidative stress, while KEGG pathway analysis showed the 10 lncRNAs were related to radiosensitivity.
    CONCLUSIONS: Microarray chip screens the expression profiles of differentially expressed lncRNA related to the radiosensitivity of melanoma cells via inhibiting glycolysis, and lncRNA RPL34-AS1 might be a potential biological target for melanoma radiotherapy.
    Keywords:  2-deoxy- D-glucose; glycolysis; lncRNA RPL34-AS1; melanoma; radiosensitivity
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2021.200549
  87. Arkh Patol. 2021 ;83(4): 61-68
    [The significance of C-KIT gene mutations in the diagnosis and prognosis of malignant tumors].
    T G Ruksha, E Yu Sergeeva, Yu A Fefelova, V A Khorzhevsky.
      Mutations in the C-KIT gene encoding type III receptor tyrosine kinase that regulates cellular processes, such as differentiation, survival, proliferation, migration, and apoptosis, are found in some neoplasms: gastrointestinal stromal tumor, mastocytosis, melanoma, breast carcinomas, myeloid leukemias, and a number of others. Tumors that exhibit these mutations are sensitive to therapy with tyrosine kinase inhibitors, which makes it necessary to correctly identify the mutation status by C-KIT in order to apply a personalized approach to therapy. This literature review shows that the type and localization of the C-KIT gene mutation are of crucial prognostic value and significance in choosing drugs for antitumor therapy, but traditional diagnostic methods fail to determine accurate mutation characteristics. Routine sequencing techniques focus on identifying the gene mutations associated with specific cellular processes, such as DNA damage and repair. The emergence of next-generation sequencing techniques has solved this problem, making it possible to fully analyze the genome of a malignant neoplasm, with constant screening for new mutations that appear as the tumor develops, affect the prognosis of the disease, and change its sensitivity to the antitumor therapy.
    Keywords:  C-KIT mutations; malignant neoplasms; next-generation sequencing techniques
    DOI:  https://doi.org/10.17116/patol20218304161
  88. Int J Mol Sci. 2021 Jul 13. pii: 7480. [Epub ahead of print]22(14):
    Synergistic Effect of 300 μm Needle-Depth Fractional Microneedling Radiofrequency on the Treatment of Senescence-Induced Aging Hyperpigmentation of the Skin.
    Young In Lee, Eunbin Kim, Dong Won Lee, Jemin Kim, Jihee Kim, Won Jai Lee, Ju Hee Lee.
      Aging-associated dermatological pigmentary diseases are associated with accumulation of senescence cells and the disruption of basement membrane due to chronic ultraviolet radiation (UVR) exposure. Our study is on the synergistic effect of the novel 300 μm needle-depth fractional microneedling radiofrequency (FMR) treatment and conventional Q-switched ND:YAG laser on aging-associated hyperpigmentation of the skin. The prospective controlled clinical trial of 25 Asian women revealed significantly higher improvements not only on wrinkles, but also on hyperpigmentation. Additional ex vivo study revealed significant reduction of pro-melanogenic markers as well as senescent keratinocytes, while increased expression of collagen type IV on the epidermal basement membrane, after additional FMR treatment on UV-irradiated human tissues. These results demonstrate that 300 μm needle-depth FMR might effectively remove senescent keratinocytes that secrete pro-melanogenic markers, and repair disrupted basement membrane, therefore preventing constant hyperpigmentation of the aged skin.
    Keywords:  Nd:YAG laser; fractional microneedling radiofrequency; lentigo; melasma; senescence; ultraviolet B
    DOI:  https://doi.org/10.3390/ijms22147480
  89. J Med Food. 2021 Jul;24(7): 741-748
    Lactobacillus paracasei HY7015 Promotes Hair Growth in a Telogenic Mouse Model.
    Woo Nam, Hyeonji Kim, Chuhyun Bae, Jisoo Kim, Bora Nam, Jooyun Kim, Soodong Park, Junglyoul Lee, Jaehun Sim.
      In this study, we describe the effects of Lactobacillus paracasei HY7015 (HY7015) on promoting mouse hair growth. Since our purpose was to increase hair growth through oral administration, medicinal yeast, at a suitable concentration for application in mice, was used as a positive control. First, experiments were conducted to determine the effect of HY7015 on proliferation of hair follicle dermal papilla cells (HFDPC), which are important contributors to hair growth. HY7015 stimulated HFDPC proliferation in vitro and increased their secretion of vascular endothelial growth factor and insulin-like growth factor-1. In mouse experiments, oral administration of HY7015 promoted hair growth and hair follicle maturation in the dorsal skin, as well as increasing growth factor levels in mouse serum. In summary, we demonstrate that L. paracasei HY7015 consumption can promote hair growth by stimulating HFDPC proliferation and growth factor secretion. Follow-up studies are warranted to determine the underlying mechanism, using various approaches, including investigation of changes in intestinal microbiota and alteration of gene and protein expression.
    Keywords:  IGF-1; VEGF; growth factor; hair loss
    DOI:  https://doi.org/10.1089/jmf.2020.4860
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